Section I: Organization & Structure of the Nervous System

OBJECTIVES

OVERVIEW: THE NERVOUS SYSTEM

The nervous system mediates a wide range of functions, from detection of environmental stimuli, to control of muscle contraction, to problem solving, language, and memory. The nervous system is divided into 2 main parts, the central nervous system (CNS) and the peripheral nervous system (PNS) (Figures 1–1 and 1–2). Anatomically, the CNS is divided into the brain and spinal cord, whereas the PNS is composed of ganglia and nerves, including cranial and spinal nerves and their branches. Functionally, the PNS can be divided into the somatic, autonomic (visceral), and enteric nervous systems. In the overall flow of information, the PNS detects and relays sensory information about the external and internal environments to the CNS. The CNS receives, integrates, and stores information and controls the output to the PNS to generate responses and behavior.

At the cellular level, the nervous system is composed of neurons and glial cells (Figure 1–3). Neurons (also called nerve cells or neuronal cells) are the main signaling cells that communicate with other neurons, muscles, or glands. Neurons can be categorized by their function as sensory neurons, motor neurons, or interneurons or by their morphology or neurotransmitter. Glial cells (also called neuroglia or glia) are the support cells in the nervous system. Astrocytes and satellite cells provide structural and metabolic support, oligodendrocytes and Schwann cells furnish myelination of axons, pericytes regulate capillaries, ependymal cells synthesize cerebrospinal fluid (CSF), microglia are immune cells, and enteric glia are part of the gastrointestinal (GI) tract. Neurons have a cell body where the nucleus and majority of cellular organelles are located and many biochemical activities occur. Neurons also contain specialized processes and regions that allow them to send and receive signals rapidly and precisely. The axon is a process by which electrical signals are conducted and where signals are sent to other neurons or target cells. The dendrites are branched processes that receive signals from other neurons. The synapse is a structure where signals are transmitted, via synaptic transmission, from the axon to its target. Neurons can receive thousands of synaptic inputs, can form neural circuits, and function in networks that underlie sensations, cognitive functions, and the generation of responses and behavior.

CNS COMPONENTS, COVERINGS, & VASCULATURE

The brain and spinal cord compose the CNS. The brain is enclosed within the cranial cavity and is protected by the cranium (skull) and meninges (Figure 1–4). The meninges are a 3-membrane system that covers, protects, and nourishes the brain and spinal cord. The outer dura mater is a thick tough membrane that is connected to the cranium and protects the brain. The middle membrane, called the arachnoid mater, cushions the brain. Below the arachnoid is the subarachnoid space, which contains CSF and where specialized regions called arachnoid granulations resorb CSF. The innermost layer, the pia mater, is a thin layer that adheres to the surface of the brain and follows its contours, forming a barrier but with many capillaries that nourish the brain and spinal cord.

The brain has 3 main regions: the forebrain, brainstem, and cerebellum. The inner spaces of these regions form the ventricles, which produce and circulate CSF and are connected to form the ventricular system (Figure 1–5). Both the meninges and brain are highly vascularized. Two main pairs of arteries supply blood to the brain (Figure 1–6). The internal carotid arteries, which are branches from the common carotid artery, supply the anterior brain, whereas the vertebral arteries, which are branches from the subclavian artery, supply the posterior brain and brainstem. The main venous blood outflow from the brain is via the jugular veins.

CNS capillaries are specialized in that their vascular endothelial cells form tight junctions and are enveloped in glial cells, together producing the blood–brain barrier (BBB). The BBB is a selective permeability barrier that prevents the direct movement of unwanted molecules, immune cells, and pathogens into the brain. The BBB allows the passage of water, oxygen, carbon dioxide, and lipid-soluble molecules, including steroid hormones, by passive diffusion. Astrocytes selectively transport ions and molecules such as glucose and amino acids and release them into the extracellular fluid to supply neurons and other glia with essential nutrients.

BASIC BRAIN ANATOMY

The forebrain is the largest part of the brain and contains the cerebrum and diencephalon (Figure 1–7). The cerebrum is formed by the large left and right cerebral hemispheres, which are separated by the medial longitudinal fissure, and contains the outer cerebral cortex, inner cerebral white matter, and subcortical nuclei. The cerebrum encloses the lateral ventricles and overlies the diencephalon, a structure that contains the thalamus and hypothalamus and that surrounds the third ventricle. Functionally, the forebrain is involved in receiving sensory information from the PNS and generating outgoing motor information, and is where executive and cognitive functions are generated. The oldest part of the brain, the brainstem, is composed of the midbrain, pons, and medulla and serves to relay information from the spinal cord and cerebellum to the forebrain and vice versa. In addition, the brainstem regulates vital functions, such as breathing, consciousness, and control of body temperature. The cerebral aqueduct and fourth ventricle lie inside the brainstem. Connected to the pons, the cerebellum forms the posterior-most region of the brain and is involved in control and coordination of movement and some cognitive tasks.

Examination of postmortem fixed brain tissue reveals that each of these brain regions contains gray and white matter areas (Figure 1–8). In living tissue, gray matter appears pinkish light brown. Gray matter contains mainly neuronal cell bodies, their dendrites, and associated glial cells. In the brain, 2 types of gray matter are present. Cortical gray matter forms the outer regions of the cerebrum and cerebellum and is distinguished by its layered organization of neurons. The other type of gray matter is called a nucleus, an aggregate of cell bodies with similar morphology and function found below the cortex (subcortical nuclei) and in the brainstem and cerebellum. White matter contains predominantly myelinated axons (which, because of their fatty rich myelin membrane, produce the white appearance) and white matter glial cells. White matter contains bundles of myelinated axons that are referred to as tracts in the CNS. In the brain, the white matter tracts include projection tracts that connect neurons in the forebrain to neurons in the brainstem or spinal cord, association tracts that connect one cortical region to another, and commissural tracts, which connect areas from one side of the brain to the other.

The exterior surface of the cerebrum is distinguished by many gyri (singular: gyrus) and sulci (singular: sulcus) that produce the characteristic folded appearance of the human and many mammalian brains. A sulcus is a groove or furrow in the cerebral cortex, whereas a gyrus is a crest or ridge. The folding created by gyri and sulci facilitates a larger surface area of cerebral cortex to fit inside the skull. Deep sulci separate the cortex into 4 cortical lobes on each side, called the frontal, parietal, temporal, and occipital lobes, named for the cranial bones that overlie each (Figure 1–9). The central sulcus forms the division between the frontal and parietal lobe. The lateral sulcus (also called the Sylvian fissure) separates the temporal lobe from the frontal and parietal lobes. The parieto-occipital sulcus forms the boundary between the parietal and occipital lobes. Many additional sulci and gyri are present in the cerebral cortex, with all cortical gyri and sulci containing an outer layer of cortical gray matter and a thin layer of underlying white matter. Each of the 4 main lobes contains distinct anatomic and functional areas.

BASIC SPINAL CORD ANATOMY

The spinal cord emerges caudally from the brainstem, within the spinal canal, and is protected by the vertebral column (also called the spine) and meninges (Figure 1–10). Along their length, the vertebral column and spinal cord inside are separated into 5 regions, called cervical, thoracic, lumbar, sacral, and coccygeal segments. Similar to the brain, the spinal cord is composed of gray and white matter regions but with an opposite organization. Spinal gray matter, composed of neuronal cell bodies, dendrites, and glia, is located medially and is surrounded by spinal white matter, which contains tracts and glia, located in the lateral areas of the spinal cord. The gray matter surrounds the inner central canal, which provides CSF to the spinal cord. Spinal gray matter is separated anatomically and functionally into dorsal (posterior) and ventral (anterior) horns on each side. Sensory information is carried by afferent axons of spinal nerves, which enter the cord via the dorsal roots. These sensory axons branch, and one branch can synapse on interneurons in the dorsal horn, whereas the other branch can ascend to the brain. These axons form the ascending tracts in the spinal cord. Descending tracts in the white matter provide outgoing motor information from the cerebrum or brainstem. The axons in the descending tracts synapse on motor neuron cell bodies in the ventral/anterior horns. The ventral horn motor neurons extend their axons out of the cord via the ventral root, and their axons form the motor components of the spinal nerves. Because the lower motor neurons cell bodies lie in the spinal cord, while their axons form the motor components of the spinal nerves, they are considered part of both the CNS and PNS. The anatomy of the brain and spinal cord is described in greater detail in Chapter 3.

PNS: FUNCTIONAL DIVISIONS

The PNS has 3 functional divisions: the somatic, autonomic (also called visceral), and enteric nervous systems. The somatic nervous system mediates conscious/voluntary movement via regulation of skeletal muscle contraction and provides sensory information from the skin, muscles, and joints. The autonomic nervous system involves unconscious/involuntary control of cardiac muscle, smooth muscle, and glands. Its sensory component, often called the visceral sensory system, provides information from the viscera, the internal organs, and vasculature. The autonomic motor system is divided into the sympathetic and parasympathetic nervous systems. The sympathetic nervous system, referred to as the “fight or flight” system, is activated under conditions requiring mobilization of energy. The parasympathetic nervous system, referred to as the “rest and digest” or “feed and breed” system, is activated when organisms are in a relaxed state. The enteric nervous system, which is also under involuntary control, governs the GI system. Although it receives considerable input from the autonomic nervous system, the enteric nervous system can function independently and is considered a separate system in the PNS.

PNS: ANATOMIC COMPONENTS

Anatomically, the PNS is composed of ganglia and nerves. Ganglia are clusters of functionally related neuronal cell bodies and their accompanying glial cells in the PNS. Cell bodies of somatic sensory neurons form the dorsal root ganglia, whereas cell bodies of autonomic neurons form the sympathetic and parasympathetic ganglia. The sympathetic ganglia lie outside of but close to the spinal cord and communicate to form the sympathetic chain. The parasympathetic ganglia in the body lie close to the organ they innervate. The cranial ganglia contain parasympathetic or sensory cell bodies.

Nerves are bundles of axons ensheathed in connective tissue that innervate all parts of the body, sending messages to and receiving messages from the CNS (Figure 1–11). The neuronal cell bodies that give rise to nerves do not lie within the nerves themselves. Rather, their cell bodies reside within the brain, spinal cord, or ganglia. Nerves can contain both efferent and afferent axons. Efferent axons transmit motor signals from the CNS to the PNS and can be somatic or autonomic. Afferent axons transmit sensory signals from the PNS to the CNS; afferents can be somatic or visceral. Afferent and efferent axons are protected by several layers of connective tissue, which together with glia and blood vessels form nerves.

Spinal and cranial nerves supply input to and output from the CNS. There are 31 pairs of spinal nerves, which emerge from and travel to the spinal cord and which are named for the spinal cord segment to which they connect (Figure 1–11). Spinal nerves are mixed nerves, containing both motor efferents and sensory afferents and containing both somatic and autonomic components. As they leave or enter the spinal cord, the afferents from the dorsal root and efferents from the ventral root bundle together, but then branch to form the rami (singular: ramus). The gray and white rami contain autonomic components, whereas the dorsal/posterior and ventral/anterior rami contain both somatic and autonomic components. Some rami form a nerve plexus, a network of interconnecting nerves. In the somatic motor system, axons emerge from lower motor neurons in the spinal cord, travel in the spinal nerves, and directly innervate skeletal muscles. In the autonomic nervous system, motor neurons in the spinal cord (called preganglionic neurons) send their axons to synapse onto a postganglionic neuron (whose cell bodies lie in the autonomic ganglia), which then send axons to innervate the target organ. Some nerve components form large distinctive bundles or branches and are referred to by their specific names, such as the splanchnic nerves or sciatic nerve.

Sensory and motor information for the head and neck (and several other parts of the body) is supplied by the 12 pairs of cranial nerves. The majority (10 of 12) of the cranial nerves are part of the PNS, with their cranial nerve nuclei located in the brainstem and nerves traveling outside the CNS. Two cranial nerves, the olfactory nerve (CN I) and the optic nerve (CN II), are CNS nerves because they emerge from the cranium and travel within the CNS. Many of the cranial nerves are mixed, with both somatic and autonomic efferents and afferents, but a few are dedicated to either motor or sensory functions. Cranial nerves with sensory or parasympathetic components have associated ganglia, which lie just outside of the brainstem. Furthermore, sensory afferents can mediate both general, somatic sensations, such as touch, pain, and temperature, and special sensations, such as taste, hearing, vision, and smell.

FUNCTIONAL CATEGORIES OF NEURONS

The 2 main cellular components of the nervous system are neurons and glial cells. In addition, the CNS and PNS are highly vascularized and contain numerous blood vessel cells. However, because vascular endothelial and smooth muscle cells derive from mesoderm and are also found outside the nervous system, they are not considered cells of the nervous system. The brain is estimated to contain approximately 86 billion neurons and about the same number of or more glial cells.

Neurons are signaling cells that transmit electrical and chemical signals. The vast majority of neurons are electrically excitable, meaning they can produce and conduct action potentials (Figure 1–12). Most neurons function as part of neuronal circuits. Neurons are distinguished from other cells by a variety of features. Morphologically, they extend specialized membrane processes including axons (for sending information), dendrites and small protrusions called dendritic spines (for receiving information), and membrane subdomains called synapses (where information is transformed and transferred from the axon to the receiving cell). Biochemically, neurons synthesize, package, and release neurotransmitters. Physiologically, they produce and conduct action potentials along the axon and graded potentials along the dendrites and cell bodies, and their receptors can detect different forms of energy, such as light and sound waves, and convert those into electrical or chemical signals. Each of these specialized functions ensures that neurons communicate specifically and rapidly with their targets.

Hundreds of different types of neurons have been identified in the human nervous system. One way neurons can be categorized is by their general function, as sensory neurons, motor neurons, or interneurons. There are 3 types of sensory neurons (also called afferent neurons) that detect and convey signals from the external and internal environments. Special sense neurons are located in special sense organs of the CNS (eg, photoreceptor cells) or the PNS (eg, hair cells). Somatosensory and visceral sensory neuron cell bodies are found in the PNS, although their axons enter the CNS and branches form components of ascending sensory tracts in the CNS. Four types of motor neuros (also called efferent neurons) are involved in control of the somatic and autonomic motor systems. Upper motor neuron cell bodies are located in either the motor cortex or brainstem, and their axons project to lower motor neurons, and those lie entirely in the CNS. Somatic and autonomic (preganglionic) lower motor neuron cell bodies are found in the spinal cord or brainstem, with their axons emerging from those regions to form the motor efferents of the spinal and cranial nerves. Thus, lower motor neurons are considered part of both the CNS and PNS. Both the cell bodies (in sympathetic or parasympathetic ganglia) and axons of postganglionic autonomic motor neurons lie entirely in the PNS.

All of the other neurons in the CNS are called interneurons (or in some cases, just neurons). There are 2 types of interneurons, which are distinguished by whether they function locally or send their axons to other parts of the CNS. Local interneurons (also called local circuit neurons) work within the same brain region, usually have short unmyelinated axons, and form circuits with nearby neurons. Projection neurons (also called principal or relay neurons) extend their axons, which are usually long and myelinated, to another brain or spinal cord region. Interneurons are also named by their morphology, neurotransmitter they release, type of response they produce in their target cells, electrophysiology properties, and/or by the person who first discovered them.

CLASSIFICATION OF NEURONS BY MORPHOLOGY

Morphologically, neurons vary widely with respect to their size and level of dendritic branching (Figure 1–13). Most interneurons and motor neurons have a single axon and multiple dendrites and are called multipolar neurons. A few populations of interneurons called bipolar neurons contain a single axon and only a single dendrite. Unipolar neurons, which contain only 1 process, are common in insects but are found in only a few brain regions in mammals. Sensory neurons do not have typical dendrites because they do not receive information from synapses, but rather have specialized sensory receptor regions to detect signals from the environment. Some sensory neurons (eg, photoreceptor, taste, and hair cells) also do not have axons but synapse onto another neuron that relays its sensory information. In other sensory neurons (eg, somatosensory neurons), the receptive region is connected to an axon, which transmits the sensory signal past the cell body and via its other axon branch into the CNS. These are called pseudounipolar neurons.

Some neurons (also called cells) are named based on their morphology (Figure 1–14). Pyramidal neurons are located in the cerebral cortex, hippocampus, and amygdala and have triangle-shaped cell bodies, with 1 large apical dendrite and several basal dendrites. Their dendrites contain many dendritic spines. Located in layers 3 to 6 of the cerebral cortex, many pyramidal neurons are projection neurons that send their axons out of the cerebral cortex. Spindle neurons are a subtype of pyramidal cell with an elongated cell body and only a single apical dendrite and are found in only 3 regions in the cerebral cortex. Stellate cells/neurons have a star shape with multiple dendrites that radiate from the cell’s body. Found in many brain regions, including the cerebral cortex, cerebellum, and striatum, stellate cell dendrites can either contain (spiny) or lack (aspiny) dendritic spines. Many stellate cells are local circuit neurons. Granule cells are also found in a variety of brain regions, including the cerebellum, hippocampus, cerebral cortex, and olfactory bulb, and are characterized by having a very small cell body. Many granule cells are local interneurons. Basket cells are another type of local interneuron, also found in the cerebellum, cerebral cortex, and hippocampus. Their name derives from the basket-like nest that their axons form around their target cells.

CLASSIFICATION OF NEURONS BY NAMES & NEUROTRANSMITTER

Neurons have also been named by the researchers who first identified them. Purkinje neurons, discovered by Jan Purkinje, are very large projection neurons that send the sole output from the cerebellar cortex. Underneath the cerebellar Purkinje neurons are a population of neurons called Lugaro cells, identified by Ernesto Lugaro. These spindle-shaped neurons have 2 dendrites that emerge from opposite poles of the cell body and provide information to many cells in the cerebellum. Also located in the cerebellum are the Golgi cells, discovered by Camillo Golgi, which are located in the granule cell layer and provide inputs to the granule cells. First described by Vladimir Betz, Betz cells are very large pyramidal neurons, a type of projection neuron, with the upper motor neurons located in layer 5 of the primary motor cortex. Discovered by Birdsey Renshaw, Renshaw cells are interneurons found in the spinal cord gray matter that provide and receive inputs to and from lower motor neurons. Constantin von Economo first identified and named the spindle neurons described earlier, which are found in only hominids, whales, dolphins, and elephants.

Other criteria by which neurons can be classified are by their neurotransmitter and the response they produce in their targets, which can be excitatory, inhibitory, or modulatory. Approximately 90% of brain neurons use either glutamate or γ-aminobutyric acid (GABA) as their neurotransmitter, with the other 10% of neurons using acetylcholine or one of the biogenic amines (ie, norepinephrine, epinephrine, dopamine, or serotonin). Neurons that release glutamate are called glutamatergic neurons. Glutamatergic neurons are found throughout the brain and spinal cord. Although glutamate can act on several types of postsynaptic receptors, the majority (in terms of numbers) of glutamate receptors are ionotropic receptors that produce an excitatory response. Therefore, glutamatergic neurons are also referred to as excitatory neurons. An important class of glutamatergic neurons are the pyramidal neurons in the hippocampus and cerebral cortex, many of which are projection/principal neurons.

Neurons that release GABA as their neurotransmitter are GABAergic neurons. The most prevalent effect of GABA is an inhibitory response, and accordingly, GABAergic neurons are categorized as inhibitory interneurons. Inhibitory interneurons are found throughout most regions of the brain and are abundant in the cerebral cortex, cerebellum, and striatum. Cerebellar Purkinje neurons are GABAergic and are one of the few types of projection/principal neurons that are inhibitory. The neurotransmitter glycine also produces inhibition, and glycinergic neurons, as well as GABAergic neurons, are inhibitory interneurons in the spinal cord. Other brain neurons release acetylcholine (called cholinergic neurons) or one of the monoamines. In the brain, many cholinergic neuron cells bodies are located in the basal forebrain and project to many areas of the cerebrum. Neurons that release biogenic amines, called noradrenergic, adrenergic, dopaminergic, or serotonergic neurons, have cell bodies located in the brainstem. Because these neurons produce a variety of excitatory, inhibitory, and modulatory effects on their targets, they are usually named for their neurotransmitter. In the PNS, somatic lower motor neurons are classified as excitatory neurons because they release acetylcholine at the neuromuscular junction, which always produces an excitatory response in the muscle cell.

NEURONAL ORGANELLES & GENE EXPRESSION

Similar to other cells, neurons possess a plasma membrane that functions as a selective permeability barrier to the extracellular fluid and that encloses the cytoplasm containing the nucleus, cytosol, and typical complement of cellular organelles and biochemical activities (Figure 1–15). The cell body of the neuron, also called the cell soma, can vary in diameter from approximately 100 µm to approximately 10 µm. The organelles include the nucleus, smooth and rough endoplasmic reticulum (ER), Golgi apparatus, lysosomes, proteasomes, and mitochondria, several of which are also localized in the axon and dendrites. Neurons contain a robust cytoskeleton with typical filaments and cytoskeletal motor proteins, which are important in the development, structure, and function of axons and dendrites.

After neurons undergo their final division during embryonic development, they become postmitotic, and the vast majority of neurons do not proliferate in the postnatal and adult brain. However, in the mammalian dentate gyrus of the hippocampus and striatum and the olfactory bulb in rodents, adult neurogenesis can lead to the generation of new neurons. The precursors for adult neurogenesis in the hippocampus have been identified as neural precursor cells that lie in the subgranular zone. The newly produced neurons migrate, differentiate into mature neurons, and form connections with existing neurons. Shown to be stimulated by exercise and activity, adult neurogenesis has been implicated in learning and memory, and errors in neurogenesis have been proposed to contribute to depression and schizophrenia.

Because mature neurons do not divide, the main activities that occur in the nucleus are transcription, the synthesis of RNA from the DNA, assembly of ribosome subunits, and the modification of DNA and DNA-binding proteins in what are referred to as epigenetic changes. Ribosomal RNA combines with proteins to form the ribosome subunits in the nucleolus. mRNA and tRNA are transcribed and transported through the nuclear pores to the cytoplasm, where they control translation, which is the synthesis of proteins by the ribosomes. In the nucleus, mRNAs are transcribed as precursors that undergo modifications and splicing to form mature mRNAs that are then transported out of the nucleus and translated using the genetic code (Figure 1–16).

Translation is the process by which ribosomes synthesize proteins, with the sequence of amino acids determined by the codons in the mRNA and its parent gene. Translation occurs in the cytoplasm on either free or ER-bound ribosomes. Proteins that are entirely water soluble, called cytoplasmic or cytosolic proteins, are synthesized on free ribosomes that, as they translate the mRNA, form polysomes. Proteins that have hydrophobic stretches of amino acids, called transmembrane spanning domains, that cause them to integrate into the membrane are synthesized on ribosomes that associate with the ER, called rough ER. Transmembrane proteins are also called integral membrane proteins. Once a transmembrane protein has been synthesized, it must traffic to its location in the plasma membrane or intracellular membrane compartment. The rough ER also synthesizes proteins and peptides destined to be secreted from neurons.

It is estimated that the human genome contains approximately 20,000 protein-coding genes. Through the process of alternative splicing, different protein variants of many genes can be produced. The control of the types and amounts of proteins that a cell expresses is referred to as gene expression (Figure 1–16). The regulation of gene expression can occur at many points along the path from DNA to protein, including at the transcriptional level by control of transcription factors and epigenetic modifications, mRNA processing, export and turnover, and in the processes of translation and protein degradation. Gene expression and control of protein expression determine the morphologic and functional phenotype of a cell. Neurons express approximately 14,000 protein-coding genes, with approximately 8000 of these expressed in other cells and involved in fundamental cellular processes and metabolism. Approximately 6000 protein-coding genes are neuronal specific genes that are only expressed in neurons and include types of transporters, channels, neurotransmitter synthetic enzymes, cytoskeletal associated proteins, scaffolding proteins, and receptors.

NEURONAL MEMBRANES & TRAFFICKING

The neuronal plasma membrane and other membrane-enclosed organelles are formed from a phospholipid bilayer and transmembrane proteins (Figure 1–17). Membranes also contain cholesterol and sphingolipids. In neurons, lipids are synthesized in the smooth ER or, in the case of cholesterol, obtained from the diet or liver. Transmembrane proteins become incorporated into the ER membrane during translation. Following translation in the rough ER, transmembrane and secreted proteins and peptides are transported via small vesicles to the Golgi, where they are further modified and then sorted and packaged into vesicles, called secretory vesicles, at the trans-Golgi network to be transported to their final destination. Called the biosynthetic or secretory pathway, it is involved in the synthesis and delivery of lipids and transmembrane proteins to the plasma membrane; the secretion of proteins and peptides outside the neuron; formation of organelles in the endosomal pathway, including the early endosome and lysosome; and production of the precursors needed to form synaptic vesicles. Proteins and lipids move between membrane compartments by a process called membrane trafficking.

Proteins and lipids are also retrieved from the plasma membrane through trafficking in the endosomal pathway. Plasma membrane lipids and transmembrane proteins undergo endocytosis, where a small patch of the membrane folds inward into the cytoplasm and pinches off to form a small endocytic vesicle. This vesicle then traffics to and fuses with the early endosome, where the proteins are sorted into small vesicles that bud off and are trafficked to different compartments. Transmembrane proteins can travel by recycling vesicles back to the plasma membrane. A specific type of endocytosis, called receptor-mediated endocytosis, is used to bring key nutrients such as cholesterol and iron into the cell. In this process, the receptors bind and deliver their nutrients to endosomal compartments and can recycle back to the plasma membrane. Transmembrane proteins that have been damaged will traffic to the late endosome and then fuse with the lysosome. A lysosome is a membrane-bound compartment with an acidic pH that contains a variety of degradative enzymes inside, which can degrade proteins, nucleic acids, and lipids. Lysosomes can also function to degrade cytoplasmic proteins or damaged organelles, such as mitochondria, by fusing with compartments in the autophagy pathway. Another intracellular compartment, called the proteasome, is involved in degrading mainly cytoplasmic proteins. Located in the cytoplasm or nucleus, proteasomes are large complexes of proteins that lack membranes. Proteasomes bind damaged proteins, unravel them, and then cleave them with proteases to produce small peptides that can be further degraded to amino acids.

NEURONAL ENERGETICS

It has been estimated that the brain consumes approximately 20% of the energy and oxygen in the body, although it only composes approximately 2% of the body’s mass. In order to meet its energy demands, neurons require energy substrates, oxygen, and mitochondria located in the cell soma, axons, and dendrites. The main energy currency in the cell is adenosine triphosphate (ATP). ATP can be generated by glycolysis, an anaerobic process that takes place in the cytoplasm, converting glucose into pyruvate, reduced nicotinamide adenine dinucleotide (NADH), and ATP. Pyruvate can be converted to lactate or shuttled with NADH into mitochondria, which synthesize ATP via the enzymes in the Krebs cycle and oxidative phosphorylation, with a yield of approximately 16 ATP molecules per pyruvate/NADH. Neurons do not contain large stores of glucose in glycogen, and therefore, they depend on nearby astrocytes to take up glucose from capillaries and release glucose and its glycolytic product lactate into the extracellular space. Neurons convert lactate back into pyruvate via lactate dehydrogenase and shuttle the pyruvate into mitochondria. Neurons are highly dependent on mitochondria for the synthesis of ATP, and conditions that lead to anoxia can rapidly lead to neuronal damage and cell death.

THE AXON

The axon is a structure that is unique to neurons (Figure 1–18). It is a process that is specialized for the generation and conduction of electrical signals called action potentials, which are sent along the axon, in some cases over long distances, to the end of the axon called the presynaptic terminus. At the terminus, the action potential electrical signal is converted into a chemical signal in the form of neurotransmitter release. Axons can be small or large in diameter, ranging from less than 1 to 10 µm. Axons can be long or short and unmyelinated or myelinated. Projection neurons and sensory neurons extend the longest axons, which are usually myelinated and can be centimeters to a meter in length. Local circuit neurons are usually unmyelinated and only a few millimeters in length. Axons can be unbranched with 1 main output or be highly branched, with the branches called collaterals, each of which can form a separate output.

All axons have several common features. The axon emerges from the neuronal cell body at a region called the axon hillock, which tapers to form the initial segment. The axon hillock helps provide a barrier to the random diffusion of organelles, and many organelles require axonal transport to move from the cell body to the axon. The axon hillock also blocks diffusion of plasma membrane proteins from the cell body membrane to the axonal membrane. The initial segment is adjacent to the axon hillock and is the region where the action potential is generated. Even in myelinated axons, the initial segment is unmyelinated and is the regions where voltage-gated sodium channels are highly concentrated. The end of the axon is called the axon terminal, presynaptic terminus, or synaptic bouton. If the axon is myelinated, the myelin membrane does not cover the presynaptic terminus.

Axons contain cytoskeletal proteins that provide structure and important functions. The largest filaments, called microtubules (MTs), give the axon stability and provide tracks to move organelles and large protein complexes up and down the axon. MTs are formed by polymerization of tubulin subunits with microtubule-associated proteins (MAPs) that associate and regulate polymerization and bundling of MTs. In addition, MT-based motors bind MTs and use the energy released by ATP hydrolysis to move cargoes along MT filaments in fast axonal transport, a type of axoplasmic transport (Figure 1–19). The kinesin family of MT-based motors moves cargoes from the cell body in the anterograde direction to the axon terminus, whereas the dynein family of MT-based motors moves cargoes in the retrograde direction, from the axon terminus to the cell body. Important cargoes moved in fast axonal transport include mitochondria, lysosomes, mRNA, ribosomes, and vesicles. Vesicles provide lipids and transmembrane proteins destined for the axonal plasma membrane, synaptic vesicle components, and peptides destined for secretion by the presynaptic terminus. Many soluble proteins and cytoskeletal components use slow axonal transport to travel along the axon.

Two other cytoskeletal filaments, an intermediate filament called neurofilament and the microfilaments composed of actin, are expressed in neurons. Mechanically strong, neurofilaments serve a mainly structural role and ensure the diameter of the axon does not diminish along its length. Actin microfilaments are found associated with the plasma membrane, along with dozens of actin-binding proteins that regulate the assembly, disassembly, and bundling of the actin filaments and binding to the plasma membrane. During development, actin filaments and the actin-based motor, called myosin, are used to provide the mechanical forces that drive the motility of the growing axon. In mature axons, actin is localized in a mesh that underlies the axonal plasma membrane and at the presynaptic terminus. Because MTs do not extend into the axon terminus, actin and myosin are involved in transporting cargoes in the axon terminal and providing scaffolds that tether transmembrane proteins at specific regions of the axonal or presynaptic membrane.

DENDRITES & SYNAPSES

Dendrites are branched processes that are specialized for receiving information (Figure 1–20). Presynaptic axon terminals form synapses on dendrites, which then produce postsynaptic signals that are passively transmitted to the cell body. Dendrites can be highly branched and referred to as the dendritic tree or arbor. The number of inputs that a neuron receives is proportional to its dendritic area. Dendrites can be distinguished from axons by their appearance. Unlike axons, which have a constant diameter, dendrites taper as they extend from the cell body. Dendrites are usually shorter than axons and may be studded with dendritic spines. Similar to the axon, dendrites contain mitochondria, secretory and endocytic vesicles, early endosomes, and an organized cytoskeleton, including MTs, microfilaments, and their regulatory proteins and motors. In addition, axons and dendrites contain ribosomes and mRNA that mediate local protein synthesis within these processes. The dendrites of some neurons contain dendritic spines along their length. Dendritic spines are actin-rich small protrusions that can have a bulbous head and are the regions where the majority of excitatory glutamate synapses occur on the dendrite. Spines are dynamic structures that can undergo changes in shape, size, and number, and this morphologic spine plasticity (and the functional plasticity of the synapses they contain) has been implicated in learning and memory.

The synapse is the structure where synaptic transmission occurs (Figure 1–21). The axon terminal is the part of the axon that forms a synapse with another neuron, muscle, or gland. When a neuron makes a synaptic connection with another cell, it is said to innervate that cell. The connections between an axon and a muscle or gland are also referred to as junctions. In neurons, synapses occur between an axon and a dendrite (axodendritic synapses), an axon and the cell body (axosomatic synapses), or an axon and another axon (axoaxonic synapses). If the axons form short branches at their ends and synapse on dendrites or cell bodies, these branches are called the terminal arbor. Some axons form bulbous presynaptic swellings and synapse on a dendrite without terminating there, but continue on to form additional synapses. These are called the en passant synapses.

Two different types of synapses, named electrical and chemical synapses, mediate transmission. Although fairly rare in the human CNS, electrical synapses allow for the direct flow of ions (current) through gap junctions between the pre- and postsynaptic neuron. The vast majority of synapses in the human brain are chemical synapses, which involve the release of neurotransmitter from the presynaptic terminus and production of electrical and other signaling responses in the postsynaptic neuron (Figure 1–22). In chemical synapses, the presynaptic terminus is distinguished by the presence of synaptic vesicles and specializations called active zones. The synaptic cleft (20 to 40 nm wide) separates the pre- and postsynaptic membrane, although synaptic adhesion molecules from the presynaptic and postsynaptic membrane bind across the synaptic cleft to help produce the stability and specificity of the synapse. The postsynaptic membrane contains neurotransmitter receptors that are tethered at the synapse by scaffolding and cytoskeletal proteins, forming a region called the postsynaptic density in excitatory/glutamatergic synapses.

GLIAL CELLS & THEIR FUNCTIONS

Neurons, axons, and synapses are surrounded by glial cells that provide structural, metabolic, and functional support in the CNS and PNS (Figures 1–23 and 1–24). Glial cells can be categorized as macroglia and microglia. Similar to neurons, macroglia are derived from the ectoderm, either the neural tube (CNS glia) or the neural crest cells (PNS glia), and include astrocytes, satellite cells, pericytes, oligodendrocytes, Schwann cells, ependymal cells, and enteric glia. There is only 1 type of microglia cell, constituting approximately 15% to 20% of total cells in the brain and functioning as the resident immune cells in the CNS. Originally thought to develop from mesoderm, microglia are likely derived from the embryonic yolk sac and are distinguished by their small cell bodies and short processes. Microglia exhibit both phagocytic and antigen-presenting functions that defend the CNS from infection by bacteria, viruses, and fungi. In addition, microglia are involved in maintaining overall brain health as they constantly scavenge the CNS for extracellular protein aggregates called plaques and damaged neurons and synapses. As phagocytic cells, microglia have also been implicated in dendritic spine removal underlying spine plasticity.

Astrocytes in the CNS and satellite cells in the PNS provide structural and metabolic support in the nervous system. Deriving their name from their star-like appearance, astrocytes (also called astroglia) are the most abundant glia in the CNS. Gray matter, type I protoplasmic astrocytes support neuronal cell bodies and dendrites, whereas white matter, type II fibrous astrocytes support axons and their myelinating cells, the oligodendrocytes. Astrocytes form structures called end feet on capillaries, a component of the BBB. Transporter proteins on the end feet allow astrocytes to take up important molecules such as glucose, lactate, amino acids, and other metabolites from the blood and release them into the extracellular fluid around neurons. Through this mechanism, astrocytes provide key nutrients to nearby neurons, axons, and oligodendrocytes. Astrocytes also express ion channels and ion transporters, which enable them to regulate the ionic concentration of the extracellular fluid.

As a result of their proximity to synapses and expression of neurotransmitter transporters, astrocytes can function in the modulation of synaptic transmission, forming the tripartite synapse (Figure 1–25). In addition, astrocytes express neurotransmitter receptors and release gliotransmitters such as ATP, which allow communication with neurons and among astrocytes. Following injury to the CNS, astrocytes respond by transforming into reactive glia, releasing immune modulatory factors, and forming glial scars, which can replace regions of lost neurons but impede the regeneration of axons. In the PNS, satellite cells are located in ganglia where they surround sensory and autonomic neuronal cells bodies and perform similar metabolic support functions.

Although the exact mechanism(s) have not been determined, in response to neuronal activity, neurons and astrocytes release vasodilators and vasoconstrictors that affect capillary blood flow. By releasing vasomodulators, neurons and astrocytes may regulate vascular endothelial cells directly and/or through another type of glial cell, the pericytes. Pericytes are contractile cells that surround capillary endothelial cells and help form and maintain the tight junctions that ensure the BBB (Figure 1–26). In addition, as contractile cells, pericytes can regulate contraction and relaxation that control capillary blood flow. Arterioles, which are larger blood vessels lined with vascular smooth muscle, have also been implicated as cells that respond to neuronal activity–dependent regulation of brain blood flow. Functional magnetic resonance imaging (fMRI) is a functional neuroimaging technique that detects changes in blood flow as an indirect measure of neuronal activity.

Oligodendrocytes and Schwann cells are the myelinating cells in the nervous system, providing specialized plasma membrane projections that wrap around the axon multiple times. With its high lipid content (80% lipid and 20% protein), the myelin membranes form an insulating sheath that ensures fast and efficient conduction of action potentials by salutatory conduction. In the CNS, each oligodendrocyte can form 1 segment of myelin for many (up to 50) adjacent axons. An individual axon (especially the longer ones) is myelinated by multiple oligodendrocytes along its length. In the CNS, axons larger than 1 µm are usually myelinated. Along the axon, myelinated segments are separated by small unmyelinated regions called nodes of Ranvier. The axon at the nodes has access to the extracellular fluid and is the region where the action potential is regenerated. Oligodendrocytes also provide trophic support to axons at the nodes. Similar to reactive glia, oligodendrocytes form barriers to axon regeneration in the CNS. If oligodendrocytes become damaged or die, oligodendrocyte precursor cells in the subventricular zone can differentiate and replace oligodendrocytes to remyelinate axons.

In the PNS, sensory and motor axons are myelinated by Schwann cells residing within the nerve. An individual Schwann cell is associated with only 1 axon, covering approximately 100 µm of the axon segment. Therefore, an axon may require many hundreds to thousands of Schwann cells to myelinate it along its length. Schwann cells also associate with unmyelinated axons in nerves, providing trophic support to their associated axons. In contrast to the CNS, following injury in the PNS, axons regenerate, an activity promoted by Schwann cells. Additional roles for Schwann cells include modulation of neuromuscular synaptic activity and presentation of antigens to immune cells. Nerves also contain capillaries with associated pericytes. The presence of the pericytes and several layers of connective tissue around the axons isolates the axons from the capillaries and establishes the blood–nerve barrier.

Ependymal cells are glia cells found in the CNS where they line the ventricles and central canal and form the choroid plexus. Forming an epithelial layer, ependymal cells produce and circulate CSF for the brain and spinal cord. Within the 4 brain ventricles (2 lateral ventricles and third and fourth ventricles), a population of specialized ependymal cells and capillaries together form a structure called the choroid plexus, which produces the majority of CSF. CSF is formed as plasma is filtered from the blood through the ependymal cells. Choroid plexus ependymal cells actively transport sodium, chloride, and bicarbonate ions, with the accompanying water, into the ventricles. Tight junctions formed between ependymal cells establish the blood–CSF barrier, and cilia on their apical surface facilitate the circulation of CSF. The other part of the blood–CSF barrier is formed by the tight junctions between the cells in the arachnoid membrane.

Other types of glia found in the PNS include cells that surround several types of sensory neuron receptors and enteric glia. Two major populations of enteric glia are found in the enteric nervous system and the epithelium throughout the intestinal mucosa. Enteric glia may communicate with a variety of cells in the GI system, including enteric neurons, enteric endocrine cells, immune cells, and epithelial cells. Proposed functions for enteric glia include regulation of fluid secretion, intestinal motility, enteric neurotransmission, neurogenesis, and immune signaling.

SUMMARY

• The nervous system has 2 major divisions: the CNS and the PNS.

• The PNS detects information about the environment and sends sensory information to the CNS. The CNS receives, integrates, and stores information and sends signals to the PNS, generating responses and behavior.

• The 2 major cell types in the nervous system are neurons, which are the signaling cells, and glial cells, which are the support cells.

• The CNS includes the brain and spinal cord. Both are protected by bones and the meninges and are highly vascularized. The brain surrounds the ventricles, which produce and circulate CSF.

• The blood–brain barrier is formed by special vascular endothelial cells and glial cells that prevent the entry of unwanted molecules and cells into the CNS.

• The brain is composed of 3 major regions: the forebrain, brainstem, and cerebellum.

• In the CNS, gray matter regions contain neuronal cells bodies, dendrites, and glia. White matter regions are enriched in myelinated axons and glia.

• Ridges (gyri) and furrows (sulci) create the folded surface of the brain. Deep sulci divide the cerebral cortex into the frontal, parietal, temporal, and occipital lobes.

• In the PNS, the somatic division controls skeletal muscle contraction and receives sensory information from skin, muscles, and joints. The autonomic division controls smooth and cardiac muscles and glands and receives sensory information from the viscera.

• The spinal cord is organized into the cervical, thoracic, lumbar, sacral, and coccygeal segments. Dorsal gray matter receives input from sensory afferents. Ventral gray matter sends output via motor efferents.

• The PNS is organized into ganglia and nerves (spinal and cranial), which enclose axons of sensory and motor neurons.

• The neuronal plasma membrane encloses the cytoplasm and nucleus; typical cellular organelles perform transcription, translation, membrane trafficking, protein turnover, and energy production.

• Axons generate and conduct action potentials, the output signals from the neuron. Cytoskeletal proteins in the axon are involved in structural support and fast and slow axonal transport. The end of the axon forms the presynaptic terminus.

• Dendrites receive inputs from axons via synapses. Some dendrites contain dendritic spines, small protrusions where synapses form. Synapses are also located on the cell body and other axons.

• Glial cells are support cells in the CNS and PNS. Astrocytes and satellite cells provide metabolic support; oligodendrocytes and Schwann cells furnish myelination; pericytes regulate capillaries; ependymal cells synthesize CSF; microglia are immune cells; and enteric glia function in the GI tract.

OBJECTIVES

CENTRAL NERVOUS SYSTEM DEVELOPMENT: OVERVIEW & TIMELINE

Development of the human nervous system involves the generation of the central nervous system (CNS) and peripheral nervous system (PNS) and occurs during embryonic, fetal, and postnatal periods. The study of nervous system development allows a better understanding of the structural organization of the adult nervous system and helps in comprehending the basis of congenital disorders that affect brain function and cause cognitive disorders. Key prenatal stages in neural development include gastrulation, neural induction (NI), neurulation, neurogenesis, gliogenesis, neural migration, and synaptogenesis. Through these prenatal stages, the gross structures of the brain, spinal cord, and nerves are formed; most neuronal and some glial populations are generated; some synapses are formed; and development is governed predominantly by hardwired intrinsic genetic programs that control gene expression and cell–cell interactions. At birth, the mass of the human brain is approximately 350 to 400 g. Postnatally, additional glial cell populations develop, myelination rapidly takes place, dendrites become highly branched, and many more synapses are established. From birth through adolescence, synapses are stabilized and pruned by activity-dependent processes for the construction of neural circuits. This enables experience-driven neuronal activity to influence the wiring of the brain. Postnatally, the human brain nearly quadruples its mass to approximately 1300 to 1400 g in adults.

Errors in development of the nervous system can result from exposure to teratogens or genetic anomalies or mutations, which can produce sensory, motor, behavioral, or cognitive deficits and also make the brain susceptible to disorders that develop in late adolescence or adulthood. A teratogen is defined as a chemical, infectious agent, physical condition, or deficiency that, upon exposure, may cause birth defects or impair future intellectual, behavioral, or emotional functioning via a toxic effect on the developing embryo, fetus, or child. Teratogens include chemical agents such as alcohol, tobacco, environmental toxins, heavy metals, therapeutic drugs and drugs of abuse, infectious agents such as bacteria and viruses, physical injury and emotional stressors, and deficiencies such as malnutrition or hypoxia. The effects of teratogens are determined by the dose or level, timing and duration of exposure, and interactions with genetic factors. The developmental time when a particular organ is most susceptible to teratogenic damage is during the prenatal critical period, usually when morphogenesis, cell proliferation, and cellular differentiation are occurring in that organ (Figure 2–1). The prenatal critical period for brain development is from approximately 2 to 18 weeks (Figure 2–2). However, because the brain continues to develop throughout gestation, postnatally and through young adulthood, exposure to teratogens after the prenatal critical period can also lead to intellectual, emotional, and behavioral disabilities.

EARLY DEVELOPMENT: THE EPIBLAST & GASTRULATION

Human development begins with fertilization of the egg cell (ovum) by a sperm cell and is followed by the embryonic period (up to 8 weeks after fertilization) and the fetal period (8 weeks to birth at approximately 38 weeks; Figure 2–3). All developmental times here refer to after fertilization in humans.

The fertilized egg, called the zygote, undergoes a series of cell divisions to produce the blastocyst, a fluid-filled cavity containing the inner cell mass (ICM) and lined by trophoblasts. Following implantation (between 8 and 10 days), the ICM of the blastocyst reorganizes to form the bilaminar embryonic disc, composed of the epiblast and underlying hypoblast. The epiblast is a flat disc of cells that gives rise to the entire embryo. The hypoblast forms the yolk sac, while the trophoblasts form the trophectoderm, which gives rise to the placenta. At about day 16, the embryonic disc undergoes the process of gastrulation (Figure 2–4). First, cells in the midline of the epiblast disc form a surface indentation called the primitive pit, which elongates to generate the primitive streak, a morphologic groove in the epiblast along the anterior-posterior axis of the embryo. During gastrulation, epiblast cells proliferate and migrate, with migrating cells moving first medially toward the primitive streak, and then ventrally, underneath the streak, and finally moving away from the midline in a process called ingression. Cells ingress in successive waves. Cells that migrate first push the hypoblast cells aside and form the inner layer, the endoderm, which gives rise to the lining of organs of the digestive and respiratory systems and several glands. Cells ingressing next will come to lie on top of the endoderm and form the middle layer, the mesoderm, which gives rise to the muscles, bones, cardiovascular system, and blood cells. Cells that do not ingress remain on the surface and become the outer layer, the ectoderm, which gives rise to the entire nervous system, epidermis (skin), some connective tissues, and related structures. Following gastrulation, the embryonic disc is transformed into the 3 primary germ layers (the trilaminar gastrula), and all 3 axes of the embryo are established: anterior-posterior (rostral-caudal), dorsal-ventral, and medial-lateral axes.

NEURAL INDUCTION & FORMATION OF THE NEURAL PLATE

The next important stage, beginning at approximately 17 days after fertilization, is the process of neural induction (Figure 2–5), which leads to the specification of neural and nonneural ectoderm. The formation of the notochord, a distinct cylinder of mesodermal cells at the midline of the gastrula, is a key step in NI. The notochord, together with the adjacent paraxial mesoderm, releases diffusible factors called morphogens. Morphogens are signaling molecules that form gradients and trigger highly orchestrated cascades of gene expression that control the levels and types of proteins expressed in the cell and underlie the specification toward a particular cell fate, as well as morphogenetic movements. Approximately half of the ectodermal cells, located closer to the midline, receive higher concentrations of neural-inducing morphogens and thus become specified as the neural ectoderm (neuroectoderm), change their shape, and form the neural plate. The lateral ectoderm located further away from the midline becomes the epidermal (nonneural) ectoderm.

Well studied in amphibians, NI involves morphogens released by the notochord, which inhibit signaling of bone morphogenetic proteins (BMPs) in the overlying ectoderm. Expressed throughout the developing embryo, BMPs are growth factors members of the transforming growth factor-β superfamily that regulates a family of transcription factors. Inhibition of BMP signaling allows neural commitment genes to be expressed, including transcription factors, which then alter gene expression in the developing neural plate cells, furthering the cells along the path of neural commitment. Ectoderm cells in which BMP signaling is inhibited become neural cells, whereas cells that do not receive sufficient levels of morphogens become epidermis. In mammals, other growth factors, such as fibroblast growth factor (FGF), are implicated in NI. The neural plate starts to differentiate from the surrounding nonneural plate as neural plate cells become tall columnar epithelial cells. The neural plate is wider in its rostral region, which will develop into the brain, and narrower at the caudal end, which will form the spinal cord.

NEURULATION: FORMATION OF THE NEURAL TUBE & NEURAL CREST

The next critical stage is neurulation, which occurs during the third and fourth weeks after fertilization, and leads to the transformation of the neural plate into the neural tube (Figure 2–5). Concomitant with neurulation is the formation of neural crest cells and placodes. Neural tube cells give rise to neurons and glia in the CNS, whereas neural crest cells give rise to neurons and glia of the PNS; placodes give rise to special sensory neurons and ganglia of several cranial nerves. Neurulation involves large morphologic changes as the neural plate cells bend, fold, and fuse to transform the neural plate into a tube of cells, with the overlying neural crest cells. Primary neurulation forms the brain and the majority of the spinal cord, whereas secondary neurulation forms the sacral region of the spinal cord.

Primary neurulation begins at approximately day 18, when the neural plate begins to fold inward, forming the neural groove along the midline of the neural plate running rostral to caudal. Cells in the neural groove become attached to the notochord and change shape, which induces the folding of the neural plate. As the neural groove deepens, this folding causes cells at the margins of the neural plate, called the neural folds, to become elevated and approach each other in the dorsal midline. Cells within the neural folds come in close apposition to each other and adhere via specific cell adhesion molecules such N-cadherin, which then promote the closure of the neural tube. Neural plate cells located in the lateral edges of the neural folds are excluded from the tube and, as the tube closes, aggregate just above (dorsal to) the neural tube and become neural crest cells. Neural crest cells are a transient population of progenitor cells that migrate to form the sensory and postganglionic autonomic neurons in the PNS and glial cells of the PNS and contribute to some glands and tissues (see later discussion). The closure of the neural tube separates it from the neural crest cells and the overlying nonneural (epidermal) ectoderm. During this period, cranial placodes develop within the medial epidermal ectoderm, which give rise to sensory neurons in the nose and ear and several cranial ganglia.

During primary neurulation, the closure of the neural tube begins on day 20 at the level of the fourth somite, where the future cervical spinal cord will be located. The closure is asynchronous, proceeding rostrally and caudally such that the ends of the neural tube close at different times. The anterior neuropore closes at approximately day 24, whereas the posterior neuropore closes at about day 26. After the posterior neuropore closes, the process of secondary neurulation forms the most rostral region of the spinal cord. During secondary neurulation, the neural ectoderm and some cells from the endoderm form the medullary cord, which condenses, separates, and then forms cavities that merge with the rostral cord to form a single tube. Failure of the neural tube to close normally produces neural tube defects, including spina bifida, the most common congenital birth defect affecting the nervous system (discussed in Chapter 35).

REGIONALIZATION & PATTERNING IN THE CNS

The anterior/rostral neural tube gives rise to the brain, while the posterior/caudal neural tube forms the spinal cord. As the neural tube is closing, between 3 and 4 weeks after fertilization, key morphologic changes occur along the anterior-posterior axis, when transient morphologic segments of the developing neural tube, called neuromeres, establish regions of the embryonic brain and spinal cord. Through a transient blockage, the pressure of the fluid inside the rostral/anterior tube increases. Differential cell adhesion leads to the ballooning of the rostral/anterior (also called cranial) tube in 3 regions, forming the 3 primary vesicles. These large macroscopic vesicles divide the neural tube into the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain) (Figure 2–6 and Figure 2–7). The entire brain is formed from these 3 primary vesicles, whereas the ventricular system is formed from the lumen of the neural tube.

By 5 weeks, 2 of the primary vesicles enlarge and undergo an additional division to yield a total of 5 vesicles. The prosencephalon, also called the cerebrum, divides to form the telencephalon and diencephalon. As the telencephalon develops, it is tethered at the rostral midline, so it bulges to form the right and left cerebral hemispheres. As it develops, the telencephalon expands to surround the diencephalon and forms 2 gray matter regions: the dorsal telencephalon (pallium), which forms the cerebral cortex and hippocampus, and the ventral telencephalon (subpallium), which gives rise to the basal ganglia and olfactory bulbs. Regions from both the pallium and subpallium form the amygdala. The diencephalon develops into the thalamus, hypothalamus, and optic vesicles, which give rise to the optic nerve and retina. The mesencephalon, which does not undergo a secondary division, forms the midbrain, with the dorsal mesencephalon forming the tectum (containing the superior and inferior colliculi) and the ventral regions forming the midbrain tegmentum. The rhombencephalon divides to form the metencephalon (future pons and cerebellum) and myelincephalon (future medulla oblongata). Together, the midbrain, pons, and medulla form the brainstem. The myelincephalon connects with the caudal neural tube, which develops into the spinal cord.

Concomitant with the formation of the vesicles, the neural tube bends along its anterior-posterior axis at 3 flexures that give an appearance of a cane at this stage. The first flexure is the cephalic flexure, occurring between the end of the third week and the beginning of the fourth week, and is located at the region of the midbrain; this flexure results in the forebrain bending ventrally to form a crook that resembles the cane handle. The cervical flexure occurs next, at approximately 5 weeks, and is located at the junction between the hindbrain and the spinal cord. The third flexure, the pontine flexure, occurs at the seventh week, and is located between the metencephalon and myelincephalon. Although this flexure does not persist as a bend in the axis of the hindbrain, it affects the future development of the rhombencephalon.

The lumen of the neural tube becomes the ventricular system and the central canal, which generate and contain the cerebrospinal fluid (CSF). The lumen of the telencephalon becomes the lateral (first and second) ventricles in the right and left cerebral cortex. The lumen of the diencephalon forms the third ventricle. The cerebral aqueduct is formed in the lumen of the mesencephalon (midbrain). The fourth ventricle is formed from the rhombencephalon (metencephalon and myelincephalon), and the central canal is formed from the lumen of the spinal cord. Glial cells called ependymal cells line the ventricles, form part of the choroid plexus, and produce the CSF that fills the ventricular system and the central canal.

The CNS is patterned along its anterior-posterior axis, which is best characterized in the hindbrain. The hindbrain divides into segments that are slightly constricted swellings called rhombomeres. These rhombomeres form the rhombencephalon, which in turn forms the hindbrain. Each rhombomere segment develops its own set of ganglia and nerves that are later responsible for rhythmic behaviors, such as respiration, mastication, and walking. The morphogens FGF and retinoic acid regulate rhombomere development. Each rhombomere expresses its own unique set of genes, a process governed by the expression of specific transcription factors of the homeobox domain (Hox) gene family.

The CNS is also patterned along its dorsal-ventral axis. Neural tube cells at the ventral midline form the floor plate, whereas cells at the dorsal region become the roof plate. Exposure of these regions of the neural tube to different gradients of morphogens from the underlying notochord and the overlying dorsal ectoderm leads to differential gene expression that impacts the differentiation of neurons in the dorsal and ventral tube. An important morphogen released from the notochord and its overlying floor plate is sonic hedgehog (SHH). Morphogens released from the roof plate include BMPs. These morphogen gradients lead to the formation of a longitudinal groove, called the sulcus limitans, during the fourth week, which appears in the lateral wall of the neural tube throughout the future spinal cord and brainstem. The sulcus limitans separates the neural tube into the dorsal alar plate and the ventral basal plate. This division is functionally important because neurons derived from the alar plate of the spinal cord form the dorsal gray matter (posterior horns), which differentiates into sensory relay neurons, whereas neurons derived from the basal plate form the ventral gray matter (anterior horns), which differentiates into motor neurons.

Similar distinctions are present in the brainstem, but with a medial-lateral arrangement. With the formation of the pontine flexure and the fourth ventricle, the rhombencephalon undergoes a shape change that pushes the dorsal alar plate laterally and shifts the ventral basal plate medially. Although the sulcus limitans does not extend beyond the brainstem, the dorsal and ventral regions of the prosencephalon and mesencephalon are exposed to similar gradients of morphogens that influence their development into morphologically and functionally distinct brain regions. Indeed, mutations in SHH cause a severe congenital malformation called holoprosencephaly (type 3), in which there is a loss of the central midline in the developing brain (see Chapter 35).

NEUROGENESIS & GLIOGENESIS

Once the neural tube closes and undergoes the morphologic changes described earlier, neurons and glia are generated from the neural tube through proliferation and differentiation, called neurogenesis (Figure 2–8) and gliogenesis. As newly born neurons and glia are generated, they also undergo migration to their final location in the brain. The majority of neurogenesis occurs during prenatal development, although a few neuronal populations are generated postnatally. Gliogenesis involves the formation of astrocytes, oligodendrocytes, and ependymal cells during the late prenatal and early postnatal periods. Different populations of neural cells develop at different times in different regions of the nervous system. Beginning after the closure of the neural tube at 4 weeks after fertilization and continuing through the early postnatal period, the peak in neurogenesis occurs between the fifth week and fifth month of gestation. It has been estimated that during its peak, approximately 250,000 neurons are produced per minute. Because the brain contains approximately 86 billion neurons, this is a period of robust neuronal proliferation and differentiation. Glia outnumber neurons in most brain regions, usually developing after neurons in a given region. Glia are continuously replaced in the adult nervous system from glial progenitors, while new neurons are generated at a very low rate only in a few specific brain regions in the adult brain, in a process called adult neurogenesis.

After the neural tube closes, it is composed of a single layer of cells called the germinal neuroepithelium (NE). NE cells develop into neural stem cells (NSCs) and neural progenitor cells (NPCs), which are populations of self-renewing cells that generate all the neurons and glial cells of the CNS. NSCs have the capacity for unlimited self-renewal and multipotency. As NSCs proliferate, they give rise to NPCs, cells that have more limited capacity for self-renewal and more restricted potency. NPCs give rise to lineage-restricted cells that migrate and differentiate into different types of neurons and glial cells.

An important type of NSC are the radial glial cells (RGC). RGCs, so named because they initially express a glial-specific protein and guide the radial migration of neurons, actually give rise to the majority of principal neurons of the cerebral cortex that use the excitatory neurotransmitter glutamate. Initially, NE cells proliferate and generate RGCs, both of which proliferate in the area next to the lumen of the neural tube (the future ventricle), forming the ventricular zone (VZ). The NE cells and RGCs are also referred to as apical progenitors. In the VZ, dividing RGCs undergo either symmetric divisions that lead to self-renewal or asymmetric cell divisions that produce 1 self-renewing daughter cell and another daughter cell that is either a postmitotic neuron or a specific type of NPC. RGCs generate 2 main types of progenitors. One type, called short neural precursors, remains in the VZ and constitutes a third category of apical progenitors. The other RGC progeny is the intermediate progenitor cell (IPC), also called basal progenitor or bRGC, the majority of which migrate to an adjacent region called the subventricular zone (SVZ), where further neurogenesis takes place. Subsequent symmetrical divisions of these progenitor cells produce self-renewing daughter cells, whereas asymmetric divisions produce daughter cells with more restricted lineage. There is a distinct progression of lineage differentiation whereby RGCs first give rise to neurons and later to astrocytes and oligodendrocytes.

MIGRATION & DIFFERENTIATION IN THE CNS

Concomitant with neurogenesis is the process of neuronal migration, during which differentiating neurons travel from their origin or birthplace to their final position in the brain. The formation of the cerebral cortex (corticogenesis) is an excellent model for the characterization of neuronal migration. Neurons formed in the VZ or SVZ migrate to their final locations in the neocortex, occurring between gestational weeks 7 and 18 in humans. A key event is the formation of the cortical plate, which includes the cortical layers 2 to 6. Corticogenesis begins with the formation of a region called the preplate (a layer that forms between the outer pial surface and the VZ/SVZ). The first-born postmitotic neurons, Cajal-Retzius cells and subplate neurons, leave the stem cell niche in the VZ/SVZ and migrate outward along the scaffolding fibers provided by RGCs to form the preplate. The preplate then separates into 2 components, as Cajal-Retzius cells migrate outward to form the marginal zone (above the cortical plate and containing layer 1) and the subplate neurons form the deeper subplate region that will become the intermediate zone.

Subsequent waves of postmitotic cells migrate along RGCs, and these new neurons form the cortical plate, which separates the superficial marginal zone and the intermediate zone (Figure 2–9). This phase involves the appearance of well-defined cell layers in the cortical plate (cortical layers 2 to 6), as each wave of newly generated neurons migrates past their predecessors to progressively more peripheral zones, while the earlier generated neurons are differentiating. In this way, the cortex is said to develop in an inside-out manner. The intermediate zone becomes the white matter region just below the cortical gray matter. The transition from preplate to cortical plate is a period during which cortical malformations are thought to occur (see Chapter 35). The extracellular matrix protein reelin (encoded by the RELN gene) and its plasma membrane receptors are implicated in neuronal migration during corticogenesis because mutations in those genes cause cortical malformations.

The majority of excitatory neurons in the neocortex (approximately 75% of the total cortical neurons) are generated from RGC precursors in the VZ or SVZ immediately below their adult location, where they arrive by radial migration as described earlier. In contrast, the majority of inhibitory interneurons (approximately 25% of cortical neurons) migrate tangentially (parallel to the ventricular surface) to reach their appropriate location in the cortex, in a process that is independent of radial glial fibers. An important structure in tangential migration is the ganglionic eminence, a transitory structure located in the ventral VZ of the telencephalon that helps guide cortical inhibitory interneurons to their destination in the cortex. A third type of migration is axophlic migration, which uses existing axon tracts to guide the migration of developing neurons.

As development proceeds, mitotically active neural progenitor cells give rise to postmitotic cells that, via different patterns of gene expression, differentiate into specific types of neurons and glial cells. Cellular differentiation during development is the result of the orchestrated activity of gene regulatory networks. One well-documented way that gene expression is controlled is via transcription, which is controlled by transcription factors and epigenetics. Control of gene expression depends on both intrinsic factors (proteins and mRNAs inherited from the mother cell after cell division) and extrinsic cues, including molecules found in the environment that function through receptor signaling pathways to control gene regulatory proteins. Gene expression controls the levels of protein expression, which influences specific biochemical, functional, and structural characteristics of different classes of neurons and glial cells.

Much research in the past 3 decades has focused on identifying the extracellular factors, receptors, and gene regulatory networks involved in controlling neuronal and glial cell differentiation, prompted in part by the potential for cell replacement therapy to treat neurodegenerative and other neurologic disorders, as well as brain and spinal cord injury. These studies have led to the identification of many genes that contribute to the neuron–glia fate decision, including many of the morphogens mentioned earlier, as well the proneural, neurogenic, and Hes genes in the basic helix-loop-helix (bHLH) transcription factor families, the Sox and Pax families of transcriptional regulators, and signaling pathways involving Notch.

An important structural feature of the human brain is the presence of several convolutions in the surface of the cerebral cortex. The grooves or depressions in the surface of the cerebral cortex are called sulci (singular: sulcus), and the bumps or ridges are called gyri (singular: gyrus), which are formed through the process of gyrification. The thickness of the 6-layered cerebral cortex (2 to 4 mm) is similar across all mammals. Because the brain is confined within the skull, brain size is limited, and the adult human cortex must fold and wrinkle to allow an expansion of cortical surface area during human fetal development. Beginning at approximately 10 weeks after fertilization, the primary cortical gyri form first, followed later by the development of secondary and tertiary gyri. Differential proliferation and differentiation in the VZ and SVZ progenitor zones may underlie differences in cortical size and gyrification among mammals. Errors that produce changes in the structure of gyri and sulci in the cerebral cortex are associated with various disorders, including lissencephaly (smooth brain), pachygyria, and polymicrogyria. These disorders reflect atypical neurogenesis and/or corticogenesis and cause various neurologic symptoms, such as epilepsy, muscle weakness, and intellectual disability (see Chapter 35).

AXONAL OUTGROWTH & PATHFINDING

As neurons migrate and differentiate, they begin to extend their axon first, followed by several dendrites, sometimes after they have arrived at their final location (Figure 2–10). Axons are guided toward their targets by a specialized structure at the tip of the growing process called the growth cone. A growth cone is a highly dynamic structure that senses guidance cues through specific membrane receptors and ion channels and translates extracellular signals into changes in the cytoskeleton that result in a tropic (movement) behavior. Axons are guided to their target by environmental cues that include soluble, cell-associated or matrix-attached molecules that act as either repellents or attractants.

In many brain regions, there are 2 main types of neurons: projection neurons, whose axons project outside of that region, and local circuit neurons, which project only to neighboring neurons within the same region. For axons that travel long distances, the axon is guided toward its postsynaptic partner by a series of intermediate targets and gradients of diffusible and tethered cues. A number of diffusible guidance cues and their receptors have been identified and include secreted proteins (and their cognate receptors) called netrins (DCC and Unc5), Slit (Robo), ephrins (Eph receptors), and semaphorins (plexins and neuropilins). Developmental morphogens such as BMPs, FGF, and Wnts also contribute to growth cone navigation. Cell adhesion molecules, such as immunoglobulin superfamily cell adhesion molecules and cadherin, and extracellular matrix proteins provide cell-attached and nondiffusible, tethered cues. Although less well characterized and usually much shorter in length, developing dendrites also project growth cones, with dendritic outgrowth likely governed by similar types of mechanisms used by the growing axon.

NEURONAL SURVIVAL & APOPTOSIS

During nervous system development, neurogenesis and gliogenesis produce more neurons and glial cells than are needed in the adult nervous system. Physiologic neural cell loss through apoptosis (programmed cell death) removes approximately one-third to one-half of all developing neural cells, including neural progenitors, postmitotic neurons, and glial cells. Apoptosis is critical to adjust the size of the input population to match the size of the target population, thus preventing erroneous or unnecessary connections.

Neurons depend on both survival factors in the environment and functional synaptic connections for their survival. Best characterized for neurons of the PNS, it was hypothesized that growing axons compete for limiting amounts of target-derived trophic factors and that axons that fail to receive sufficient trophic support do not survive (Figure 2–11). Classical studies on target-derived factors that support sympathetic neuron survival led to the discovery of nerve growth factor (NGF). Subsequently, the related neurotrophins, neurotrophin (NT)-3, NT-4, and brain-derived neurotrophic factor (BDNF), were identified. In both the CNS and PNS, neurotrophins and a variety of other trophic factors produced during different stages of development contribute to the survival of specific neuronal classes. Other trophic factors include BMPs, glial cell line–derived neurotrophic factor, ciliary neurotrophic factor, insulin-like growth factor, cytokines, and even classical neurotransmitters such as glutamate, which can support neuronal survival. Once functional synaptic connections have been established, activity also contributes to neuronal survival. Interestingly, some trophic factors such as BDNF play important roles not only in survival, but also neurogenesis and synaptic plasticity in the adult brain. Because adult neurons die by apoptosis in neurodegenerative disorders, identification of the molecular mechanisms underlying neuronal apoptosis is an intensely studied topic with the goal of identifying novel treatments and strategies to prevent apoptosis in the adult brain.

SYNAPTOGENESIS & SYNAPTIC REFINEMENT

Once neurons have reached their final destinations and extended their axon and dendrites and the axonal growth cone has contacted its postsynaptic target, a synapse is ready to be formed. Formation of a synapse between a neuron and its target cell is termed synaptogenesis and occurs prenatally, throughout postnatal development and adolescence, as well as into adulthood. Neurons form synapses in order to communicate with other neurons in the CNS or with target muscles or glands in the PNS, for the establishment of functional neural circuits that mediate sensory and motor processing, and underlie behavior and memory. Chemical synapses use neurotransmitters that diffuse across the extracellular space between presynaptic and postsynaptic neurons and bind to selective membrane receptors, whereas electrical synapses formed by gap junction channels allow direct electrical communication between neurons. Many different morphologic and functional types of chemical synapses exist in the CNS. Chemical synapses are formed between the specialization of a presynaptic axon, called a presynaptic terminal or bouton, and a dendrite, cell body, or presynaptic terminal of the postsynaptic neuron. Synapses on dendrites can be formed on the shaft of the dendrite or on small protrusions called dendritic spines. Dendrites undergo extensive branching during postnatal development, which increases the area and number of synapses that can form on the dendrites.

During CNS synaptogenesis, the presynaptic growth cone contacts the postsynaptic neuron, which sends retrograde signals that transform the growth cone into a presynaptic terminal. If the target is a dendrite, a dynamic protrusion called a filopodium attracts the presynaptic growth cone and helps initiate synapse formation. Once contacted, the presynaptic and postsynaptic compartments become highly specialized with the clustering of multiple proteins in and near the plasma membranes of both regions. Many of the presynaptic and postsynaptic proteins, including the synaptic vesicle release machinery, ion channels, receptors, and scaffolds, are delivered to the developing synapses in preassembled membrane-bound packets. Contact between the 2 neurons involves the binding of cell adhesion molecules, such as neuroligin and neurexin, synCAMs, cadherins, ephrins, and Eph receptors, across the synaptic cleft, which adheres the synaptic partners to each other. Some synapses have been shown to be active within minutes after initial contact, but it usually takes much longer (hours to days) for mature synapses to become functional.

The development of proper brain function involves a careful balance between the production and elimination of cells and synapses. Neurons often extend axonal branches and form synapses with both appropriate and inappropriate targets, and the inappropriate connections are eventually pruned away. During development and throughout life, synapses are reconfigured both morphologically and functionally, through a process called synaptic refinement, a type of synaptic plasticity that involves the formation of new synapses, elimination of unwanted or unused synapses, and changes in synaptic morphology and synaptic transmission, called synaptic strength (Figure 2–12). Although initial synapse formation does not depend on neuronal activity, elimination of supernumerary and inappropriate synapses and the ongoing modification of existing synapses depend on neuronal activity. Activity-dependent mechanisms driven by sensory inputs and behavioral experiences modulate the development of neural circuits and their connectivity maps.

Many synapses that form during prenatal and early postnatal periods are eliminated between early childhood and the onset of puberty. Synaptic refinement and circuit formation occur and peak at different developmental times, called sensitive and critical periods, in different brain systems. Developmental sensitive and critical periods are time windows when experiences have a greater impact on certain areas and functions of brain development and when the brain is most likely to strengthen important connections and eliminate unneeded ones in specific brain regions. A postnatal critical period is a somewhat narrower window during the sensitive period, during which the nervous system is especially impacted by environmental stimuli (Figure 2–13); if the organism does not receive the appropriate stimulus during the critical period for a given skill or function, it may be difficult, or even impossible, to develop that function later in life. Critical periods for development of the visual and auditory systems occur in the first 6 to 9 months, whereas language peaks around 6 to 12 months and higher cognitive functions peak in childhood. Lifelong changes in the strength of synapses, so called synaptic plasticity, is considered a key mechanism that underlies learning and memory and is discussed in detail in Chapter 10.

MYELINATION

Myelination, the formation of the insulating myelin sheath around axons, begins in late embryonic stages and continues through early postnatal stages and adolescence (Figure 2–14). The myelinating cells of the CNS, oligodendrocytes, develop from precursors called oligodendrocyte precursor cells and, in general, myelinate axons that are larger than 1 μm in diameter. Oligodendrocytes are numerous in white matter (where 1 oligodendrocyte can myelinate up to 50 axons), whereas satellite oligodendrocytes are located in gray matter. The myelin sheath provides electrical insulation for axons that ensures efficient and fast conduction of action potentials, in addition to providing trophic and metabolic support for the axons. Myelination is especially important for long axons that travel long distances to their targets, such as fibers from projection neurons. Once myelinated, axons from similar regions bundle together to form the major white matter systems in the brain: the cortical white matter, the corpus callosum, and the internal capsule, as well as the major tracts in the spinal cord. Impairments in the function of oligodendrocytes cause myelination defects that lead to demyelinating disorders and hypomyelinating leukodystrophies (described in Chapter 35).

PNS DEVELOPMENT

The vast majority of neurons and glia of the PNS are generated from neural crest cells (Figure 2–15). Formed from the margins of the developing neural plate (the neural folds), neural crest cells are ectoderm derivatives that first aggregate above the roof of the neural tube, but then migrate away to give rise to peripheral neurons and glial cells, as well as pigmented skin cells and parts of glands and facial structures.

Cells from the cranial neural crest migrate dorsolaterally, forming the craniofacial mesenchyme that differentiates into the sensory components of cranial nerves, various cranial ganglia, PNS glia, and craniofacial cartilage and bone. Entering the pharyngeal pouches and arches, some cells contribute to the thymus, odontoblasts of the tooth primordia, and bones of the jaw and middle ear. The trunk neural crest produces cells that form 1 of 2 pathways. Cells that migrate dorsolaterally into the ectoderm and toward the ventral midline become pigment-synthesizing melanocytes. Cells that migrate ventrolaterally through the anterior portion of each sclerotome and remain there form the sensory neurons of the dorsal root ganglia, whereas those that continue to migrate ventrally form the sympathetic ganglia, adrenal medulla, Schwann cells, and the aortic nerve clusters. Cells from the vagal and sacral neural crest give rise to the ganglia of the enteric nervous system and the parasympathetic ganglia. Cells from the cardiac neural crest develop into cartilage, connective tissue, and neurons of some pharyngeal arches, in addition to musculo-connective tissue of the large arteries in the heart and regions of the heart septum and semilunar valves, as well as melanocytes. Finally, some PNS neurons are derived from the neural placodes, small islands of neural ectoderm located in the medial regions of epidermal ectoderm after the neural tube closes. Neural placodes give rise to olfactory and auditory sensory neurons and contribute to several ganglia in cranial nerves.

SUMMARY

• Nervous system development begins in the embryonic period and continues through fetal stages and during postnatal life.

• Prenatal development is governed mainly by intrinsic hardwired genetic programs that involve gene expression and cell–cell interactions.

• The entire nervous system develops from the ectoderm layer.

• Neural induction involves the release of morphogens from the notochord, which control differentiation of overlying ectoderm cells that generate the neural plate.

• Neurulation leads to the formation of the neural tube, which gives rise to neurons and glial cells of the CNS.

• During neurulation. the neural crest forms above (dorsal to) the neural tube, and neural crest cells migrate to form the PNS.

• Neurogenesis and gliogenesis involve the proliferation and differentiation of neural stem cells and neural progenitor cells.

• Newly generated neurons and glia migrate to their final position in the brain.

• The formation of gyri and sulci through gyrification significantly increases the surface area of the cerebral cortex.

• Outgrowth of axons and dendrites involves guidance from environmental cues.

• Final neuron numbers are determined by neurogenesis, neuronal survival, and cell death (apoptosis) modulated by neurotrophins.

• Synapse formation (synaptogenesis) occurs in prenatal and postnatal periods, followed by activity-dependent pruning during postnatal sensitive and critical periods.

• Postnatal development is controlled mainly by extrinsic, activity-dependent mechanisms that impact neuronal survival, synapses, and neural circuits.

• Synapse number and strength are dynamic and modified throughout life by experience-driven neuronal activity.

• Myelination of CNS axons by oligodendrocytes during early postnatal development produces white matter in the CNS.

• Neural crest cells migrate and differentiate into neurons and glial cells in the PNS and several types of nonneural cells.

OBJECTIVES

OVERVIEW OF THE NERVOUS SYSTEM

The mammalian nervous system has 2 major divisions: the central nervous system (CNS) and the peripheral nervous system (PNS). The general structure of the nervous system and its cellular components were provided in Chapter 1. The CNS is composed of the brain and the spinal cord. Protected on the outside by bones and the meninges, the CNS is suspended in and contains cerebrospinal fluid (CSF) and is highly vascularized. Functionally, the CNS receives and processes sensory information from the PNS and special sense organs, integrates and stores that information, and sends instructions to coordinate and control responses, activities, and movements of the body. In addition, the CNS constructs emotion, perception, and cognition. The CNS can be generally divided into the forebrain, the midbrain, and the hindbrain, which form the brainstem and cerebellum, and the spinal cord. Derived from the embryonic telencephalon and diencephalon, the forebrain encompasses the cerebral hemispheres, including the cerebral cortex, cerebral white matter, and structures located within the white matter, including the basal ganglia, limbic system, thalamus, and hypothalamus. In this chapter, key anatomic and functional components of the forebrain are described. In the next chapter (Chapter 4), the anatomy and function of the brainstem, cerebellum, spinal cord, PNS, meninges, ventricular system, and vascular supply are further elaborated.

ANATOMIC REFERENCES & TERMS

For neuroanatomic descriptions, definitions of anatomic reference directions and terms are useful (Figure 3–1). In the human brain, anterior/rostral means toward the front of the brain and face, whereas posterior/caudal means toward the back of the cranial cavity or tail. In the brain, the direction pointing up is dorsal, and the direction pointing down is ventral. Below the midbrain and in the spinal cord, the direction pointing toward the back is dorsal, and the direction pointing toward the chest/stomach is ventral. The invisible line running down the middle of the nervous system is called the midline. Structures closer to the midline are medial; structures further away from the midline are lateral. A structure that is above a specific reference area is called superior, and one that is below is termed inferior. Structures that are on the same side of the midline are said to be ipsilateral to each other; structures that are on opposite sides of the midline are said to be contralateral to each other.

For postmortem brain tissue, a brain slice is called a section, and standard cuts occur in 1 of the 3 anatomic planes (Figure 3–2). The plane of section resulting from cutting the brain into equal right and left halves is called the midsagittal plane. Sections parallel to the midsagittal plane are in the sagittal plane. The other 2 anatomic planes, horizontal and coronal, are perpendicular to the sagittal plane and to one another. The horizontal plane is parallel to the ground. Hence, horizontal sections separate the brain into dorsal and ventral parts. The coronal plane is perpendicular to the ground and to the sagittal plane. Thus, the coronal plane divides the brain into anterior/rostral and posterior/caudal parts.

In postmortem tissue, gray matter (which appears gray in preserved tissue, but is pink or light brown in living tissue) contains neuronal cell bodies, dendrites, synapses, and astrocytes (Figure 3–3). White matter is composed of myelinated axons, oligodendrocytes, and astrocytes. Gray matter forms the cortical layers of the brain and clusters of neurons, called nuclei, in the brain and spinal cord. Groups of nuclei form several subcortical gray matter areas. A bundle of myelinated axons (also called fibers) in the CNS is called a tract (or sometimes referred to as a nerve tract), with tracts forming the white matter regions in the brain and spinal cord.

OVERVIEW OF THE HUMAN BRAIN

The adult human brain weighs between 1200 and 1500 g (2.6 and 3.1 lb) and occupies a volume of between 1130 and 1260 cm³. Although only about 2% of the total body weight, the brain consumes 20% of the oxygen and calories supplied to the body. As described in Chapter 2, the brain and the spinal cord arise in embryonic development from the neural tube, which expands in the anterior half to form the 3 primary brain divisions: the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain). These 3 vesicles further differentiate into 5 subdivisions: the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon (Figure 3–4). The telencephalon forms the cerebrum, which includes the cerebral cortex, cerebral white matter, and several subcortical structures, including the amygdala and majority of the basal ganglia. The diencephalon forms the thalamus, subthalamus, hypothalamus, posterior pituitary, and epithalamus. Together, the telencephalon and diencephalon compose the forebrain. The mesencephalon forms the midbrain, the metencephalon forms the pons and cerebellum, and the myelencephalon forms the medulla. The brainstem consists of the midbrain, pons, and medulla. The cerebellum lies adjacent to the brainstem and underneath the forebrain and forms the posteriormost part of the brain. The spinal cord is continuous with the medulla.

The brain is enclosed in the cranial cavity (intracranial space), which is the space formed inside the skull (Figure 3–5). The skull is composed of 2 major parts: the neurocranium, which encases the brain, and the facial skeleton, which forms and supports the face, with the mandible being the largest component. In addition to protecting the brain, the skull fixes the distance between the eyes to allow stereoscopic vision and fixes the position of the ears to enable sound localization. Together, 8 fused cranial bones form the cavity: the frontal, occipital, sphenoid, and ethmoid bones, and 2 each of the parietal and temporal bones. The spinal cord passes through the foramen magnum, the large opening in the occipital bone at the base of the skull, as it exits the cranial cavity.

THE CEREBRUM

Derived from the telencephalon, the cerebrum forms the largest part of the brain, is situated above the other brain structures, and consists of the 2 cerebral hemispheres that are separated by the longitudinal fissure, also called the deep sagittal fissure. The right and left sides of the brain are anatomically mirror images of each other, a characteristic known as bilateral symmetry. The right cerebral hemisphere receives sensory information from and controls the motor functions of the left side of the body. Likewise, the left cerebral hemisphere is concerned with sensations and movements on the right side of the body. Functionally, the 2 halves of the brain are not exactly alike. Some cognitive functions, such as language, are said to be lateralized, since they are more dominant on one side of the brain than the other.

The cerebral hemispheres contain the cerebral cortex, which is the thin outer layer of gray matter that covers the core of cerebral white matter. Within the cerebral white matter lie several subcortical gray matter structures, including the amygdala and basal ganglia. The cerebral hemispheres also house the lateral ventricles, where CSF is produced and circulated. The surface of the human cerebrum has many convolutions, where the brain is folded into ridges (gyri; singular: gyrus) and grooves (sulci; singular: sulcus) (Figure 3–6). Gyri and sulci include both the cortical gray matter and a small portion of underlying white matter. The largest, primary grooves show a consistent location and are named according to their position or by the person who first described them. The locations of secondary and tertiary gyri and sulci can vary somewhat among individuals.

Each cerebral hemisphere is divided into 4 main lobes, the frontal, temporal, parietal, and occipital lobes, which are separated by primary sulci, and named according to the skull bone that overlies each (see Figure 3–6). The frontal lobe is separated from the parietal lobe by the central sulcus (also called the fissure of Rolondo), with the gyri on either side called the precentral gyrus and postcentral gyrus. The temporal lobe is separated from the frontal and parietal lobes by the lateral sulcus (Sylvian fissure). The parieto-occipital sulcus separates the parietal and occipital lobes. Two additional cortical lobes have also been described in humans. The insular lobe is formed from the insular cortex, a portion of the cerebral cortex folded deep within the lateral sulcus. The limbic lobe is an arc-shaped rim of cortex on the medial surface of each cerebral hemisphere surrounding the corpus callosum, composed of parts of the frontal, parietal, and temporal lobes.

Each of the cortical lobes is associated with 1 or a few specialized functions, although there is functional overlap between the lobes and extensive connections within and among the lobes. Within each of the cortical lobes, specific cortical areas called sensory, motor, and association areas are attributed with specific functions (Figure 3–7). The primary sensory areas receive inputs from the sensory tracts by way of relay nuclei in the thalamus, with the exception of the olfactory cortex. Primary sensory areas include the visual cortex in the occipital lobe, the auditory cortex and olfactory cortex in the temporal lobe, and the somatosensory cortex in the parietal lobe. The primary motor cortex, which sends axons down to motor neurons in the brainstem and spinal cord, occupies the posterior portion of the frontal lobe. The remaining parts of each cortex are association areas. Association areas receive input from the sensory areas and subcortical structures of the brain and function together with other association areas in complex networks to construct perception, emotion, and cognitive processes.

THE CEREBRAL CORTEX

The cerebral cortex is a thin layer of gray matter between 2 and 4 mm thick and overlying the cerebral white matter. In humans, the largest part of the cerebral cortex (∼90%) is the neocortex, which has 6 neuronal layers and is present only in mammals (Figure 3–8). A few small regions of human cerebral cortex (∼10%) are allocortex, which has only 3 or 4 layers and is evolutionarily older, evolving in vertebrates. Although the cerebral cortex is only a few millimeters thick, it occupies a sizeable area in humans; it is estimated that the human neocortex represents approximately 75% of the total brain gray matter. It has been proposed that, in humans, gyri and sulci result from the expansion of the surface area of the cerebral cortex during fetal development, allowing a greater area of cerebral cortex to fit into the confines of the skull. The increased cortical areas have been proposed to underlie the evolution of higher cognitive functions in humans.

Although the neocortex displays a consistent 6-layer organization, different regions of the cerebral cortex are composed of distinguishably different neuronal morphologies and connections. Mapped by microscopic analysis into 52 areas by Brodmann in the early 20th century, each numbered Brodmann area has a common cytoarchitecture (Figure 3–9). At that time, Brodmann, Ramon y Cajal, and others predicted that cortical areas that look different perform different functions. Through numerous types of analyses in the past century, we now know this to be true. Because there is little difference in the thickness of the neocortex in different mammals, Brodmann also predicted that the neocortex expanded by the insertion of new areas. The neocortex contains approximately 80% excitatory glutamatergic neurons and approximately 20% inhibitory GABAergic neurons and receives inputs from neurons in all the major neurotransmitter systems. Many neuroscientists propose that the smallest functional unit of the neocortex is a cylinder of neurons approximately 2 to 3 mm in height (the distance from the white matter to the pial surface) and approximately 0.5 mm in diameter. A cortical column or hypercolumn consists of ~50-100 minicolumns and is estimated to contain ~10,000 neurons and 100 million synapses (∼10,000 synapses per neuron). Cortical columns have been characterized in primary visual and somatosensory cortex, in which the neurons have similar sensory receptive fields.

THE FRONTAL LOBE

The frontal lobe is involved in voluntary motor control, production of language, and a majority of cognitive functions, including short-term working memory, attention, behavioral control, and executive functions. Motor areas include the motor cortex, frontal eye fields, and the Broca area. The prefrontal cortex and other areas are involved in cognitive functions. The frontal lobe also contains a small region of sensory cortex. The primary gustatory cortex, responsible for the reception of taste, consists of the frontal operculum on the inferior frontal gyrus of the frontal lobe and the anterior insula in the insular lobe.

The motor cortex is the region of the frontal lobe involved in the planning, control, and execution of voluntary movements and is composed of 3 regions: the primary motor cortex, the premotor cortex, and the supplemental motor area (SMA) (Figure 3–10). The primary motor cortex is located in the precentral gyrus immediately anterior to the central sulcus. The primary motor cortex contains upper motor neurons that send impulses via axons to the brainstem and spinal cord for the execution of movement. The premotor cortex is located anterior to the primary motor cortex and is involved both directly and indirectly in the control of movement. The premotor cortex sends axons to the spinal cord for direct motor control of some movements, especially proximal and trunk muscles of the body, and sends inputs to the primary motor cortex for the preparation for and sensory guidance of movement. Both the primary motor and premotor cortices are somatotopically organized.

The SMA is located in the anterior paracentral lobule. Together, the premotor cortex and SMA are involved in planning of movement, selection of appropriate motor plans and sequences, and coordination of the 2 sides of the body for complex patterns of motor output. The motor cortex receives inputs from the prefrontal cortex, thalamus, primary somatosensory cortex, and posterior parietal lobe. Other brain regions including the cerebellum, basal ganglia, and brainstem nuclei are also critical in the control of motor function, but send information to the motor cortex via the thalamus.

The frontal eye field (FEF) is a frontal lobe motor area involved in the control of visual attention and eye movements. Located in a region around the intersection of the middle frontal gyrus with the precentral gyrus, the FEF is responsible for saccadic eye movements for visual field perception and awareness, as well as for voluntary eye movement. The FEF communicates with the extraocular muscles indirectly through the paramedian pontine reticular formation. Another motor area, the Broca area, is a small region in the frontal lobe of 1 hemisphere (usually the left in the majority of humans), with functions linked to language. Located in the inferior frontal gyrus of the dominant hemisphere, the Broca area has a key role in various speech and language processing functions, including speech production and language comprehension. The Broca area receives substantial inputs from the other important language area, the Wernicke area, in the temporal lobe.

The other role of the frontal lobe is to produce cognitive functions that orchestrate thoughts with the selection of appropriate actions to achieve particular goals. For example, the frontal lobe constructs the ability to predict outcomes, project future consequences resulting from current activities, work toward a defined goal, make expectations based on actions and evaluate the consequences of a particular course of action, differentiate among conflicting thoughts, determine similarities and differences between things or events, choose between good (or better) and bad (or worse) actions, suppress impulses, and override and control socially unacceptable responses.

The frontal lobe is involved in what are termed executive functions, including attentional control, short-term working memory, self-control and moderation of social behavior, decision making, judgment, planning, reasoning, problem solving, and abstract thinking, as well as the expression of emotion and personality. These cognitive functions require the prefrontal cortex, the region located anterior to the motor cortex, as well as other cortical and subcortical regions. The prefrontal cortex can be divided into lateral, polar, orbital, and medial domains (Figure 3–11). Each of these domains consists of a particular gyrus and has a specific function. The prefrontal cortex is highly interconnected with much of the brain, including extensive connections with other cortical, subcortical, and brainstem regions. The prefrontal cortex receives massive inputs from the somatosensory, visual, and auditory sensory association cortices and also from the thalamus. The dorsal prefrontal cortex is especially interconnected with brain regions involved with attention, cognition, and action, whereas the ventral prefrontal cortex interconnects with brain regions involved with emotion.

The dorsolateral prefrontal cortex (DLPFC) is involved in executive functions, as well as motor planning. The DLPFC has connections with the orbitofrontal cortex (OFC), thalamus, basal ganglia, hippocampus, and association areas of the temporal, parietal, and occipital lobes. The OFC is considered anatomically synonymous with the ventromedial prefrontal cortex. The OFC and medial prefrontal cortex have direct connections to the thalamus, amygdala, and cingulate cortex of the limbic lobe and are thought to be involved in impulse control and to provide the emotional component to decision making, planned behavior, and memory. The ventrolateral prefrontal cortex is thought to play a critical role in motor inhibition and spatial attention.

THE OCCIPITAL LOBE

The smallest lobe, the occipital lobe, is located in the rearmost portion of the skull and is dedicated to vision. The occipital lobe contains the visual cortex and is involved in visual reception, visual-spatial processing, motion perception, and color recognition (Figure 3–12). The primary visual cortex is commonly called V1 or the striate cortex because of the prominent band of myelin in cortical layer 4. In humans, V1 is located in the posterior pole of the occipital lobe, on the medial side within the calcarine sulcus, although V1 often continues to the posterior pole of the occipital lobe. V1 receives direct input via the optic radiations from the lateral geniculate nucleus of the thalamus, which is the relay from the retina. V1 in the left hemisphere receives visual information from the right visual field, and V1 in the right hemisphere receives visual information from the left visual field. Surrounding V1 are the visual areas (V2, V3, and V4) forming the extrastriate cortex, which are specialized for different visual tasks. Each of these visual areas contains a map of the visual world. The visual association cortex extends anteriorly from the extrastriate cortex to encompass adjacent areas of the posterior parietal lobe and much of the posterior temporal lobe.

V1 is involved in the initial cortical processing of all visual information necessary for visual perception. Visual information then flows through a cortical hierarchy. In the mammalian visual system, visual sensory information is transmitted from V1 along anatomically separate and parallel streams, called the ventral and dorsal streams. The ventral stream begins with V1, goes through V2 to V4, and then to the inferior temporal cortex. The ventral stream is also called the “what” pathway, is associated with form and object recognition and object representation, and provides important information for the identification of stimuli for memory storage. The dorsal stream begins with V1, goes through V2, then to V5/middle temporal area and V6/dorsomedial area, and to the posterior parietal cortex. The dorsal stream is also called the “where” or “how” pathway and is associated with motion, spatial orientation, representation of object locations, binocular/depth perception, and guidance of behaviors to spatial locations. Originally thought to be parallel, the 2 streams are in fact heavily interconnected, and evidence suggests that both steams are essential for successful perception, especially as the stimuli take on more complex forms.

As part of visual processing, the visual system is involved in assessing distance, size, and depth; identifying visual stimuli, particularly objects and familiar faces; continually responding to changing information from the external environment; and transmitting visual information to brain regions in other lobes that encode memories, assign meaning, and guide appropriate motor and linguistic responses.

THE PARIETAL LOBE

The parietal lobe is positioned anterior to the occipital lobe, posterior to the frontal lobe, and dorsal to the temporal lobe (Figure 3–13). The parietal lobe contains the somatosensory cortex, which receives and processes touch, temperature, pain, and conscious proprioceptive information from the body and provides some motor control. The posterior parietal cortex (PPC) is important in visuospatial perception, spatial attention, and integration of somatosensory, visual, and auditory input, with connections to the motor cortex to control and plan specific movements. Several areas of the parietal lobe are also important in cognitive processing including language, learning and memory-related processes, knowledge of numbers (numerosity), categorization, and decision making.

The primary somatosensory cortex (S1) is located in the postcentral gyrus in Brodmann areas (BA) 3, 2, and 1. Area 3b in S1 receives sensory information about touch, temperature, and pain from the skin that is relayed via the thalamus from the contralateral side of the body. Neurons in 3b project to BA2 and BA1. Area 3a receives proprioceptive information via the thalamus about body position and movement. Similar to the motor cortex, which lies directly on the opposite side of the central sulcus, there is a somatotopic map in S1. Area 3a is sometimes considered to be functionally part of the motor control circuitry and may contain neurons that directly control movement. S1 sends information to region S2, located in the parietal operculum on the ceiling of the lateral sulcus. Specific areas in region S2 connect to the premotor cortex, insular cortex, amygdala, and hippocampus.

An association cortex, the PPC plays an important role in transforming multisensory information into planned movements and motor commands, localization of the body and external objects in space, spatial reasoning, learning motor skills, and spatial attention. The PPC receives input from 3 sensory systems: the somatosensory, visual, and auditory systems. In turn, much of the output of the PPC projects to areas of the frontal cortex, including the motor cortex, DLPFC, and FEFs. Regions of the PPC are components of the dorsal stream (the where and how stream) in visual processing, and the PPC has been proposed to play a role in sustaining attention to spatial locations. Furthermore, the PPC is involved in ensuring that movements are targeted accurately to objects in external space. The PPC is involved in processing spatial relationships of objects in the world and in constructing a representation of external space, which allows a stable percept of the world and a representation of desired trajectories in space that are independent of viewer orientation or body position.

Human functional imaging and neuropsychological studies demonstrate that the parietal lobe and adjacent temporoparietal junction (TPJ) contribute to a variety of higher cognitive functions, including both bottom-up and top-down attention, working memory, multimodal episodic memory, and semantic cognition, which is the ability to use, manipulate, and generalize knowledge. The parietal lobe and TPJ have also been shown to function in aspects of language perception and processing, including phonology and syntax, mathematical cognition, and theory of mind, which is the ability to attribute mental states, including beliefs, intents, desires, and knowledge, to oneself and to others.

THE TEMPORAL LOBE

The temporal lobe is involved in receiving and processing auditory (sound) information and is key for humans to comprehend meaningful speech and language (Figure 3–14). The temporal lobe also receives and processes olfactory information and participates in visual processing to establish object and face recognition and interpretation of the meaning of visual stimuli. Important regions in the medial temporal lobe are the hippocampus and adjacent parahippocampal, entorhinal, and perirhinal cortices, which are crucial for the encoding of long-term declarative and spatial memories and the transmission of those into long-term memory stores. Through its connections with other structures such as the amygdala in the limbic lobe, the temporal lobe is also involved in emotional processing and providing emotional content to long-term memories.

One key function of the temporal lobe is in perceiving sounds, assigning meaning to those sounds, and remembering sounds. The primary auditory cortex (A1) is located bilaterally in the superior temporal gyrus. A1 receives auditory information from the ipsilateral cochlea in the ear via the thalamus. Neurons in A1 are organized in a tonotopic map. Secondary auditory areas adjacent to A1, including A2 and areas in the superior, posterior, and lateral parts of the temporal lobes, are involved in auditory processing and perception. Secondary auditory areas process auditory information into semantic (meaningful) units such as speech and words and are involved in comprehension and verbal memory. Speech processing is lateralized, and the majority of humans have left hemisphere specialization. One such lateralized area is the Wernicke area, which spans the region between the temporal and parietal lobes, plays a key role in speech comprehension, and is highly connected with the Broca area, the speech production area in the frontal lobe. Final sound processing is performed by the parietal and frontal cortices.

The ventral regions of the temporal cortices form the ventral stream or “what” pathway of the visual system, which is involved in visual processing that aids in the assignment of meaning to visual information received and interpreting the meaning of visual stimuli, including recognizing faces and objects and reading body language. Two identified regions involved in the interpretation of complex visual stimuli are the fusiform gyrus involved in face recognition and the parahippocampal gyrus involved in interpretation of visual scenes.

The temporal lobe contains the olfactory cortex, one of the regions where olfactory information is received and processed. The olfactory cortex includes areas within the piriform (also spelled pyriform) cortex and likely involves parts of the prepyriform area, entorhinal cortex, and periamygdaloid cortex. The olfactory cortex is evolutionarily older allocortex that comprises 3 layers. Unlike the other senses, the olfactory system does not receive sensory input from the thalamus. Rather the olfactory cortex receives inputs from the olfactory bulb, a region of subcortical gray matter dorsal to the prefrontal cortex, which receives odorant information via the olfactory nerve. The olfactory bulb also sends direct inputs to the amygdala, anterior olfactory nucleus, and olfactory tubercle. The piriform cortex projects to the medial dorsal nucleus of the thalamus, which then projects to the OFC in the frontal lobe that mediates conscious perception of odor.

The medial temporal lobe contains the hippocampus and associated cortical structures that are critical for encoding long-term declarative and spatial memory and transmission of memories to other cortical regions for long-term memory storage. The hippocampus has also been implicated in navigation and spatial cognition. The shape of a curved tube, the hippocampus looks similar to a seahorse or ram’s horn and has functionally distinguishable anterior and posterior regions in primates (Figure 3–15). The main input to the hippocampus is from the entorhinal cortex. Located in the parahippocampal gyrus (near the perirhinal cortex), the entorhinal cortex is reciprocally connected with many cortical and subcortical structures including sensory areas, thalamic nuclei, medial septal nucleus, hypothalamus, and brainstem. The main output from the hippocampus is to the subiculum, which projects to numerous areas including the prefrontal cortex, hypothalamus, entorhinal cortex, amygdala, nucleus accumbens, septal nucleus, nucleus reuniens, and mammillary nuclei. The anatomy of the hippocampus and mechanisms of memory encoding are described in Chapters 10 and 20.

THE INSULAR LOBE

Each hemisphere of the human brain also contains the insular lobe (also called the island of Reil). The insular lobe is formed from the insula cortex, a region of cerebral cortex folded deep within the lateral sulcus between the temporal, frontal, and parietal lobes. Because it is covered by the frontoparietal and temporal operculum (meaning lid), the insular cortex is the only cortical region that is not visible on the surface of the brain. The insula has widespread bidirectional connections with the frontal, parietal, and temporal lobes; the cingulate gyrus; and subcortical structures such as the amygdala, brainstem, thalamus, and basal ganglia. These connections provide integration of autonomic, sensory, motor, and limbic functions in the insular lobe.

The insular cortex is divided into 2 parts: the larger anterior insula and the smaller posterior insula in which more than a dozen field areas have been identified. The anterior insular cortex contains part of the primary gustatory cortex, with the other part located in the frontal operculum of the frontal lobe. In addition to taste reception and processing, the insula is believed to participate in pain perception, speech production, processing of social emotions and emotional self-awareness, interpersonal experience, compassion and empathy, consciousness, and the regulation of the body’s homeostasis.

THE AMYGDALA & THE LIMBIC LOBE

The amygdala is a subcortical almond-shaped group of nuclei derived from telencephalon located deep and medially within the temporal lobes (Figure 3–16). Considered part of the limbic system, the amygdala is an integration center that is critical for the processing of emotion, including emotional reactions, emotional communication, emotional memory, motivation, and decision making. The amygdala is interconnected with numerous cortical and subcortical areas, receiving inputs from all the senses via the thalamus and cerebral cortex and from the hypothalamus and brainstem. Connections to these areas allow the amygdala to process information from sensory areas and areas associated with behavior and autonomic function. The amygdala interacts directly with other parts of the limbic system, generating autonomic emotional reactions particularly related to survival, such as fear and the fight-or-flight response. In addition, the amygdala is involved in processing of other emotions, such as anger, pleasure, and motivation, and is responsible for providing emotional content to long-term memories.

Composed of approximately 13 nuclei, the amygdala is functionally divided into 3 major interconnected regions: the basolateral complex, the corticomedial nuclear group, and the central nucleus. The largest subdivision, the basolateral complex, has reciprocal connections with the cerebral cortex, thalamus, and hippocampus. Information from the olfactory system is received by the corticomedial nuclei. The corticomedial nuclei and central nucleus provide direct outputs to the hypothalamus, and the central nucleus also provides direct output to brainstem areas that control expression of innate behaviors and associated physiologic responses.

Because the amygdala encodes information about emotional events, it participates in emotional memory, a type of implicit or unconscious form of memory. Fear conditioning and reward learning, types of conditioning responses, have been shown to involve the amygdala. In addition, through the amygdala’s processing of the emotional significance of external stimuli, the amygdala is also involved in the modulation of a variety of cognitive functions, such as attention and perception. The amygdala also provides emotional content to long-term declarative memories encoded by the hippocampus. Modulation of these cognitive functions may occur through direct inputs from the amygdala to cortical areas or indirectly via the effect of hormones and/or neuromodulators that alter cognitive processing.

The amygdala is a component of the limbic system, which also includes the limbic lobe. The limbic lobe is an arc-shaped region of cerebral cortex on the medial surface of each cerebral hemisphere and includes the hippocampus, associated medial temporal lobe structures, and the cingulate gyrus and sulcus. The limbic system also includes the fornix, mammillary body, and regions of the thalamus, hypothalamus, and basal ganglia, which establish a functionally interconnected group of structures involved in emotional states, motivation and drives, affect, olfactory perception, attentional processing, time perception, autonomic regulation, arousal, consciousness, and learning and memory. The limbic system operates by influencing the endocrine system and autonomic nervous system. Although still commonly used in neuroanatomic descriptions, the historical concept of a functionally unified limbic system has been criticized as obsolete.

THE BASAL GANGLIA

The basal ganglia, also called the basal nuclei, include a set of subcortical structures located deep within the cerebral hemispheres (Figure 3–17). Functionally, the basal ganglia are involved in the control and coordination of voluntary motor movements, decisions about which motor actions to select, eye movements, procedural learning, some behaviors and habits, cognition, and emotions such as motivation and reward. The basal ganglia are strongly interconnected with areas of the cerebral cortex, thalamus, and brainstem, as well as several other brain areas.

The basal ganglia comprise a distributed set of brain structures derived from the telencephalon, diencephalon, and mesencephalon (Figure 3–18). The largest component is the striatum (also called the corpus striatum), which includes the dorsal striatum (neostriatum) formed from the caudate nucleus and putamen and the ventral striatum formed by the nucleus accumbens and olfactory tubercle. The other regions include the globus pallidus (also called the dorsal pallidum), ventral pallidum, subthalamic nucleus, and substantia nigra in the brainstem. The caudate nucleus is a C-shaped structure that extends around and next to the lateral ventricles. The putamen and globus pallidus are separated from the lateral ventricles, the caudate nucleus, and the thalamus by the internal capsule, a large white matter region containing both ascending and descending axons to and from the cerebral cortex.

Forming the neostriatum, the caudate nucleus and putamen are considered functionally equivalent to each other. The putamen is connected to the caudate head by cellular bridges that traverse the internal capsule, producing a striated appearance. The putamen and the globus pallidus are collectively called the lenticular nucleus or the lentiform nucleus. The globus pallidus is divided into 2 segments: the internal globus pallidus (GPi) and the external globus pallidus (GPe).

Located just below the thalamus is the subthalamic nucleus, a part of the diencephalon. The substantial nigra is a brainstem structure located between the red nucleus and the cerebral peduncle on the ventral part of the midbrain, composed of the pars compacta and pars reticulata. The pars compacta contains the cell bodies of dopaminergic neurons that innervate the neostriatum. A functionally analogous midbrain area is the ventral tegmental area, which contains dopaminergic neurons that project to the nucleus accumbens.

The striatum is the main recipient of inputs to the basal ganglia. Inputs to the striatum are excitatory afferents from the entire cerebral cortex and intralaminar nuclei of the thalamus. The primary motor and somatosensory cortices project mainly to the putamen, whereas the premotor cortex and SMA project to the caudate head, and other cortical areas project primarily to the caudate. The nucleus accumbens receives a large input from the limbic cortex.

The main output structures of the basal ganglia are the GPi of the globus pallidus and the substantia nigra pars reticulata (SNr). The GPi projects to a number of thalamic structures by way of 2 tracts. The circuit that processes sensorimotor information from the motor cortex and the somatosensory cortex projects to the ventral anterior (VA) and ventral lateral (VL) nuclei of the thalamus. The circuit that processes other neocortical information projects to the dorsomedial nucleus, the intralaminar nuclei, and parts of the VA nucleus of the thalamus. The SNr projects to the superior colliculus, an area involved in eye movements, as well as to the VA/VL thalamic nuclei.

Two distinct pathways process signals through the basal ganglia. Called the direct pathway and the indirect pathway, they have opposite net effects on thalamic target structures. Excitation of the direct pathway has the net effect of exciting thalamic neurons (which in turn make excitatory connections onto cortical neurons). Excitation of the indirect pathway has the net effect of inhibiting thalamic neurons (rendering them unable to excite motor cortex neurons). The normal functioning of the basal ganglia involves a balance between the activity of these 2 pathways.

The dorsal striatum contributes directly to decision making, especially to action selection and initiation, through the integration of sensorimotor, cognitive, and motivational/emotional information. The dorsal striatum primarily mediates cognition involving motor function, certain executive functions such as inhibitory control, and stimulus-response learning. It is associated with the acquisition of habits and is the main region linked to procedural memory.

The ventral striatum is associated with the limbic system and has been implicated as an essential component of the circuitry for decision making and reward-related behavior. As part of the reward system, the nucleus accumbens plays an important role in processing rewarding stimuli, reinforcing stimuli, and stimuli that are both rewarding and reinforcing such as addictive drugs.

The nucleus accumbens is often considered to be part of the basal forebrain, which lies anterior and ventral to the neostriatum. The other basal forebrain structures include the nucleus basalis, diagonal band of Broca, substantia innominata, and the medial septal nucleus. The basal forebrain is considered to be the major cholinergic output of the CNS to the striatum and neocortex, with important functions in sleep and wakefulness and learning and memory.

CEREBRAL WHITE MATTER

Three types of white matter tracts, called commissural, projection, and association tracts, connect gray matter areas in the CNS and form the majority of cerebral white matter (Figure 3–19). The 2 hemispheres are connected by commissural tracts that span the longitudinal fissure at different regions, allowing the 2 hemispheres to communicate. The largest commissure is the corpus callosum, a broad band of about 200 million axons that join the majority of corresponding regions in the left and right hemispheres. It is the largest white matter structure in the brain. A few tracts pass through the much smaller anterior and posterior commissures. The projection tracts connect the cerebral cortex with other regions, including the striatum, thalamus, brainstem, and spinal cord. Many ascending and descending projection tracts are located in the internal capsule, which surrounds the thalamus and basal ganglia. Within the internal capsule, the largest descending projection tract is the corticospinal tract. The association tracts connect specific cortical areas within the same hemisphere. Short association tracts connect different gyri within a single lobe, whereas long association tracts connect different lobes of a hemisphere to each other. Among their many important roles, association tracts link sensory perceptual, cognitive, and memory regions of the brain. Well-characterized long association tracts include the cingulum, the fornix, and the arcuate, uncinate, occipitofrontal, and superior and inferior longitudinal fasciculi.

THALAMUS, HYPOTHALAMUS, & PITUITARY

The 2 largest structures of the diencephalon are the thalamus and the hypothalamus. Considered the gateway to the cerebral cortex, the thalamus is positioned in the center of the brain, located between the cerebral cortex and midbrain, adjacent to the basal ganglia and dorsal to the cerebellum, and has extensive connections to all 4 regions (Figure 3–20). One of the main functions of the thalamus is to transmit sensory and motor information to the cerebral cortex. However, not merely a “relay station,” the thalamus is also engaged in integration and sorting of sensory and motor information that will reach the cerebral cortex and impacts cognitive functions.

The thalamus is a midline symmetrical structure of 2 halves (Figure 3–21). The medial surface of the thalamus constitutes the upper part of the lateral wall of the third ventricle and is connected to the opposite thalamus by the interthalamic adhesion. The thalamus is an organized group of approximately 60 specific nuclei, each with defined connections and roles in sensory, motor, and some cognitive functions. The lateral and posterior parts of the thalamus are continuous with the underlying midbrain; the internal capsule serves as the lateral boundary of the thalamus; the posterior commissure serves as the posterior boundary. The thalamus is separated from the frontal cortex by the anterior commissure and linea terminalis. The ventral boundary is the hypothalamic sulcus, which separates the thalamus from the hypothalamus below.

Every sensory system (with the exception of the olfactory system) involves a specific thalamic nucleus in the dorsal/sensory thalamus that receives sensory signals from ascending tracts or cranial nerves and transmits sensory information to the specific primary sensory cortex (Figure 3–22). For example, outputs from the retina, via the optic nerve, are sent to the lateral geniculate nucleus of the thalamus, which in turn projects to V1 in the occipital lobe. The medial geniculate nucleus relays auditory information, the ventral posterior nucleus is the somatosensory relay, and the ventral posterior medial nucleus relays gustatory sensation. The thalamus also processes sensory information and receives reciprocal connections from the sensory cortex it innervates. A current concept about the sensory thalamus is that inputs can be divided into “drivers,” which provide the primary excitatory drive for the relay of information to cortex, and “modulators,” which alter the gain of signal transmission.

The thalamus plays a critical role in regulation of motor function. A region of the ventral thalamus called the motor thalamus (Mthal) encompasses thalamic nuclei that are functionally positioned between cerebral cortical motor areas and 2 subcortical networks, the basal ganglia and cerebellum. Consequently, the thalamus provides specific channels from the basal ganglia and cerebellum to the cortical motor areas and receives reciprocal connections from those motor areas. Mthal receives output of the basal ganglia, the SNr, and GPi proposed to be involved in the complex cognitive control of movement. Mthal receives major inputs from the dentate nucleus and interposed nucleus, 2 deep cerebellar nuclei, which provide proprioceptive control of posture and movement. Mthal is also proposed to have a role in motor learning.

The thalamus receives inputs from the reticular thalamic nucleus, the superior colliculus, the pedunculopontine nucleus, and the somatosensory spinal cord, and has been implicated in wakefulness and sleep, awareness and alertness, and consciousness. Connections with the prefrontal cortex, hippocampus, and other cortical association areas also likely underlie the contribution of the thalamus to cognitive functions, including language processing, attention, short-term working memory, long-term memory, and decision making.

Two additional regions of the diencephalon are the subthalamus, which contains the subthalamic nucleus, and the epithalamus. Located ventral to the thalamus, the subthalamic nucleus receives inputs from the basal ganglia, specifically from the globus pallidus and substantia nigra, and sends outputs back to the basal ganglia, with a proposed function in action selection. The epithalamus, which includes the pineal gland, connects the limbic system to other parts of the brain, and has been implicated in secretion of melatonin and other neurohormones, circadian rhythm, and regulation of motor pathways and emotions.

The single hypothalamus lies beneath the thalamus and anterior to the midbrain. The overarching function of the hypothalamus is integration and control of body functions for survival and reproduction. The hypothalamus acts as an integrator to regulate basic life- and species-sustaining functions such as fluid and electrolyte balance, drinking and feeding behavior, energy metabolism, thermoregulation, stress responses, and sleep–wake cycles, as well as sexual behavior and reproduction. To produce control over so many bodily functions, the hypothalamus uses 3 major outputs: the behavioral, autonomic, and endocrine systems.

The hypothalamus receives sensory inputs necessary for the detection of changes in both the internal and external environments and controls behaviors related to those inputs. The hypothalamus receives direct sensory inputs from the visual, olfactory, gustatory, and somatosensory systems. In addition, regions within the hypothalamus contain sensors for blood sugar, temperature, and ion levels and receptors for stress hormones, such as cortisol, and appetite hormones, such as leptin and orexin. As part of the limbic system, the hypothalamus receives inputs from the hippocampus, amygdala, and cingulate cortex, which provide highly processed sensory and salience information from the rest of the cerebral cortex. These inputs to the hypothalamus contribute to a range of emotional responses, feelings, and expressions, as well as behaviors such as aggression and motivational behaviors, such as drinking, feeding, and sexual behaviors.

Well interconnected with the brainstem and spinal cord, the hypothalamus is also involved in control of the autonomic nervous system (ANS) (Figure 3–23). Hypothalamic neurons located in the paraventricular nuclei, arcuate nuclei, and lateral hypothalamic area send axons directly to the preganglionic neurons in both the sympathetic and parasympathetic ANS. Hypothalamic control of the ANS includes regulation of heart rate, blood pressure, the extent and regions of blood flow, and peristalsis. In addition, the hypothalamus has extensive outputs to adjust brainstem circuits that regulate autonomic output. Projections to the reticular formation are also involved in certain behaviors, particularly emotional reactions.

The hypothalamus links the nervous system to the endocrine system via the pituitary gland (hypophysis), which releases hormones into the bloodstream and consequently controls many physiologic functions of the body (Figure 3–24). Neurons in the paraventricular and supraoptic nuclei of the hypothalamus send their axons through the infundibulum to form the posterior pituitary (neurohypophysis) where they secrete oxytocin and vasopressin (antidiuretic hormone) directly into the circulation. Oxytocin is involved in contraction of the uterus during childbirth and lactation, whereas vasopressin regulates water retention and the control of blood pressure.

Neurons in the periventricular, paraventricular, and arcuate nuclei send axons that release hypothalamic hormones, which act on the anterior pituitary to either stimulate or inhibit the secretion of specific anterior pituitary hormones into the circulation. Hypothalamic hormones include growth hormone–releasing hormone, thyrotropin-releasing hormone, corticotropin-releasing hormone, gonadotropin-releasing hormone, somatostatin, and follistatin. The 6 anterior pituitary hormones are growth hormone, prolactin, thyroid-stimulating hormone, adrenocorticotropic hormone, follicle-stimulating hormone, and luteinizing hormone, which are released into the bloodstream.

Another key function of the hypothalamus is regulation of body functions in concert with the daily light–dark cycle. A small percentage of axons from the optic nerve go directly to a small nucleus within the hypothalamus called the suprachiasmatic nucleus, which is responsible for entraining circadian rhythms to the day–night cycle.

SUMMARY

• The nervous system is composed of the CNS and PNS.

• The brain and spinal cord compose the CNS.

• Standard anatomic directional axes, such as anterior-posterior, dorsal-ventral, medial-lateral, and superior-inferior, and planes, such as sagittal, coronal, and horizontal, are useful in neuroanatomic descriptions.

• Regions of the CNS are often described in terms of gray and white matter. Gray matter contains neuronal cell bodies, dendrites, and astrocytes, whereas white matter contains myelinated axons, oligodendrocytes, and astrocytes.

• The cortex and nuclei compose the 2 types of gray matter in the CNS. White matter contains tracts, which are bundles of myelinated axons in the CNS.

• The brain develops from the 5 embryonic vesicles of the neural tube, called the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon. The telencephalon and diencephalon form the forebrain.

• The brain is enclosed in the cranial cavity and encased by the skull, which is formed from the fusion of 8 cranial bones.

• Developing from the telencephalon, the cerebrum comprises the left and right cerebral hemispheres separated by the longitudinal fissure.

• The cerebrum is composed of cerebral cortex, cerebral white matter, and subcortical structures.

• The cerebral cortex is a thin layer of gray matter that forms the outer surface of the brain, overlying the cerebral white matter. The 2 types of cerebral cortex are neocortex (6 layers) and allocortex (3 to 4 layers).

• The cerebral cortex forms many ridges called gyri (singular gyrus) and grooves called sulci (singular sulcus). The cerebral cortex constitutes approximately 75% of the total CNS gray matter.

• The cerebrum is separated by prominent sulci into 4 visible lobes—the frontal, parietal, occipital, and temporal lobes—which are named for the skull bone that overlies them. The insular lobe and limbic lobe are situated deeper inside the sulci.

• Different cortical regions named Brodmann areas can be distinguished by their cytoarchitecture and connections and have distinct functions.

• Identified cortical areas are called sensory, motor, and association cortices based on their function. Small functional units of neocortex are called cortical columns.

• The anteriormost lobe, the frontal lobe, contains the motor cortex, frontal eye fields, and the Broca area, which are involved in voluntary motor control, eye movements, and language production, respectively.

• The prefrontal region of the frontal lobe contains association cortex that constructs many cognitive functions, including short-term working memory, executive functions, and behavioral control.

• The posteriormost lobe, the occipital lobe, contains the visual cortex and functions in visual reception, visual-spatial processing and motion perception, and color recognition.

• The parietal lobe contains the somatosensory cortex, which receives and processes touch, temperature, pain, and conscious proprioceptive information from the body and provides some motor control.

• A main association area, the posterior parietal cortex, is involved in visuospatial perception, attention, and integration of somatosensory, visual, and auditory input, and provides output to the frontal lobe for motor control and cognitive functions.

• The temporal lobe contains the auditory cortex involved in receiving and processing auditory information. The auditory association areas include the Wernicke area, which is involved in language comprehension.

• The olfactory cortex in the temporal lobe contributes to reception and processing of olfactory information. The temporal lobe also participates in visual processing for object and facial recognition.

• The temporal lobe houses the hippocampus, entorhinal cortex, and associated cortical structures involved in encoding long-term declarative and spatial memories.

• The insular lobe is formed by the insular cortex located deep within the lateral sulcus with functions in sensory perception, processing social emotions such as compassion and empathy, emotional self-awareness, and consciousness.

• The limbic lobe is formed from the limbic cortex, which includes the cingulate cortex, hippocampus, and associated cortices in the medial temporal lobe. The limbic system comprises the limbic lobe and subcortical areas.

• The amygdala contains a group of subcortical nuclei located within each temporal lobe. Part of the limbic system, the amygdala functions in processing and communication of emotion and emotional memory.

• The basal ganglia are a set of subcortical structures involved in the control and coordination of voluntary motor movements, decisions about which motor actions to select, procedural learning, and motivation and reward.

• Three types of white matter tracts, called commissural, projection, and association tracts, connect gray matter areas in the CNS.

• Positioned in the center of the brain, the thalamus receives inputs from sensory systems, the basal ganglia, the cerebellum, and the cerebral cortex. The main functions of the thalamus are in sorting and relaying sensory and motor information to the cerebral cortex and in modulation of cognitive functions.

• The hypothalamus regulates body functions for survival and reproduction. Through outputs that control behavioral, autonomic, and endocrine systems, the hypothalamus is involved in electrolyte balance, feeding and energy metabolism, thermoregulation, sleep–wake cycles, sexual behavior, and reproduction.

OBJECTIVES

INTRODUCTION

The forebrain is highly interconnected with the midbrain, hindbrain, and spinal cord. These regions also provide the connections to the peripheral nervous system (PNS); the PNS includes the cranial nerves, spinal nerves, peripheral nerves, and ganglia located outside of the brain and spinal cord. The midbrain, pons, and medulla oblongata (hereafter medulla) compose the brainstem, which contains nuclei that are critical for survival through automatic responses such as breathing and reflexes such as coughing. The brainstem also contains nuclei for cranial nerves (CNs) III to XII. Emerging from the brainstem, CNs III to XII serve somatic and autonomic motor and sensory functions in the face, head and neck, special senses, and autonomic innervation of the heart, lungs, and other organs. The other region of the hindbrain is the cerebellum, which is connected to the rest of the brain and spinal cord via the pons. The cerebellum functions in motor functions including coordination, precision, timing, and motor learning and has been implicated in cognition and emotion.

Caudal to the medulla is the spinal cord. The spinal cord contains both ascending and descending white matter tracts and neurons involved in motor output, sensory relay, integration, and spinal reflexes. Spinal cord gray matter contains the cell bodies of somatic motor neurons, preganglionic autonomic neurons, and sensory relay neurons, as well as spinal interneurons involved in integration and spinal reflexes. The spinal cord is the origin of the 31 pairs of spinal nerves and their branches, called peripheral nerves, which contain axons that innervate the skin, muscles, tendons, joints, and organs (viscera). The circuitry within the spinal cord generates spinal reflexes and contributes to central pattern generators. Another component of the PNS is the enteric nervous system (ENS); located in the gastrointestinal (GI) tract, the ENS functions in peristalsis and secretions.

The central nervous system (CNS) is protected on the outside by the skull and meninges, membranes that prevent the movement of the brain within the skull and contain cerebrospinal fluid (CSF) that helps cushion the CNS. Inside the CNS lies the ventricular system and central canal, with the main function of production and circulation of CSF. The CNS has a robust vascularization, with blood supplied from branches of the dorsal aorta and drainage via the jugular vein. The nerves are also vascularized and contain layers of protective connective tissue.

THE BRAINSTEM

Considered one of the most primitive parts of the human brain, the brainstem is the structure most important to life (Figures 4–1 and 4–2). The brainstem contains white matter tracts involved in transmission of motor impulses that control the body and head and the largest majority of sensory tracts. In addition, 10 of the 12 pairs of CNs emerge directly from the brainstem, with nuclei involved in both somatic motor and sensory functions of the head, face, and neck and in autonomic parasympathetic functions. The brainstem also contains nuclei involved in essential automatic processes, including breathing, and encompasses the reticular formation, a group of nuclei that function in arousal, alertness, and consciousness. Anatomically, the brainstem rests on the base of the skull, known as the clivus, and ends at the foramen magnum, the large opening in the occipital bone.

THE MIDBRAIN

Rostrally, the midbrain adjoins the thalamus; caudally, the midbrain connects to the pons (Figure 4–3). During development, the dorsal surface of the mesencephalic vesicle becomes a structure called the tectum or roof, while the ventral region becomes the tegmentum or floor of the midbrain. The smaller tectum and larger tegmentum are separated at the midline by the narrow CSF-filled cerebral aqueduct, which connects rostrally with the third ventricle and caudally with the fourth ventricle. As the midbrain develops, large white matter regions called the cerebral peduncles form ventral to and laterally around the tegmentum.

During development, the tectum differentiates into 2 structures: the superior colliculus and inferior colliculus. Together, the superior and inferior colliculi are called the corpora quadrigemina. The superior colliculus, which is called the optic tectum in lower vertebrates, receives direct input from the retina and visual cortex and is a primary integration center that provides key output to the thalamus and nearby nuclei of the oculomotor nerve (CN III) and the trochlear nerve (CN IV). One function of the superior colliculus is to control visual reflexes, such as eye movements, lens shape, and pupil diameter. The inferior colliculus is involved in processing auditory information. It receives input from several brainstem nuclei in the auditory pathway and the auditory cortex and provides a major output to the thalamus. Although the tectum is localized to the midbrain region, the tegmentum extends through the pons.

The midbrain tegmentum contains 4 regions distinguished by their pigmentation. The substantia nigra is a large highly pigmented nucleus that consists of the pars reticulata and pars compacta. The pars compacta contains dopaminergic neurons that project to the caudate nucleus and putamen, which form the striatum of the basal ganglia involved in mediating movement and motor coordination. The striatal neurons in turn project to neurons in the pars reticulata, which, by projecting fibers to the thalamus, are part of the output system of the striatum. Located near the midline, the ventral tegmental area is the origin of dopaminergic neurons of the mesocorticolimbic dopamine system that is widely implicated in the reward circuitry of the brain. The red nucleus is a large centrally located structure that receives inputs from the motor and sensory cortices via the corticorubral tract and from the cerebellum via the cerebellar peduncles; it gives rise to the rubrospinal tract, providing motor information to the spinal cord. The periaqueductal gray functions as a primary control center for descending pain modulation.

The midbrain contains a number of other important nuclei and white matter tracts, including the mesencephalic nucleus of the trigeminal nerve (CN V) involved in proprioception of the face and a portion of the reticular formation, a neural network that is involved in arousal and alertness (see later discussion). The cerebral peduncles house the crus cerebri, which contain the descending motor axons of the corticospinal, corticobulbar, and corticopontine tracts. The ascending sensory axons from the spinothalamic and dorsal column medial lemniscus (DCML) tracts are located more dorsally, closer to the tegmentum.

THE PONS

Caudal to the midbrain is the pons (Figure 4–4). The dorsal/posterior border of the pons is separated from the cerebellum by the aqueduct of Sylvius and, more inferiorly, by the fourth ventricle. The pons appears as a broad anterior bulge rostral to the medulla that consists of 2 pairs of thick stalks called cerebellar peduncles; the specific nuclei in the pons are located in the medial regions. An important function of the pons is to relay information between the cortex and the cerebellum. The pons contains a number of other important nuclei, including those involved in automatic functions and numerous CN nuclei.

The pons can be broadly divided into 2 parts: the basilar part of the pons, located ventrally, and the pontine tegmentum, located dorsally. The ventral pons contains numerous pontine nuclei that relay signals between the cerebral cortex and the cerebellum. The pontine nuclei receive inputs from many parts of the cerebral cortex including the motor cortex and auditory, visual, somatosensory, and association regions, as well as subcortical areas. In turn, the pontine nuclei project, via the middle cerebellar peduncle, to the cerebellar cortex and interposed nucleus. Information relayed via the corticopontocerebellar tract represents a critical contribution from the cortex to the cerebellar regulation of motor function and movement. In addition, the cerebellum has been implicated in several cognitive processes (see later discussion).

The pons is involved in several automatic functions necessary for life. In the dorsal posterior pons lie nuclei that have critical functions in breathing (respiration), sleep, and swallowing. In addition, the pons contains nuclei involved in bladder control, hearing, equilibrium, taste, eye movement, facial expressions, facial sensation, and posture. The pons contains the breathing pneumotaxic center, which regulates the change from inhalation to exhalation. The pons has been implicated in sleep paralysis and rapid eye movement (REM) sleep and may also play a role in sleep cycles and generating dreams. The pons contains a number of CN nuclei, including the pontine nucleus and motor nucleus for the trigeminal nerve (CN V), the abducens nucleus (CN VI), the facial nerve nucleus (CN VII), and the vestibulocochlear nuclei (vestibular nuclei and cochlear nuclei) (CN VIII). The functions of these 4 CNs (V to VIII) include sensory roles in hearing, equilibrium, and taste and in facial sensations such as touch and pain, as well as motor roles in eye movement, facial expressions, chewing, swallowing, and the secretion of saliva and tears.

Similar to the midbrain, the pons contains the descending motor and ascending sensory white matter tracts between the forebrain, medulla, and spinal cord. Other white matter regions include the superior cerebellar peduncles, which contain the main output route from the cerebellum and extend to the red nucleus in the midbrain or to the thalamus. The inferior cerebellar peduncle is a region of the medulla that contains tracts that connect the spinal cord and medulla with the cerebellum.

THE MEDULLA

The medulla is the caudal-most region of the brainstem situated between the pons and the spinal cord and ventral/anterior to the cerebellum. The medulla merges with the spinal cord at the opening called the foramen magnum at the base of the skull. The lateral areas of the medulla form the inferior cerebellar peduncles. In the upper or superior part, the dorsal surface of the medulla is formed by the fourth ventricle. In the lower or inferior part, the fourth ventricle narrows at the obex in the caudal medulla and becomes the central canal.

Motor and sensory tracts passing between the brain and spinal cord pass through the medulla. The medulla contains the pyramids, a region where the crossing (decussation) of motor axons that form the lateral corticospinal tract occurs, and the medial lemniscus, where decussation of sensory axons of the DCML tract takes place. The medulla contains CN nuclei (Figure 4–5) and other nuclei and serves as a major processing center involved in automatic, autonomic, and somatic functions.

Automatic functions and reflexes of the medulla include breathing, vomiting, sneezing, coughing, swallowing, and balance. Two of the major regions (the dorsal and ventral respiratory groups) of the respiratory center are located in the medulla, with the other regions located in the pons. The respiratory center receives input from chemoreceptors, mechanoreceptors, the cerebral cortex, and the hypothalamus and is responsible for generating and maintaining the rhythm and rate of respiration and adjusting those to physiologic needs. Some other reflexes may involve the raphe nucleus and the solitary nucleus (SN). The SN contains a series of sensory nuclei forming a vertical column of gray matter in the medulla. The nuclei are part of the medullary reticular formation and contain serotonergic neurons (see later discussion).

Four CNs originate from the medulla oblongata; these are the glossopharyngeal nerve (CN IX), vagus nerve (CN X), accessory nerve (CN XI), and hypoglossal nerve (CN XII), which serve both autonomic and somatic functions. Autonomic functions include maintaining blood pressure and regulation of heart rate and contraction force, with control by the cardiovascular centers. The medulla also contributes to autonomic control of the digestive system. Somatic motor and sensory functions include taste, hearing, and control of muscles of the face and neck. The SN has been implicated in regulation of autonomic functions since it receives input from the facial, glossopharyngeal, and vagus nerves. The SN projects to the reticular formation, parasympathetic preganglionic neurons, hypothalamus, and thalamus.

The medulla also contains important relay nuclei. Forming the olivary nucleus (or olive), the superior olivary nuclei form an important component of the ascending and descending auditory pathways of the auditory system, whereas the inferior olivary nuclei coordinate signals from the spinal cord to the cerebellum to regulate motor coordination and learning. The cuneate nucleus and gracile nucleus are part of DCML pathway, carrying fine touch and proprioceptive information from the upper body (cuneate) and the legs and trunk.

Phylogenetically one of the oldest parts of the brain, the reticular formation is a set of interconnected nuclei that are located throughout the brainstem, from the midbrain to the lower medulla. The reticular formation contains the raphe nuclei, which encompass the majority of serotonergic neurons in the CNS and have been implicated in mood, pain, alertness, and memory. One of its 2 components, the ascending reticular formation is called the reticular activating system (RAS), is responsible for the sleep–wake cycle, and controls various levels of alertness. The RAS projects to the thalamus, which transmits this information to the cortex. The other component, the descending reticular formation (DRF), is involved in posture and equilibrium, as well as motor movement and autonomic functions. The DRF receives information from the hypothalamus and some fibers from the corticobulbar tract that originate in the motor cortex and are involved in eye movement. Other corticobulbar fibers innervate CNs directly. Nuclei in the DRF have also been implicated in reflexes such as coughing, chewing, swallowing, and vomiting.

THE CRANIAL NERVES

The CNs are a set of 12 paired nerves that emerge from the brain. The first 2 CNs arise from the cerebrum, whereas the remaining 10 emerge from the brainstem. The CNs provide motor and sensory innervation to structures within the head, face, and neck and autonomic regulation of organs in the body. Assigned Roman numerals I to XII based on the order from which they emerge from the cerebrum or brainstem, the CNs are also named based on their function or appearance. The CNs serve functions such as smell, sight, eye movement, feeling in the face, balance, hearing, movement of the mouth and tongue for speech, chewing and swallowing, and parasympathetic control of heart rate, GI peristalsis, and sweating.

The olfactory nerve (CN I) and optic nerve (CN II) are considered CNS nerves because they emerge from the cerebrum and the tracts travel within the CNS. CNs III to XII are considered part of the PNS. The nuclei for CNs III to XII lie in the brainstem, and their axons exit or enter the skull bone and relay information between the brain and the body, primarily to and from regions of the head and neck. A thirteenth CN designated 0 in lower vertebrates does not appear to have a function in humans.

The CNs provide sensory innervation that includes general somatic sensation such as touch, temperature, and pain; visceral somatic sensation from internal regions; and special sense innervation such as smell, vision, taste, hearing, and balance. Motor function can involve somatic motor or autonomic motor innervation. Hence, CNs can include fibers for somatic sensory, visceral sensory, special sensory, somatic motor, or autonomic motor functions. Some CNs contain only 1 type of fiber. Many of the CNs contain mixtures of fiber types.

The PNS CNs (III to XII) have nuclei in the brainstem, and their axons exit or enter the skull bone via foramina and innervate regions of the head, face, neck, and body on the same side from which they originate. CNs and the axons inside travel in regions within the skull called intracranial paths; they travel outside the skull via extracranial paths. The CN nuclei in the brainstem contain the cell bodies of the neurons that send or receive the axons that form the CNs. The midbrain of the brainstem has the nuclei of CN III and IV. The pons contains the nuclei of CNs V to VIII. The medulla houses the nuclei of CNs IX to XII.

All the CNs, except CNs I, II, and IV, have associated ganglia, which are groups of neuronal cell bodies that are located outside the brainstem. The sensory ganglia are directly correspondent to dorsal root ganglia of spinal nerves and are known as cranial sensory ganglia. Sensory ganglia exist for nerves with somatic sensory components: CNs V, VII, VIII, IX, and X. Parasympathetic ganglia are present for the autonomic components of CNs III, VII, IX, and X that innervate the glands in the head and neck and include the ciliary, pterygopalatine, submandibular, and otic ganglion. In addition, the vagus nerve (CN X) supplies the output to parasympathetic ganglia that lie in the body, close to the organs they innervate in the chest and abdomen.

Considered part of the ANS, the general visceral afferent (GVA) fibers transmit sensory information about local changes in chemical and mechanical environments, including pain and reflex sensations, from the internal organs, glands, and blood vessels to the CNS. Unlike the efferent motor fibers of the ANS, the GVA fibers are not classified as sympathetic or parasympathetic. The CNs that contain GVA fibers include the facial nerve, glossopharyngeal nerve, and vagus nerve. CN GVA fibers are important in complex automatic motor acts such as swallowing, vomiting, and coughing.

CN I

The olfactory nerve conveys the sense of smell. Containing only special sensory fibers, the olfactory nerve is a purely sensory nerve in charge of transmitting olfactory sensation from the nose to the brain. The olfactory nerve originates in the olfactory epithelium and contains sensory axons (afferents) that extend to the olfactory bulb. Derived from the nasal (otic) placodes, neurons in the olfactory epithelium can be replaced and extend new axons within the nerve. Hence, the olfactory nerve is unique in that it is capable of some regeneration if damaged. The olfactory bulb extends axons via the olfactory tract, which transmits olfactory information to the primary olfactory cortex in the temporal lobe. The olfactory nerve is unmyelinated but covered with meningeal-like membranes. It is the shortest CN and does not exit the brain.

CN II

The optic nerve is dedicated to vision. Composed of axons from retinal ganglion cells, the optic nerve transsensory visual information from the retina of the eye to the brain. Emerging from the retina, the optic nerve travels through the optic canal, partially decussates in the optic chiasm and becomes the optic tract. The majority of optic tract axons terminate in the lateral geniculate nucleus of the thalamus, while a few project to nuclei in the midbrain and hypothalamus. The thalamus transmits visual perception information to the visual cortex in the occipital lobe. The few axons that terminate in the superior colliculus are responsible for reflexive eye movements and those that terminate in the pretectum control the pupillary light reflex. Axons that project to the suprachiasmatic nucleus in the hypothalamus are involved in circadian rhythms. The optic nerve is heavily myelinated by oligodendrocytes and is encased in the 3 meningeal layers. Since retinal ganglion neurons and axons do not regenerate, damage to the optic nerve can produce irreversible blindness.

CN III

The oculomotor nerve controls eye movements and pupil size. The oculomotor nerve originates in 2 nuclei in the midbrain called the oculomotor nucleus and Edinger-Westphal nucleus. The nerve enters the orbit via the superior orbital fissure to innervate muscles that enable most movements of the eye and that raise the eyelid. Located in the midbrain, the oculomotor nucleus controls striated muscle in levator palpebrae superioris and extraocular muscles except for the superior oblique muscle and the lateral rectus muscle. The Edinger-Westphal nucleus supplies parasympathetic nerve fibers via the ciliary ganglion to the eye to control the pupillae muscle for pupil constriction and the ciliary muscle for the accommodation reflex, the ability to focus on near objects as in reading. Sympathetic postganglionic fibers join the oculomotor nerve to innervate the superior tarsal muscle, a smooth muscle. CNs IV and VI also participate in control of eye movement.

CN IV

The trochlear nerve is a somatic motor nerve that enters the orbit through the superior orbital fissure and innervates a single muscle, the superior oblique muscle of the eye. This eye muscle ends in a tendon, which passes through a fibrous loop called the trochlea that functions through a pulley-like mechanism to make the eyeballs move and rotate. The nucleus of the trochlear nerve originates in the midbrain immediately below the oculomotor nucleus. The trochlear nerve is the smallest nerve in terms of its axon number but has the longest intracranial path and is the only CN that exits from the dorsal aspect of the brainstem.

CN V

The trigeminal nerve contains both sensory and motor fibers and is responsible for sensation in the skin of the face and mouth and motor functions such as biting, chewing, and swallowing. The largest of the CNs, its name derives from the fact that it contains 3 branches, the ophthalmic nerve (V1), the maxillary nerve (V2), and the mandibular nerve (V3). The ophthalmic and maxillary nerves are purely somatic sensory, whereas the mandibular nerve supplies both somatic motor and some sensory functions.

The sensory functions of the trigeminal nerve are to provide the tactile, motion, position, temperature, and pain sensations of the top and front of the head, the face, and the mouth. Each of the 3 nerves innervates specific regions of the front of the head and face, with V1 innervating the approximate dorsal third of the face and head, V2 innervating the middle third, and V3 providing information from the approximate ventral third of the face.

The 3 trigeminal branches converge on the trigeminal ganglion, a sensory ganglion. It contains the cell bodies of incoming sensory nerve fibers from the face. From the trigeminal ganglion, a single large sensory root enters the brainstem at the level of the pons and synapses on the sensory nuclei. Immediately adjacent to the sensory root, a smaller motor root emerges from the pons at the same level. The trigeminal motor nuclei are located in the pons, and the motor fibers pass through the trigeminal ganglion en route to their muscle targets.

CN VI

The abducens nerve is also known as the abducent nerve. It is a responsible for somatic motor output to control the lateral rectus muscle of the ipsilateral eye. In humans, this allows the eyes to move horizontally and is responsible for outward, lateral gaze. The abducens nerve nucleus is present in the pons, and the nerve exits the brainstem at the junction of the pons and the medulla and ascends upward to the eye. The exact control of eye movements requires input from integration centers in the brain that coordinate the output from the oculomotor, trochlear, and abducens nuclei, which control the 6 extraocular muscles.

CN VII

The facial nerve is a mixed nerve that has 4 components with distinct functions. The facial nerve is responsible for producing facial expressions by voluntary movements, including brow wrinkling, teeth showing, frowning, eyes closing, lip pursing, and cheek puffing. It also controls the stapedius muscle of the ear. The facial nerve also functions in the transmission of taste sensations from the anterior two-thirds of the tongue and oral cavity. A somatic sensory component innervates the external ear. It also supplies preganglionic parasympathetic fibers to several head and neck ganglia and signals to the salivary, mucous, and lacrimal glands. The facial nerve’s motor component originates in the facial nerve nucleus in the pons, and the sensory nuclei are located near the pons–medulla junction. The section of the facial nerve that arises from the sensory root is also known as the intermediate nerve. The geniculate ganglion contains the cell bodies of the sensory component of the intermediate nerve. The nerve traverses the facial canal, through the parotid gland, and divides into 5 branches.

CN VIII

The vestibulocochlear nerve transmits hearing (sound) information and balance (equilibrium) information from the inner ear to the brain. It contains 2 functionally separate nerves, the vestibular nerve and the cochlear nerve, which are both sensory nerves that combine in the pons. The vestibular nuclei complex, situated in the pons and medulla, receives input from 5 sensory organs in the vestibules and semicircular canal of the inner ear. The vestibular ganglion includes the cell bodies of the sensory neurons. The vestibular nerve transmits information about balance and movement and is an important component of the vestibulo-ocular reflex, which keeps the head stable and allows the eyes to track moving objects.

The ventral and dorsal cochlear nuclei, located in the inferior cerebellar peduncle, receive information from the cochlear nerve, also known as the auditory nerve, which transmits sound information for the sensation of hearing. Sound waves are detected by hair cells in the cochlea that send information to the spiral ganglia, which house the cell bodies of neurons of the cochlear nerve, and information is then transmitted to the cochlear nuclei.

CN IX

The glossopharyngeal nerve is a mixed nerve, consisting of both sensory and motor nerve fibers, and is responsible for swallowing, the gag reflex, taste sensation from the back of the tongue, and saliva production. It contains somatic sensory fibers that originate in the tonsils, pharynx, middle ear, and posterior third of the tongue. It also contains special sense fibers from the posterior third of the tongue, and GVA fibers from the carotid sinus and bodies. These various sensory fibers terminate in nuclei in the medulla. The motor fibers originate in nuclei in the medulla. Parasympathetic fibers innervate the parotid salivary gland and glands of the posterior tongue. Somatic motor fibers innervate the stylopharyngeus muscle, which provides voluntary muscle control that elevates the pharynx during swallowing and speech. GVAs synapse on neurons of the nucleus of the solitary tract.

CN X

The vagus nerve is also known as the pneumogastric nerve. The vagus nerve supplies motor parasympathetic fibers to all the organs, except the adrenal glands, from the neck down to the second segment of the transverse colon. The vagus nerve sends somatic and visceral sensory information about the body’s organs to the brain, with estimates that 80% to 90% of the nerve fibers in the vagus nerve are afferent (sensory) nerves. Vagal GVAs carry information from aortic, cardiac, pulmonary, and GI receptors and synapse on neurons of the nucleus of the solitary tract.

The vagus nerve is responsible for such varied tasks as regulation of heart rate, GI peristalsis, sweating, the gag reflex, and satiation following food consumption. It also controls a few skeletal muscles, including muscles of the mouth and larynx involved in speech, swallowing, and keeping the larynx open for breathing. The vagus nerve also has a minor sympathetic function via peripheral chemoreceptors. Upon leaving the medulla between the medullary pyramid and the inferior cerebellar peduncle, it extends through the jugular foramen, then passes into the carotid sheath between the internal carotid artery and the internal jugular vein below the head, to the neck, chest, and abdomen, where it contributes to the innervation of the viscera.

CN XI

The accessory nerve is also called the spinal accessory nerve. The accessory nerve provides motor innervation from the CNS to 2 neck muscles, the sternocleidomastoid, which tilts and rotates the head, and the trapezius muscle, which has several actions on the scapula, including shoulder elevation and adduction of the scapula. Thus, the accessory nerve governs movements of the head and shoulders. Most of the fibers of the accessory nerve originate in neurons situated in the upper spinal cord. These fibers enter the skull through the foramen magnum and proceed to exit the jugular foramen with CNs IX and X. Due to its unusual course, the accessory nerve is the only nerve that enters and exits the skull. Traditional descriptions of the accessory nerve divide it into 2 components: a spinal component and a cranial component. However, contemporary characterizations of the nerve regard the cranial component as separate and part of the vagus nerve.

CN XII

The hypoglossal nerve is a somatic motor nerve that, similar to the glossopharyngeal and vagus nerves, is also involved in tongue muscles, swallowing, and speech. A nerve with solely motor function, the hypoglossal nerve provides motor control of the extrinsic muscles of the tongue (genioglossus, hyoglossus, and styloglossus) and the intrinsic muscles of the tongue. These represent all muscles of the tongue except the palatoglossus muscle, which is innervated by the vagus nerve. These muscles are involved in moving and manipulating the tongue. The hypoglossal nerve also supplies movements including clearing the mouth of saliva and other involuntary activities. The hypoglossal nucleus interacts with the reticular formation, which is involved in the control of several reflexive or automatic motions, and several corticonuclear originating fibers supply innervation, aiding in unconscious movements relating to speech and articulation. The hypoglossal nerve (CN XII) is unique in that it is innervated from the motor cortex of both hemispheres of the brain. See Table 4–1 for a summary of the CNs.

THE CEREBELLUM

Lying underneath the forebrain and adjacent to the brainstem is the cerebellum (Figure 4–6). The cerebellum receives substantial motor and sensory inputs via the cerebellar peduncles, directly from the brainstem and spinal cord and indirectly from the cerebral cortex. Primarily a movement control center, cerebellar functions include control of posture and balance, coordination of voluntary movements that result in smooth and balanced muscular activity of parts of the body, and learning motor behaviors. The cerebellum has also been implicated in mood and cognitive functions including language, attention, and mental imagery. Receiving extensive inputs, the cerebellar intrinsic circuits are thought to have substantial computational capacity in producing their outputs.

The cerebellum rests at the back of the cranial cavity, with the appearance of being a separate structure lying beneath the cerebral lobes, and is separated from the occipital lobes by a sheet of fibers called the cerebellar tentorium. However, the cerebellum is robustly connected with other regions of the CNS via the cerebellar peduncles. The cerebellum has fissures that divide it into 3 lobes. The primary fissure divides the anterior lobe from the posterior lobe, which are connected in the midline by the vermis. The posterolateral fissure divides the posterior lobe from the medial flocculonodular lobe. Each of the 3 lobes has a left and right half, and each lobe consists of an inner medulla of white matter and a richly folded thin outer layer of cortical gray matter.

The continuous cortical surface contains finely spaced parallel grooves with the appearance of an accordion. Although it represents only 10% of the brain mass, the cerebellum contains as many neurons as the entire cerebrum, but many fewer types of neurons. The outer cortical layer consists of a regular 3-layer arrangement that contains Purkinje neurons and granule neurons. The majority of inputs reach the cerebellar cortex, where Purkinje neurons integrate incoming signals and send outputs to the deep cerebellar nuclei located in the white matter interior and the vestibular nuclei. Hence, the majority of outputs from the cerebellum to the brainstem and thalamus occur via the deep cerebellar nuclei.

The cerebellum has 3 functional subdivisions and is involved in control of both conscious and unconscious movement. The flocculonodular lobe and adjacent vermis is called the vestibulocerebellum (archicerebellum) and is involved in balance and eye movements. The spinocerebellum (paleocerebellum) includes the vermis and paravermis in the anterior lobe and paramedian lobules and functions in posture and proprioception. The cerebrocerebellum (neocerebellum or pontocerebellum) makes up the lateral hemispheres of the anterior and posterior lobes and functions in control of voluntary movement.

The cerebral cortex provides the largest source of inputs to the cerebellum, although indirectly via the pons. Corticopontine fibers originate in the frontal lobe motor cortex and the parietal lobe somatosensory cortex and visual association areas, which project to the pontine nuclei in the pons. Neurons in the pons send outputs to the cerebellum by the middle cerebellar peduncles. The target of the pontine output is the cerebrocerebellum, which functions in coordination and smoothing of complex motor movements, evaluation of sensory information for action, and some cognitive functions. The cerebrocerebellum sends output via the dentate nucleus and fibers in the superior cerebellar peduncles to both the red nucleus and the ventral lateral nucleus of the thalamus. Hence, the thalamus provides the feedback to the motor cortex for the adjustment of movement.

The vestibulocerebellum is involved in maintenance of balance and coordinating eye movements. It receives direct input from the vestibular nerve and the vestibular nuclei and sends output to the medial and lateral vestibular nuclei by 2 pathways. One output pathway originates directly from the cerebellar cortex and sends fibers to the vestibular nuclear complex in the brainstem. The other output occurs via nuclei in the flocculonodular lobe. The vestibulocerebellum also receives visual input from the superior colliculus via the superior peduncles and is involved in coordinating eye movements and speech.

The spinocerebellum regulates body and limb movements involved in proprioception and posture. It receives proprioception input from the spinocerebellar tract, other dorsal columns of the spinal cord, and the trigeminal nerve nuclei. It also receives vestibular input and sensory information from visual and auditory systems. The spinocerebellum sends fibers to deep cerebellar nuclei (including the fastigial and interposed nuclei), for modulation of descending motor systems. The fastigial and interposed nuclei project to the cerebral cortex, via the thalamus, and to the brainstem, via the red nucleus, reticular formation in the pons, and vestibular nuclei in the medulla.

Numerous studies support the conclusion that the cerebellum plays an important role in some types of motor learning, in particular those voluntary motor actions that require fine adjustments for performance. In addition, a well-studied cerebellar learning task involves involuntary muscle contractions that underlie the eye blink conditioning response. Lesions or pharmacologic disruption of circuits to specific deep cerebellar nuclei or cerebellar cortical regions abolish learning in the conditioned eye blink response. Studies have identified candidate learning circuits involving Purkinje cells and their synapses, which undergo long-term plasticity.

THE SPINAL CORD

The spinal cord is a long, thin, tubular bundle of nervous tissue that is continuous with the medulla and emerges from the foramen magnum, where it enters the spinal (vertebral) canal at the beginning of the cervical vertebrae (Figures 4–7 and 4–8). It extends down to the first or second lumbar region, terminating in the conus medullaris. Between 40 and 50 cm long, the human spinal cord diameter is variable along its length, between 0.6 and 1.3 cm. Two prominent grooves, or sulci, run along its length. The posterior median sulcus is the groove in the dorsal side, and the anterior median fissure is the groove in the ventral side. The spinal cord is protected by the meninges and the bony vertebral column. In the median, the central canal is an extension of the fourth ventricle and contains CSF.

Along its length, the spinal cord connects with the spinal nerves of the PNS. The human spinal cord contains 31 segments, consisting of cervical, thoracic, lumbar, sacral, and coccygeal regions, with each region connecting to a spinal nerve on either side. The spinal nerves enter and exit the cord via roots, which then merge into bilaterally symmetrical pairs of spinal nerves. The spinal roots, nerves, and associated ganglia functionally connect the spinal cord to the skin, muscles, joints, and viscera.

Functionally, the spinal cord transmits both somatic and autonomic motor and sensory information between the brain and the body and accomplishes important integration tasks. The spinal cord white matter is found in the more lateral regions and contains ascending sensory and descending motor tracts that are often described as columns. Located more medially, spinal cord gray matter contains motor neurons, secondary sensory neurons, and interneurons (Figure 4–9). Ten regions of gray matter are named the Rexed laminae and are numbered from dorsal to ventral. The dorsal (posterior) horns are dedicated to sensory functions (laminae I to VI). The ventral (anterior) horns are involved in motor functions (laminae VIII and IX). Between the horns is the intermediate gray region (laminae VII and X).

The spinal cord plays a major role in transmission of both somatic and visceral sensory information to the brain. Axons from somatosensory neurons and GVAs enter the spinal cord via the dorsal root from the dorsal root ganglia. Depending on the sensory modality relayed, the entering axons either ascend in the cord, forming some of the sensory tracts, or synapse with sensory relay neurons, which are located in the dorsal horn and extend axons to form other sensory tracts. The 3 main ascending white matter tracts are the DCML tract, the spinothalamic tracts, and the spinocerebellar tracts.

The DCML transmits sensory information about fine touch, vibration, 2-point discrimination, and conscious proprioception. In the DCML, the primary somatosensory axons enter the cord and form the dorsal column. If an axon enters below T6, it travels in the fasciculus gracilis of the DCML. If the axon enters above T6, it travels in the fasciculus cuneatus of the DCML. For both, the primary sensory axons ascend in the dorsal column to the lower medulla, where they synapse on sensory relay neurons (called secondary sensory neurons) located in the nucleus gracilis or nucleus cuneatus. Axons from the medullary neurons form the internal arcuate fibers, which cross and ascend to become the medial lemniscus. These axons connect to neurons in the thalamus, and the thalamic neurons project to the primary somatosensory cortex.

The spinothalamic tract (also called the anterolateral system) transmits crude touch, pain, and temperature sensation. Axons from the primary somatosensory neurons enter the spinal cord and synapse on secondary sensory neurons located in the dorsal horn. The axons of the secondary sensory neurons cross over to the contralateral side of the spinal cord and form the spinothalamic tract, which ascends in the anterolateral region of the white matter and extend all the way to the thalamus. The thalamic neurons project to the primary somatosensory cortex, cingulate cortex, and insular cortex. Traveling along side the spinothalamic tract, the spinoreticular tract and spinotectal tracts also transmit information to the brainstem.

The spinocerebellar tracts transmit unconscious proprioception from the muscles and joints to the cerebellum. The axons from primary somatosensory neurons enter the spinal cord via the dorsal root and synapse on secondary sensory neurons in or near the dorsal horn. Depending on where the sensory information originates and enters the spinal cord, the ascending axons sort into 1 of 4 tracts called the dorsal (posterior), ventral (anterior), and rostral spinocerebellar tracts and the cuneocerebellar tract. After traversing the medulla, the axons travel via the inferior cerebellar peduncle to innervate the ipsilateral cerebellum.

Part of the ANS, GVA fibers transmit visceral sensory information about local changes in the chemical and mechanical environments from the internal organs, glands, and blood vessels to the CNS. The GVAs transmit conscious sensations, such as gut distention and cardiac ischemia, and unconscious sensations, such as blood pressure and chemical composition of the blood. Some of the key functions of GVAs are to initiate autonomic reflexes at the local, ganglion, spinal, and supraspinal levels.

Visceral sensory neuronal cell bodies are located in the dorsal root ganglia of the spinal nerves. After they enter the spinal cord, the axons branch extensively and synapse on viscerosomatic neurons in the dorsal horn and intermediate gray matter. Visceral sensation is carried primarily by the spinothalamic and spinoreticular pathways, which transmit visceral pain and sexual sensations. The DCML tract may relay sensations related to micturition, defecation, and gastric distention. After relay in the thalamic nuclei, viscerosensory inputs project to the insula and other cortical autonomic areas. Viscerosomatic neurons in the dorsal gray regions that receive convergent visceral and somatic inputs have been implicated in referred pain.

The spinal cord white matter contains descending somatic motor tracts involved in both voluntary and involuntary control of muscle contraction (Figure 4–10). The axons in these tracts synapse on lower motor neurons (LMNs) and spinal interneurons (SIs) in the ventral horn. The 2 corticospinal tracts (CSTs) originate in the motor cortex with upper motor neurons. About 85% to 90% of the axons cross to the contralateral side at the pyramids of the medulla, forming the lateral CST. The remaining 10% to 15% of uncrossed axons descend on the ipsilateral side, forming the anterior CST, with most axons crossing to the contralateral side of the cord right before synapsing. The lateral CST axons synapse on dorsolateral (DL) LMNs in the ventral horn and control distal limb movement; these DL LMNs are located in the cervical and lumbosacral enlargements within the spinal cord. Anterior CST axons synapse on ventromedial (VM) LMNs in the ventral horn. The VM LMNs control the large, postural muscles of the axial skeleton and are located along the length of the spinal cord.

Four additional motor tracts (called extrapyramidal tracts) extend axons down the spinal cord to LMNs and SIs. These tracts originate with upper motor neurons located in specific nuclei in the brainstem. Their tracts include the rubrospinal, vestibulospinal, tectospinal, and reticulospinal tracts. The rubrospinal tract descends with the lateral CST and synapses on cervical DL LMNs involved in voluntary control of arm muscles. The remaining 3 tracts descend with the anterior CST, synapse on VM LMNs, and are involved in involuntary muscle control for reflexes, locomotion, complex movements, and postural control.

LMNs in the dorsal horn receive descending inputs directly from the upper motor neurons. They also receive inputs from SIs, including a type of SI called propriospinal neurons that interconnect multiple spinal cord segments. LMNs also receive direct sensory signals from 1a somatosensory neurons and both excitatory and inhibitory SIs that relay sensory information. The axons of the LMNs exit through the ventral roots of the spinal cord and merge with the sensory components to form the spinal nerves, eventually emerging from the nerve to innervate its specific skeletal muscle.

For the autonomic motor system, preganglionic sympathetic neurons originate from the thoracolumbar region of the spinal cord, specifically at T1 to L2-L3 (Figure 4–11). A gray matter region in the intermediolateral nucleus of the lateral horn contains these neurons. These are analogous to somatic LMNs, with axons that leave the cord via the ventral root, but instead travel to either the paravertebral or prevertebral ganglia, where they synapse with the postganglionic sympathetic neurons, which extend their axons to their targets. Although the majority of parasympathetic motor neurons emerge from the brainstem via CNs, 3 spinal nerves in the sacral region (S2 to S4), commonly referred to as the pelvic splanchnic nerves, include parasympathetic preganglionic neurons located in the spinal cord. The targets of the splanchnic nerves include the bladder, colon, and genital organs.

In addition to motor and sensory relaying functions, the spinal cord contains neuronal circuits that generate spinal reflexes, such as the stretch reflexes involved in balance and the withdrawal reflex involved in removing a limb from a noxious stimulus. The circuits within the spine also contribute to more complex movements involving central pattern generators. For example, networks responsible for locomotion have been shown to be distributed throughout the lower thoracic and lumbar regions of the mammalian spinal cord.

THE SPINAL NERVES

The spinal nerves are components of the PNS that transmit motor and sensory signals between the spinal cord and the body. As mixed nerves, the spinal nerves include both somatic motor axons that control the actions of striated muscles and somatic sensory fibers that receive sensory information from the skin, muscles, and joints. Many spinal nerves also contain autonomic motor and visceral sensory components that provide information to and from organs, smooth muscles, and glands in the body. Humans have 31 pairs of spinal nerves, 1 on each side of the vertebral column, which arise from the spinal cord and are named for the spinal cord segment where they originate, with 8 cervical pairs, 12 thoracic pairs, 5 lumbar pairs, 5 sacral pairs, and 1 coccygeal pair. The spinal nerves branch and reorganize to form what are called peripheral nerves.

Sensory axons enter the spinal cord via small rootlets that combine to form the dorsal root (Figure 4–12). Sensory neuron cell bodies form the dorsal root ganglia that lie just outside the spinal cord. The sensory axons are called the general somatic afferents, which transmit information from the skin, muscles, and tendons, and the GVAs, which send information from the visceral organs. Motor axons leave the spinal cord via small rootlets that combine to form the ventral root. Motor neuron cell bodies lie in the ventral or lateral horn gray matter in the spinal cord itself. The motor axons include the general somatic efferents to striated muscle and the general visceral efferents, which are autonomic (sympathetic and a few parasympathetic) axons that transmit impulses to smooth muscle, cardiac muscle, and glands. The ventral and dorsal roots also provide the anchorage and fixation of the spinal cord to the vertebral cauda.

Spinal nerves initially form by the union of sensory axons from the dorsal root and motor axons from the ventral root. After joining, the spinal nerves exit the spinal canal and vertebral column. All spinal nerves, except the first spinal nerve C1 pair, emerge from the vertebral column through the intervertebral foramina between adjacent vertebrae. C1 emerges between the occipital bone and the first vertebra called the atlas. After it exits, each nerve then divides into branches called the dorsal ramus, the ventral ramus, and the rami communicates (Figure 4–13).

The dorsal ramus contains nerves that supply the dorsal portion of the trunk, with somatic and visceral motor and somatic sensory information relayed to and from the back muscles, dorsal muscles, and skin (Figure 4–14). The ventral ramus supplies somatic and visceral motor and sensory information to and from the ventrolateral body surface, structures in the body wall, trunk, and limbs. The rami communicantes contain autonomic axons that transmit sympathetic motor and visceral sensory information to and from the visceral organs. Additional small branches from the spinal nerves, called meningeal branches, supply nerve function to the vertebrae themselves, including the ligaments, dura, blood vessels, intervertebral disks, facet joints, and periosteum.

In the thoracic region, the ventral rami, which form the intercostal nerves, remain distinct from each other, and each innervates a narrow strip of muscle and skin along the sides, chest, ribs, and abdominal wall (Figure 4–15). In other regions, ventral rami converge with each other to form networks of nerves called nerve plexuses. Within each nerve plexus, fibers from various ventral rami branch and become redistributed such that each nerve exiting the plexus has fibers from several different spinal nerves, which travel together to their target location, mainly to the limbs. The major nerve plexuses are the cervical, brachial, lumbar, and sacral plexuses.

The cervical plexus is formed by the ventral rami from spinal nerves C1 to C4. The cervical plexus innervates muscles of the neck and diaphragm and the skin of the neck and upper chest. One branch forms the phrenic nerve, which provides motor innervation of the diaphragm. The brachial plexus is formed by ventral rami from spinal nerves C5 to T1. The brachial plexus provides almost all the innervation of the upper limb. The lumbar plexus contains ventral rami from spinal nerves L1 to L4. The sacral plexus contains ventral rami from spinal nerves L4 to S4. Together, the lumbar and sacral plexuses innervate the pelvic girdle and lower limbs.

Each spinal nerve receives a branch called a gray ramus communicans from the adjacent paravertebral ganglion of the sympathetic trunk. The gray rami contain postganglionic nerve fibers of the sympathetic neurons. The white rami communicantes exist only at the levels of the spinal cord where the intermediolateral cell column is present (T1-L2), which contain the sympathetic motor neuron cell bodies and are responsible for carrying preganglionic nerve fibers from the spinal cord to the adjoining paravertebral sympathetic ganglia. The 3 sacral parasympathetic spinal nerves in S2-S4 emerge from the spinal cord and form nerve plexuses with sympathetic fibers called the pelvic splanchnic nerves (Figure 4–16). Table 4–2 lists the peripheral nerves and their functions.

THE ENTERIC NERVOUS SYSTEM

Formerly thought to be part of the ANS, the ENS is now considered a separate component of the PNS. The ENS consists of a system of approximately 200 to 600 million neurons and glial cells distributed in many thousands of small ganglia in the lining of the GI system. Two types of ENS ganglia have been identified, called the myenteric and submucosal plexuses. The myenteric plexus forms a continuous network that extends from the upper esophagus to the internal anal sphincter. Submucosal ganglia and connecting fiber bundles form plexuses in the small and large intestines, but not in the stomach and esophagus. The ENS forms a neuronal circuitry that controls or modulates most aspects of GI function, including motility and GI transit, secretion and adsorption, water and electrolyte balance, chemical sensing, and communication between intestinal segments and the CNS.

The ENS is derived from the neural crest. A variety of different subtypes of enteric neurons and glia differentiate from neural crest progenitors that undergo proliferation and migration into the GI tract during embryonic and postnatal development. The ENS includes motor (efferent) neurons, sensory (afferent) neurons, and interneurons, all of which make the ENS capable of generating reflexes and acting as an integration center in the absence of input from the CNS or ANS. The ENS controls various types of primary GI effector cells, including epithelial cells and smooth muscle cells, which mediate GI functions. ENS sensory neurons report on mechanical and chemical conditions. Motor neurons control peristalsis, the coordinated contraction and relaxation of intestinal smooth muscles, and churning of intestinal contents. Contact with the GI epithelium can modulate nutrient uptake. Alteration of regional blood flow can allow responses to metabolic needs. Other neurons control the secretion of enzymes. ENS interneurons coordinate the various activities.

In addition to containing the ENS, the digestive system is innervated and controlled by both the CNS and ANS. For example, movements of the striated muscles of the esophagus are determined by neural pattern generators in the CNS. Sympathetic stimulation causes inhibition of GI secretion and motor activity and contraction of GI sphincters and blood vessels. Conversely, parasympathetic stimuli typically stimulate these digestive activities. Thus, although the ENS can function as an independent system, it works in concert with CNS reflex and ANS command centers to control digestive function. Moreover, there is bidirectional information flow between the ENS and CNS and between the ENS and ANS, via the pelvic nerves and ANS pathways. Neurons also project from the ENS to prevertebral ganglia and the gallbladder, pancreas, and trachea. Approximately 30 different types of neurotransmitters have been identified in the ENS, including acetylcholine and glutamate. Interestingly more than 90% of the body’s serotonin and about 50% of the body’s dopamine are found in the intestine.

THE MENINGES & VENTRICULAR SYSTEM

Both the brain and spinal cord are covered and protected by the meninges (Figure 4–17), which is composed of 3 layers: the dura mater, arachnoid mater, and pia mater. The dura mater is the outermost layer, which is a thick, tough double membrane composed of collagenous connective tissue. The middle layer is called the arachnoid mater because of spider web–like processes called arachnoid trabeculae. Composed of a fine collagenous layer, regions of the arachnoid mater extend toward the third layer, the pia mater, and also contain the arachnoid granulations and villi that resorb CSF. The pia mater is a thin, delicate translucent layer of connective tissue that attaches to the outermost region of neural tissue, called the glia limitans, a thin barrier of astrocyte foot processes associated with the parenchymal basal lamina.

The arachnoid mater is attached to the dura mater, whereas the pia mater is attached to the CNS tissue. Between the arachnoid mater and the pia mater is the subarachnoid space, which contains CSF and blood vessels. The CSF serves to support the CNS and to cushion and protect it from physical shock and trauma. The falx cerebri is a double-fold of dura mater that descends through the interhemispheric fissure in the midline of the brain to separate the cerebral hemispheres and is attached to the cerebellar tentorium. The dural venous sinuses are venous channels found between the endosteal and meningeal layers of dura mater in the brain. The transverse and superior sagittal sinuses are the largest dural venous sinuses. The space between the bone and the dura mater is known as the epidural space, which is prominent in the spinal canal where it contains spinal nerve roots, connective tissue, and blood vessels.

The ventricular system is a series of interconnected, CSF-filled spaces, called ventricles, that lie in the core of the forebrain and brainstem (Figure 4–18). The ventricles produce CSF and circulate CSF. The ventricles originate as the inside or lumen of the neural tube during fetal development. The lumen of the telencephalon gives rise to the left and right lateral ventricles (formerly called the first and second ventricles). The largest of the ventricles, each lateral ventricle has a C shape that mirrors the cerebral hemisphere where it is located, and each contains a posterior horn that extends into the occipital lobe and an anterior horn that extends into the frontal lobe. The third ventricle originates from the diencephalon and is located in the midline between the left and right halves of the thalamus. CSF flows from the lateral ventricles through 2 small openings (called the interventricular foramen or foramen of Monro) into the third ventricle.

The third ventricle is continuous caudally with the cerebral aqueduct (also called the aqueduct of Sylvius). The cerebral aqueduct, which forms from the lumen of the mesencephalon, proceeds though the midbrain and then opens into the fourth ventricle. The fourth ventricle arises from the lumen of the metencephalon and myelencephalon and is located in the dorsal or roof of the pons and medulla. At the posterior region of the medulla, the fourth ventricle narrows to form the central canal of the spinal cord. As it flows from the fourth ventricle, some CSF is diverted to the subarachnoid space and some continues through the central canal.

CSF is a clear extracellular fluid that is constantly synthesized and resorbed. CSF is produced by a modified vascular structure called the choroid plexus, which is present in each of the 4 ventricles. The ventricles are lined by glial cells called ependymal cells. The choroid plexus consists of a layer of specialized choroid ependymal cells (CECs) surrounding a core of capillaries and loose connective tissue. CSF is formed as plasma is filtered from the blood through the CECs. The CECs use active transport mechanisms to transport ions and glucose into the ventricles, and water follows the resulting osmotic gradient. Hence, the ependymal cells form the blood–CSF barrier in the choroid plexus, which serves the same purpose as the blood–brain barrier in the rest of the brain. In addition to the production of CSF, the choroid plexus also acts as a filter to remove metabolic waste and excess neurotransmitters from the CSF. CSF is produced at a rate of about 600 mL/d, replacing the entire volume about once every 5 to 6 hours.

As it is produced, CSF flows from the lateral ventricles to the third and then the fourth ventricle. From the fourth ventricle, CSF can flow through the median aperture (foramina of Magendie) and 2 lateral apertures (foramina of Luschka) to the cisterna magna. From there, CSF flows to the subarachnoid space around the brain and spinal cord, where it resorbed by specialized structures called arachnoid villi and granulations and returned to the venous circulation (Figure 4–19).

In other parts of the body, circulation in the lymphatic system participates in the clearing of extracellular waste products and damaged cells from tissues and the movement of immune cells, such as white blood cells. For many years, a similar system was thought to be absent from the brain. However, recent studies have demonstrated the presence of lymphatic vessels that run parallel with blood vessels in the meninges. A potential role for brain lymphatic vessels may be to provide a route for transport of fluid and immune cells such as T cells from the CSF.

THE CNS VASCULAR SYSTEM

The CNS is highly vascularized. The adult cerebral blood flow is approximately 750 mL/min, consuming about 15% to 20% of the cardiac output. Similar to other organs and tissues, the arteries deliver oxygen, glucose, and other nutrients to the brain, and the veins carry deoxygenated blood back to the heart, removing carbon dioxide and other metabolic products. The larger arteries and veins branch to smaller arterioles and venules, and then to smaller capillaries, which supply and remove blood from the nervous tissue. Brain capillaries are lined by specialized vascular endothelial cells joined by tight junctions and covered by pericytes and astrocytic end feet, so hydrophilic molecules are unable to diffuse directly into the brain, thereby creating the blood–brain barrier. Astrocytic end feet transport specific nutrients from the blood into the brain.

The entire blood supply to the brain arises from 2 paired arteries, the internal carotid arteries and vertebral arteries, which form from branches of the dorsal aorta and ascend to the cranium (Figure 4–20). The internal carotid arteries arise from the bifurcation of the left and right common carotid arteries, on each side of the head and neck, and supply blood to the front and middle regions of the brain. The vertebral arteries emerge as branches of the left and right subclavian arteries, ascend separately, and converge near the base of the pons to form the unpaired basilar artery and supply blood to the back of the brain. The blood supply to the spinal cord is via the vertebral arteries, which branch to form the anterior and posterior spinal arteries, and the medullary arteries.

The internal carotid arteries enter the cranium through the carotid canal of the temporal bone, travel through the cavernous sinus, and penetrate the dura just ventral to the optic nerve. At the level just lateral to the optic chiasm, the internal carotid artery branches to form the anterior cerebral artery and continues to form the middle cerebral artery (Figure 4–21). The left and right anterior cerebral arteries supply blood to most medial portions of the frontal lobes and anterior parietal lobes. The anterior cerebral arteries travel along the sphenoid bone of the eye socket, then upward through the insula cortex, where final branches arise. The middle cerebral artery is the larger branch of the internal carotid and continues into the lateral sulcus, where it then branches and projects to lateral portions of the frontal, temporal, and parietal lobes. It also supplies blood to deeper structures of the basal forebrain and the insular cortices.

The vertebral arteries ascend upward through foramen transversarium of the cervical spine and enter the cranial cavity via the foramen magnum, emerging as 2 vessels, 1 on the left and 1 on the right of the medulla. Within the cranial vault, each vertebral artery gives off 3 branches that form the posterior inferior cerebellar artery and 2 spinal arteries. The vertebral arteries then join in front of the middle part of the medulla to form the larger basilar artery, which sends multiple branches to supply the medulla and pons, and the anterior inferior cerebellar artery. Finally, the basilar artery terminates by bifurcating into the posterior cerebral arteries and superior cerebellar artery. The posterior cerebral arteries supply the midbrain, thalamus, and subthalamic nucleus. They also travel outward, around the superior cerebellar peduncles and top of the cerebellar tentorium, where they send branches to supply the temporal and occipital lobes. The blood supply to the medulla includes the anterior spinal artery, the posterior inferior cerebellar artery, and the vertebral artery’s direct branches.

The carotid and vertebral systems join together to form the cerebral arterial circle (circle of Willis), a ring of connected arteries that lies in the interpeduncular cistern between the midbrain and pons. The circle is formed by the posterior cerebral arteries, the posterior communicating arteries, and the internal carotids (from a region immediately proximal to the origin of the middle cerebral arteries, the anterior cerebral arteries, and the anterior communicating artery). Importantly, the circle of Willis provides alternative inputs to the internal carotid and posterior cerebral arteries, which is crucial in the event of stroke.

The brain is drained by a system of veins that empty into the dural sinuses, which eventually empty into the internal jugular veins (Figure 4–22). The brain has 2 main networks of veins: an exterior 3-branch network on the surface of the cerebrum and an interior network. The exterior and interior networks communicate via anastomosing (joining) veins. In the brain, the veins drain into larger cavities called the dural venous sinuses, which are typically located between the dura mater and the covering of the skull.

The great cerebral vein drains blood from the cerebellum and midbrain. The spinal veins or adjacent cerebral veins drain blood from the medulla and pons. Blood in the deep parts of the brain drains into region-specific sinuses. For the exterior network, the superior sagittal sinus, which is located at the midline at the top of the brain, receives blood from the outer portion of the brain and combines its drainage with the outflow from the straight sinus, at the confluence of sinuses, which drains into the transverse sinuses. Next, these drain into the sigmoid sinuses, which also receives blood from the cavernous sinus and superior and inferior petrosal sinuses. The sigmoid sinuses then drain into the left and right internal jugular veins.

The spinal cord is primarily supplied by 3 longitudinal arteries, the anterior spinal artery and 2 posterior spinal arteries, and the medullary arteries (Figure 4–23). In the cranium, at the medullary level, each vertebral artery branches to produce the anterior spinal artery and the posterior inferior cerebellar artery, which in about 75% of people gives rise to the posterior spinal artery. The anterior spinal artery travels along the midline of the ventral surface of the spinal cord and gives rise to the sulcal arteries, which enter the spinal cord and supply blood to the anterior two-thirds of the spinal cord. The paired posterior spinal arteries descend on the dorsolateral surface of the spinal cord slightly medial to the dorsal roots and supply blood to the posterior third of the cord.

Additional arterial supply occurs via the anterior and posterior segmental medullary arteries, which arise from the vertebral and other arteries and join with the anterior and posterior spinal arteries along the length of the cord. Venous drainage of the cord occurs via 3 anterior and 3 posterior spinal veins, which in turn empty into the systemic segmental veins. The internal vertebral plexus also empties into the dural venous sinuses. Radicular veins also contribute to venous drainage of the cord.

SUMMARY

• The brainstem and cerebellum develop from the mesencephalon and rhombencephalon vesicles of the neural tube.

• The midbrain, pons, and medulla form the brainstem, which contains nuclei for essential automatic, reflex, and autonomic functions that are critical for survival, and white matter tracks that connect the forebrain with the cerebellum and spinal cord.

• The brainstem houses the reticular formation, a set of interconnected nuclei located from the upper midbrain to the lower medulla involved in sleep and wakefulness, arousal and alertness, consciousness, and other motor and sensory functions.

• The midbrain encompasses nuclei in the superior and inferior colliculi involved in vision and hearing, nuclei for cranial nerves III and IV, and white matter regions including the cerebral peduncles.

• Also located in the midbrain are the substantia nigra and ventral tegmental area, 2 regions that contain dopaminergic neurons that contribute to the basal ganglia and are involved in motor control and the reward pathway.

• The pons contains nuclei that relay signals between the forebrain and cerebellum and nuclei involved in sleep, respiration, swallowing, and bladder control.

• The pons also houses nuclei for cranial nerves V to VIII, which are involved in hearing and taste, equilibrium, eye movement, facial expressions, and facial sensations.

• The pons includes the cerebellar peduncles, which are large white matter areas that provide the routes for all information transmitted to and from the cerebellum.

• The medulla includes nuclei involved in the automatic reflex of breathing and the autonomic regulation of heart rate and blood pressure, as well as control of several somatic functions.

• The medulla contains the nuclei for cranial nerves IX to XII and a white matter region called the pyramids, where the corticospinal tract and dorsal column medial lemniscus tract travel and decussate.

• The cranial nerves emerge from either the cerebrum or brainstem and transmit both special sense and somatic motor and sensory information between the brain and the head, face, and neck.

• The cranial nerves also supply parasympathetic motor control to and receive visceral sensory information from the head, neck, and organs of the body.

• The cerebellum functions in motor control, including coordination, precision and timing of movements, and motor learning, and has been implicated in cognitive functions and emotion.

• A component of the CNS, the spinal cord is a thin tube of nervous tissue that is enclosed in the vertebral canal, protected by meninges and the vertebral column, and divided into cervical, thoracic, lumbar, sacral, and coccygeal regions along its length.

• The spinal cord contains white matter tracts and gray matter regions that transmit and relay motor signals from the CNS to the body and sends sensory signals from the PNS to the CNS.

• Motor axons exit the spinal cord via the ventral roots, whereas sensory axons enter the spinal cord via the dorsal roots, forming the spinal nerves with 31 pairs along the length of the cord.

• The peripheral nerves assemble from branches of the spinal nerves and innervate the body and limbs.

• The enteric nervous system involves neurons and glia located in the gastrointestinal tract that function in regulation of peristalsis and secretions.

• The meninges include the dura mater, arachnoid mater, and pia mater, which cover, protect, and cushion the brain and spinal cord.

• The brain ventricular system unites the brain ventricles, which house the choroid plexuses that synthesize cerebrospinal fluid and circulate it within and around the brain and spinal cord.

• The CNS arterial system arises from 2 branches from the dorsal aorta: the internal carotid arteries, which supply the anterior and middle regions of the brain, and the vertebral arteries, which supply the posterior brain, brainstem, and spinal cord.

• The CNS venous system involves numerous venous sinuses that drain into the jugular vein.