1. FUNDAMENTALS OF NEUROSCIENCE the sea horse)or amygdala(shaped like the almond), Neurons Communicate Chemically through cerebrum(the main brain), and cerebellum (a small Specialized Contact Zones brain) The sites of interneuronal communication in the central nervous system(CNS) are termed synapses in JEURONS AND GLIA ARE the CNS and junctions in somatic, motor, and auto- nomic nervous systems. Paramembranous deposits of CELLULAR BUILDING BLOCKS OF THE NERVOUS SYSTEM specific proteins essential for transmitter release, esponse, and catabolism characterize synapses and tions morp phologically. These specialized sites are e This book lays out our current understanding in presumed to be the active zone for transmitter release and response. Paramembranous proteins constitute a full scope of modern neuroscience. The structure and specialized junctional adherence zone, termed the syn function of the brain and spinal cord are most appro- aptolemma Like peripheral junctions, central synapses priately understood from the perspective of their also are denoted by accumulations of tiny(500 to highly specialized cells: the neurons, the intercon- 1500 A)organelles, termed synaptic vesicles.The pro- nected, highly differentiated, bioelectrically driven, teins of these vesicles have been shown to have specific cellular units of the nervous system; and their more roles in transmitter storage; vesicle docking onto pre- numerous support cells, the glia. Given the importance synaptic membranes, voltage- and Ca-dependent of these cellular building blocks in all that follows, a secretion, and the recycling and restorage of previ brief overview of their properties may be helpful ously released transmitter molecules. Neurons Are Heterogeneously Shaped, Highly Synaptic Relationships Fall into Several Active Secretory Cells Structural categories Neurons are classified in many diffe Synaptic arrangements in the CNS fall into a wide ccording to function(sensory, motor, or interneuron), variety of morphological and functional forms that are location(cortical, spinal, etc. ) the identity of the trans- specific for the neurons involved. The most common mitter they synthesize and release (glutamatergic, arrangement, typical of hierarchical pathways, is either cholinergic,etc.),and their shape(pyramidal, granule, the axodendritic or the axosomatic synapse, in which mitral, etc. ) Microscopic analysis focuses on their the axons of the cell of origin make their functional general shape and, in particular, the number of exten- contact with the dendrites or cell body of the target sions from the cell body. Most neurons have one axon, neuron, respectively. A second category of synaptic often branched, to transmit signals to interconnected arrangement is more rare-forms of functional contact target neurons. Other processes, termed dendrites, between adjacent cell bodies(somasomatic)and over extend from the nerve cell body (also termed the peri- lapping dendrites(dendrodendritic). Within the spinal karyon-the cytoplasm surrounding the nucleus of cord and some other fields of neuropil(relatively acel the neuron) to receive synaptic contacts from other lular areas of synaptic connections), serial axoaxonic neurons; dendrites may branch in extremely complex synapses are relatively frequent. Here, the axon of an called dendritic spines. Neurons exhibit the cytological neuron as that terminal contacts a dendrite, or on the characteristics of highly active secretory cells with segment of the axon that is immediately distal to the large nuclei; large amounts of smooth and rough endo- soma, termed the initial segment, where action poten- plasmic reticulum; and frequent clusters of specialize tials arise. Many presynaptic axons contain local col- mooth endoplasmic reticulum( Golgi apparatus), lections of typical synaptic vesicles with no opposed which secretory products of the cell are packaged into specialized synaptolemma. These are termed boutons membrane-bound organelles for transport out of the en passant. The release of a transmitter may not always cell body proper to the axon or dendrites. Neurons and occur at such sites their cellular extensions are rich in microtubules elongated tubules approximately 24nm in diameter. Synaptic Relationships Also Belong to Diverse Functional Categories drites and assist in the reciprocal transport of essentia macromolecules and organelles between the cell body As with their structural representations, the quali and the distant axon or dendrites ties of synaptic transmission can also be functionally I. NEUROSCIENCI
4 1. FUNDAMENTALS OF NEUROSCIENCE I. NEUROSCIENCE the sea horse) or amygdala (shaped like the almond), cerebrum (the main brain), and cerebellum (a small brain). NEURONS AND GLIA ARE CELLULAR BUILDING BLOCKS OF THE NERVOUS SYSTEM This book lays out our current understanding in each of the important domains that together defi ne the full scope of modern neuroscience. The structure and function of the brain and spinal cord are most appropriately understood from the perspective of their highly specialized cells: the neurons, the interconnected, highly differentiated, bioelectrically driven, cellular units of the nervous system; and their more numerous support cells, the glia. Given the importance of these cellular building blocks in all that follows, a brief overview of their properties may be helpful. Neurons Are Heterogeneously Shaped, Highly Active Secretory Cells Neurons are classifi ed in many different ways, according to function (sensory, motor, or interneuron), location (cortical, spinal, etc.), the identity of the transmitter they synthesize and release (glutamatergic, cholinergic, etc.), and their shape (pyramidal, granule, mitral, etc.). Microscopic analysis focuses on their general shape and, in particular, the number of extensions from the cell body. Most neurons have one axon, often branched, to transmit signals to interconnected target neurons. Other processes, termed dendrites, extend from the nerve cell body (also termed the perikaryon—the cytoplasm surrounding the nucleus of the neuron) to receive synaptic contacts from other neurons; dendrites may branch in extremely complex patterns, and may possess multiple short protrusions called dendritic spines. Neurons exhibit the cytological characteristics of highly active secretory cells with large nuclei; large amounts of smooth and rough endoplasmic reticulum; and frequent clusters of specialized smooth endoplasmic reticulum (Golgi apparatus), in which secretory products of the cell are packaged into membrane-bound organelles for transport out of the cell body proper to the axon or dendrites. Neurons and their cellular extensions are rich in microtubules— elongated tubules approximately 24 nm in diameter. Microtubules support the elongated axons and dendrites and assist in the reciprocal transport of essential macromolecules and organelles between the cell body and the distant axon or dendrites. Neurons Communicate Chemically through Specialized Contact Zones The sites of interneuronal communication in the central nervous system (CNS) are termed synapses in the CNS and junctions in somatic, motor, and autonomic nervous systems. Paramembranous deposits of specifi c proteins essential for transmitter release, response, and catabolism characterize synapses and junctions morphologically. These specialized sites are presumed to be the active zone for transmitter release and response. Paramembranous proteins constitute a specialized junctional adherence zone, termed the synaptolemma. Like peripheral junctions, central synapses also are denoted by accumulations of tiny (500 to 1500 Å) organelles, termed synaptic vesicles. The proteins of these vesicles have been shown to have specifi c roles in transmitter storage; vesicle docking onto presynaptic membranes, voltage- and Ca2+ -dependent secretion, and the recycling and restorage of previously released transmitter molecules. Synaptic Relationships Fall into Several Structural Categories Synaptic arrangements in the CNS fall into a wide variety of morphological and functional forms that are specifi c for the neurons involved. The most common arrangement, typical of hierarchical pathways, is either the axodendritic or the axosomatic synapse, in which the axons of the cell of origin make their functional contact with the dendrites or cell body of the target neuron, respectively. A second category of synaptic arrangement is more rare–forms of functional contact between adjacent cell bodies (somasomatic) and overlapping dendrites (dendrodendritic). Within the spinal cord and some other fi elds of neuropil (relatively acellular areas of synaptic connections), serial axoaxonic synapses are relatively frequent. Here, the axon of an interneuron ends on the terminal of a long-distance neuron as that terminal contacts a dendrite, or on the segment of the axon that is immediately distal to the soma, termed the initial segment, where action potentials arise. Many presynaptic axons contain local collections of typical synaptic vesicles with no opposed specialized synaptolemma. These are termed boutons en passant. The release of a transmitter may not always occur at such sites. Synaptic Relationships Also Belong to Diverse Functional Categories As with their structural representations, the qualities of synaptic transmission can also be functionally
THE OPERATIVE PROXCESSES OF NERVOUS SYSTEMS ARE ALSO HIERARCHICAL categorized in terms of the nature of the neurotransmit- lation(through alterations in gene expression). Com- ter that provides the signaling: the nature of the recep- pletion of the human, chimpanzee, rat, and mouse tor molecule on the postsynaptic neuron, gland, or genomes can be viewed as an extensive inventory muscle; and the mechanisms by which the postsynap these molecular elements more than half of which are tic cell transduces the neurotransmitter signal into thought to be either highly enriched in the brain or transmembrane changes. So-called"fast"or"classical" even exclusively expressed there neurotransmission is the functional variety seen at the At the cellular level of neuroscience, the emphasis vast majority of synaptic and junctional sites, with a on interactions between neurons through their synap- rapid onset and a rapid ending, generally employing tic transactions and between neurons and glia. Much excitatory amino acids (glutamate or aspartate)or current cellular level research focuses on the biochemi inhibitory amino acids (y-aminobutyrate, GABA, or cal systems within specific cells that mediate such phe. glycine)as the transmitter. The effects of those signals nomena as pacemakers for the generation of circadian are largely attributable to changes in postsynaptic rhythms or that can account for activity-dependent membrane permeability to specific cations or anions adaptation. Research at the cellular level strives to and the resulting depolarization or hyperpolarization, determine which specific neurons and which of their respectively. Other neurotransmitters, such as the most proximate synaptic connections may mediate a monoamines(dopamine, norepinephrine, serotonin) behavior or the behavioral effects of a given experi- and many neuropeptides, produce changes in excita- mental perturbation bility that are much more enduring. Here the receptors At the systems level, emphasis is on the spatially activate metabolic processes within the postsynaptic distributed sensors and effectors that integrate the cells-frequently to add or remove phosphate groups bodys response to environmental challenges. There from key intracellularproteins; multiple complex forms are sensory systems, which include specialized senses of enduring postsynaptic metabolic actions are under for hearing, seeing, feeling, tasting, and balancing the investigation. The brain s richness of signaling possi- body. Similarly, there are motor systems for trunk, bilities comes from the interplay on common postsyn- limb, and fine finger motions and internal regulatory aptic neurons of these multiple chemical signals systems for visceral regulation(e.g, control of body temperature, cardiovascular function, appetite, salt and water balance). These systems operate throug THE OPERATIVE PROCESSES relatively sequential linkages, and interruption of any OF NERVOUS SYSTEMS ARE link can destroy the function of the system. ALSO HIERARCHICAL Systems level research also includes research into cellular systems that innervate the widely distributed neuronal elements of the sensory, motor, or visceral As research progressed, it became clear that neuro- systems, such as the pontine neurons with highly nal functions could best be fitted into nervous system branched axons that innervate diencephalic, cortical, function by considering their operations at four funda and spinal neurons. Among the best studied of these mental hierarchical levels: molecular, cellular, systems, divergent systems are the monoaminergic neurons, and behavioral. These levels rest on the fundamental which have been linked to the regulation of many principle that neurons communicate chemically, by behavioral outputs of the brain, ranging from feeding, the activity-dependent secretion of neurotransmitters, drinking, thermoregulation, and sexual behavior at specialized points of contact named synapses Monoaminergic neurons also have been linked to such At the molecular level of operations, the emphasis is higher functions as pleasure, reinforcement, attention, on the interaction of molecules-typically proteins motivation, memory, and learning. Dysfunctions of that regulate transcription of genes, their translation these systems have been hypothesized as the basis for into proteins, and their posttranslational processing. some psychiatric and neurological diseases, supported Proteins that mediate the intracellular processes of by evidence that medications aimed at presumed transmitter synthesis, storage, and release, or the intra- monoamine regulation provide useful therapy cellular consequences of intercellular synaptic signal At the behavioral level of neuroscience research ng are essential neuronal molecular functions. Such emphasis is on the interactions between individuals transductive molecular mechanisms include the neu- and their collective environment. Research at the rotransmitters'receptors, as well as the auxiliary mol- behavioral level centers on the integrative phenomena cules that allow these receptors to influence the that link populations of neurons(often operationally regulation of ion channels)and their longer-termregul Q empirically defined)into extended specialized short-term biology of responsive neurons(through ircuits, ensembles, or more pervasively distributed L NEUROSCIENCE
I. NEUROSCIENCE categorized in terms of the nature of the neurotransmitter that provides the signaling; the nature of the receptor molecule on the postsynaptic neuron, gland, or muscle; and the mechanisms by which the postsynaptic cell transduces the neurotransmitter signal into transmembrane changes. So-called “fast” or “classical” neurotransmission is the functional variety seen at the vast majority of synaptic and junctional sites, with a rapid onset and a rapid ending, generally employing excitatory amino acids (glutamate or aspartate) or inhibitory amino acids (g-aminobutyrate, GABA, or glycine) as the transmitter. The effects of those signals are largely attributable to changes in postsynaptic membrane permeability to specifi c cations or anions and the resulting depolarization or hyperpolarization, respectively. Other neurotransmitters, such as the monoamines (dopamine, norepinephrine, serotonin) and many neuropeptides, produce changes in excitability that are much more enduring. Here the receptors activate metabolic processes within the postsynaptic cells—frequently to add or remove phosphate groups from key intracellular proteins; multiple complex forms of enduring postsynaptic metabolic actions are under investigation. The brain’s richness of signaling possibilities comes from the interplay on common postsynaptic neurons of these multiple chemical signals. THE OPERATIVE PROCESSES OF NERVOUS SYSTEMS ARE ALSO HIERARCHICAL As research progressed, it became clear that neuronal functions could best be fi tted into nervous system function by considering their operations at four fundamental hierarchical levels: molecular, cellular, systems, and behavioral. These levels rest on the fundamental principle that neurons communicate chemically, by the activity-dependent secretion of neurotransmitters, at specialized points of contact named synapses. At the molecular level of operations, the emphasis is on the interaction of molecules—typically proteins that regulate transcription of genes, their translation into proteins, and their posttranslational processing. Proteins that mediate the intracellular processes of transmitter synthesis, storage, and release, or the intracellular consequences of intercellular synaptic signaling are essential neuronal molecular functions. Such transductive molecular mechanisms include the neurotransmitters’ receptors, as well as the auxiliary molecules that allow these receptors to infl uence the short-term biology of responsive neurons (through regulation of ion channels) and their longer-term regulation (through alterations in gene expression). Completion of the human, chimpanzee, rat, and mouse genomes can be viewed as an extensive inventory of these molecular elements, more than half of which are thought to be either highly enriched in the brain or even exclusively expressed there. At the cellular level of neuroscience, the emphasis is on interactions between neurons through their synaptic transactions and between neurons and glia. Much current cellular level research focuses on the biochemical systems within specifi c cells that mediate such phenomena as pacemakers for the generation of circadian rhythms or that can account for activity-dependent adaptation. Research at the cellular level strives to determine which specifi c neurons and which of their most proximate synaptic connections may mediate a behavior or the behavioral effects of a given experimental perturbation. At the systems level, emphasis is on the spatially distributed sensors and effectors that integrate the body’s response to environmental challenges. There are sensory systems, which include specialized senses for hearing, seeing, feeling, tasting, and balancing the body. Similarly, there are motor systems for trunk, limb, and fi ne fi nger motions and internal regulatory systems for visceral regulation (e.g., control of body temperature, cardiovascular function, appetite, salt and water balance). These systems operate through relatively sequential linkages, and interruption of any link can destroy the function of the system. Systems level research also includes research into cellular systems that innervate the widely distributed neuronal elements of the sensory, motor, or visceral systems, such as the pontine neurons with highly branched axons that innervate diencephalic, cortical, and spinal neurons. Among the best studied of these divergent systems are the monoaminergic neurons, which have been linked to the regulation of many behavioral outputs of the brain, ranging from feeding, drinking, thermoregulation, and sexual behavior. Monoaminergic neurons also have been linked to such higher functions as pleasure, reinforcement, attention, motivation, memory, and learning. Dysfunctions of these systems have been hypothesized as the basis for some psychiatric and neurological diseases, supported by evidence that medications aimed at presumed monoamine regulation provide useful therapy. At the behavioral level of neuroscience research, emphasis is on the interactions between individuals and their collective environment. Research at the behavioral level centers on the integrative phenomena that link populations of neurons (often operationally or empirically defi ned) into extended specialized circuits, ensembles, or more pervasively distributed THE OPERATIVE PROCESSES OF NERVOUS SYSTEMS ARE ALSO HIERARCHICAL 5
1. FUNDAMENTALS OF NEUROSCIENCE systems"that integrate the physiological expression cerebral cortex, hippocampal formation, and cerebel- of a learned, reflexive, or spontaneously generated lum)or in clustered groupings(the defined collections behavioral response. Behavioral research also includes of central neurons, which aggregate into"nuclei"in the the operations of higher mental activity, such as central nervous system and into"ganglia"in the peri memory, learning, speech, abstract reasoning, and pheral nervous system, and in invertebrate nervous consciousness. Conceptually ly,"animal models"of systems) The specific connections between neurons human psychiatric diseases are based on the assump- within or across the macro-divisions of the brain are tion that scientists can appropriately infer from obser- essential to the brains functions. It is through their vations of behavior and physiology (heart rate, patterns of neuronal circuitry that individual neurons respiration, locomotion, etc. that the states experi form functional ensembles to regulate the flow of infor- enced by animals are equivalent to the emotional states mation within and between the regions of the brain. experienced by humans expressing these same sorts of physiological changes as the neuroscientific bases for some elemental behaviors have become better understood, new aspects CELLULAR ORGANIZATION of neuroscience applied to problems of daily life have OF THE BRAIN begun to emerge. Methods for the noninvasive detec- tion of activity in certain small brain regions have Present understanding of the cellular organization improved such that it is now possible to link these of the CNS can be viewed simplistically according to changes in activity with discrete forms of mental activ- three main patterns of neuronal connectivity ity. These advances have given rise to the concept that it is possible to understand where in the brain the deci Three basic patterns of neuronal sion-making process occurs, or to identify the kinds of Circuitry Exist information necessary to decide whether to act or not The detailed quantitative data that now exist on the Long hierarchical neuronal connections typically are details of neuronal structure, function, and behavior found in the primary sensory and motor pathway have driven the development of computational neuro- Here the transmission of information is highly sequen- sciences. This new branch of neuroscience research tial, and interconnected neurons are related to each seeks to predict the performance of neurons, neuronal otherin a hierarchical fashion. Primary receptors(in the properties, and neural networks based on their dis- retina, inner ear, olfactory epithelium, tongue, or skin cernible quantitative propertie transmit first to primary relay cells, then to secondary relay cells, and finally to the primary sensory fields of Some Principles of Brain Organization the cerebral cortex. For motor output systems, the and Function reverse sequence exists with impulses descending hier archically from the motor cortex to the spinal motoneu The central nervous system is most commonly ron. It is at the level of the motor and sensory systems divided into major structural units, consisting of the that beginning scholars of the nervous system will major physical subdi of the brain. Thus, mam- begin to appreciate the complexities of neuronal cir malian neuroscientists divide the central nervous cuitry by which widely separated neurons communi- system into the brain and spinal cord and further cateselectively Thishierarchicalschemeoforganization divide the brain into regions readily seen by the provides for a precise flow of information, but such simplest of dissections. Based on research that has organization suffers the disadvantage that destruction demonstrated that these large spatial elements derive of any link incapacitates the entire system from independent structures in the developing brain, Local circuit neurons establish their connections these subdivisions are well accepted. Mammalian mainly within their immediate vicinity. Such local brain thusly is divided into hindbrain, midbrain, and circuit neurons frequently are small and may have forebrain, each of which has multiple highly special- relatively few processes. Interneurons expand or con- ized regions within it. In deference to the major strain the flow of information within their small spatial differences in body structure, invertebrate nervous domain and may do so without generating action systems most often are organized by body segment potentials, given their short axons (cephalic, thoracic, abdominal) and by Single-source divergent circuitry is utilized by certain posterior placement neurons of the hypothalamus, pons, and medulla Neurons within the vertebrate CNS operate either From their clustered anatomical location, theseneurons within layered structures(such as the olfactory bulb, extend multiple branched and divergent connections I. NEUROSCIENCI
6 1. FUNDAMENTALS OF NEUROSCIENCE I. NEUROSCIENCE “systems” that integrate the physiological expression of a learned, refl exive, or spontaneously generated behavioral response. Behavioral research also includes the operations of higher mental activity, such as memory, learning, speech, abstract reasoning, and consciousness. Conceptually, “animal models” of human psychiatric diseases are based on the assumption that scientists can appropriately infer from observations of behavior and physiology (heart rate, respiration, locomotion, etc.) that the states experienced by animals are equivalent to the emotional states experienced by humans expressing these same sorts of physiological changes. As the neuroscientifi c bases for some elemental behaviors have become better understood, new aspects of neuroscience applied to problems of daily life have begun to emerge. Methods for the noninvasive detection of activity in certain small brain regions have improved such that it is now possible to link these changes in activity with discrete forms of mental activity. These advances have given rise to the concept that it is possible to understand where in the brain the decision-making process occurs, or to identify the kinds of information necessary to decide whether to act or not. The detailed quantitative data that now exist on the details of neuronal structure, function, and behavior have driven the development of computational neurosciences. This new branch of neuroscience research seeks to predict the performance of neurons, neuronal properties, and neural networks based on their discernible quantitative properties. Some Principles of Brain Organization and Function The central nervous system is most commonly divided into major structural units, consisting of the major physical subdivisions of the brain. Thus, mammalian neuroscientists divide the central nervous system into the brain and spinal cord and further divide the brain into regions readily seen by the simplest of dissections. Based on research that has demonstrated that these large spatial elements derive from independent structures in the developing brain, these subdivisions are well accepted. Mammalian brain thusly is divided into hindbrain, midbrain, and forebrain, each of which has multiple highly specialized regions within it. In deference to the major differences in body structure, invertebrate nervous systems most often are organized by body segment (cephalic, thoracic, abdominal) and by anterior– posterior placement. Neurons within the vertebrate CNS operate either within layered structures (such as the olfactory bulb, cerebral cortex, hippocampal formation, and cerebellum) or in clustered groupings (the defi ned collections of central neurons, which aggregate into “nuclei” in the central nervous system and into “ganglia” in the peripheral nervous system, and in invertebrate nervous systems). The specifi c connections between neurons within or across the macro-divisions of the brain are essential to the brain’s functions. It is through their patterns of neuronal circuitry that individual neurons form functional ensembles to regulate the fl ow of information within and between the regions of the brain. CELLULAR ORGANIZATION OF THE BRAIN Present understanding of the cellular organization of the CNS can be viewed simplistically according to three main patterns of neuronal connectivity. Three Basic Patterns of Neuronal Circuitry Exist Long hierarchical neuronal connections typically are found in the primary sensory and motor pathways. Here the transmission of information is highly sequential, and interconnected neurons are related to each other in a hierarchical fashion. Primary receptors (in the retina, inner ear, olfactory epithelium, tongue, or skin) transmit fi rst to primary relay cells, then to secondary relay cells, and fi nally to the primary sensory fi elds of the cerebral cortex. For motor output systems, the reverse sequence exists with impulses descending hierarchically from the motor cortex to the spinal motoneuron. It is at the level of the motor and sensory systems that beginning scholars of the nervous system will begin to appreciate the complexities of neuronal circuitry by which widely separated neurons communicate selectively. This hierarchical scheme of organization provides for a precise fl ow of information, but such organization suffers the disadvantage that destruction of any link incapacitates the entire system. Local circuit neurons establish their connections mainly within their immediate vicinity. Such local circuit neurons frequently are small and may have relatively few processes. Interneurons expand or constrain the fl ow of information within their small spatial domain and may do so without generating action potentials, given their short axons. Single-source divergent circuitry is utilized by certain neurons of the hypothalamus, pons, and medulla. From their clustered anatomical location, these neurons extend multiple branched and divergent connections
ORGANIZATION OF THIS TEXT to many target cells, almost all of which lie outside the by the greatly diminished rate of access of most lipo- brain region in which the neurons of origin are located. Phobic chemicals between plasma and brain; specific Neurons with divergent circuitry could be considered energy-dependent transporter systems permit selected more as interregional interneurons rather than as access. Diffusional barriers retard the movement of sequential elements within any known hierarchical substances from brain to blood as well as from blood system. Forexample, differentneurons of thenoradren- to brain. The brain clears metabolites of transmitters ergic nucleus, the locus coeruleus (named for its blue into the cerebrospinal fluid by excretion through pigmented color in primate brains) project from the the acid transport system of the choroid plexus. The pons to either the cerebellum, spinal cord, hypothala- blood-brain barrier is much less prominent in the mus,or several cortical zones to modulate synaptic hypothalamus and in several small, specialized organs operations within those regions (termed circumventricular organs; see Chapters 34 and 39)lining the third and fourth ventricles of the brain Glia Are Supportive Cells to Neurons the median eminence, area postrema, pineal gland, subfornical organ, and subcommissural organ. The Neurons are not the only cells in the CNS Accord- peripheral nervous system( e.g., sensory and auto- ing to most estimates, neurons are outnumbered, nomic nerves and ganglia)has no such diffusional perhaps by an order of magnitude, by the various non- barrier neuronal supportive cellular elements. Nonneuronal cells include macroglia, microglia, and cells of the The Central Nervous System Can Initiate secrete the cerebrospinal fluid, and meninges, sheets of Limited Responses to Damage onnective tissue that cover the surface of the brain Because neurons of the CNs are terminally diffe and comprise the cerebrospinal fluid-containing enve- entiated cells, they cannot undergo proliferative lope that protects the brain within the skull. responses to damage, as can cells of skin, muscle, bone, Macroglia are the most abundant supportive cells and blood vessels. Nevertheless, previously unrecog some are categorized as astrocytes(nonneuronal cells nized neural stem cells can undergo regulated prolif interposed between the vasculature and the neurons, eration and provide a natural means for selected often surrounding individual compartments of synap neuronal replacement in some regions of the nervous tic complexes). Astrocytes play a variety of metabolic system. As a result, neurons have evolved other adap. support roles, including furnishing energy intermedi tive mechanisms to provide for the maintenance of ates and providing for the supplementary removal function following injury. These adaptive mechanisms of excessive extracellular neurotransmitter secretions range from activity dependent regulation of gene (see Chapter 13). A second prominent category of mac- expression, to modification of synaptic structure, func- roglia is the myelin-producing cells, the oligodendro- tion, and can include actual localized axonal sprouting glia. Myelin, made up of multiple layers of their and new synapse creation. These adaptive mechanisms impacted membranes, insulates segments of long endow the brain with considerable capacity for struc axons bioelectrically and accelerates action potential tural and functional modification well into adulthood terized supportive cells believed to be of mesodermal dependent, but also to be reversible with disuse.Plas- origin and related to the macrophage/monocyte ticity is pronounced within the sensory systems(see lineage. Some microglia reside quiescently within the Chapter 23), and is quite prominent in the motor rain uring periods of intracerebral inflammation systems as well. The molecular mechanisms employed (e.g, infection, certain degenerative diseases, or trau- in memory and learning may rely upon very similar matic injury), circulating macrophages and other white processes as those involved in structural and func blood cells are recruited into the brain by endothelial tional plasticity signals to remove necrotic tissue or to defend against the microbial infection ORGANIZATION OF THIS TEXT The blood-Brain barrier protects against With these overview principles in place, which are The blood-brain barrier is an important permeabil- detailed more extensively in Section II, we can resume ity barrier to selected molecules between the blood our preview of this book. Another major domain of stream and the CNS. Evidence of a barrier is provided our field is nervous system development(Section IIl) L NEUROSCIENCE
I. NEUROSCIENCE to many target cells, almost all of which lie outside the brain region in which the neurons of origin are located. Neurons with divergent circuitry could be considered more as interregional interneurons rather than as sequential elements within any known hierarchical system. For example, different neurons of the noradrenergic nucleus, the locus coeruleus (named for its blue pigmented color in primate brains) project from the pons to either the cerebellum, spinal cord, hypothalamus, or several cortical zones to modulate synaptic operations within those regions. Glia Are Supportive Cells to Neurons Neurons are not the only cells in the CNS. According to most estimates, neurons are outnumbered, perhaps by an order of magnitude, by the various nonneuronal supportive cellular elements. Nonneuronal cells include macroglia, microglia, and cells of the brain’s blood vessels, cells of the choroid plexus that secrete the cerebrospinal fl uid, and meninges, sheets of connective tissue that cover the surface of the brain and comprise the cerebrospinal fl uid-containing envelope that protects the brain within the skull. Macroglia are the most abundant supportive cells; some are categorized as astrocytes (nonneuronal cells interposed between the vasculature and the neurons, often surrounding individual compartments of synaptic complexes). Astrocytes play a variety of metabolic support roles, including furnishing energy intermediates and providing for the supplementary removal of excessive extracellular neurotransmitter secretions (see Chapter 13). A second prominent category of macroglia is the myelin-producing cells, the oligodendroglia. Myelin, made up of multiple layers of their compacted membranes, insulates segments of long axons bioelectrically and accelerates action potential conduction velocity. Microglia are relatively uncharacterized supportive cells believed to be of mesodermal origin and related to the macrophage/monocyte lineage. Some microglia reside quiescently within the brain. During periods of intracerebral infl ammation (e.g., infection, certain degenerative diseases, or traumatic injury), circulating macrophages and other white blood cells are recruited into the brain by endothelial signals to remove necrotic tissue or to defend against the microbial infection. The Blood–Brain Barrier Protects Against Inappropriate Signals The blood–brain barrier is an important permeability barrier to selected molecules between the bloodstream and the CNS. Evidence of a barrier is provided by the greatly diminished rate of access of most lipophobic chemicals between plasma and brain; specifi c energy-dependent transporter systems permit selected access. Diffusional barriers retard the movement of substances from brain to blood as well as from blood to brain. The brain clears metabolites of transmitters into the cerebrospinal fl uid by excretion through the acid transport system of the choroid plexus. The blood–brain barrier is much less prominent in the hypothalamus and in several small, specialized organs (termed circumventricular organs; see Chapters 34 and 39) lining the third and fourth ventricles of the brain: the median eminence, area postrema, pineal gland, subfornical organ, and subcommissural organ. The peripheral nervous system (e.g., sensory and autonomic nerves and ganglia) has no such diffusional barrier. The Central Nervous System Can Initiate Limited Responses to Damage Because neurons of the CNS are terminally differentiated cells, they cannot undergo proliferative responses to damage, as can cells of skin, muscle, bone, and blood vessels. Nevertheless, previously unrecognized neural stem cells can undergo regulated proliferation and provide a natural means for selected neuronal replacement in some regions of the nervous system. As a result, neurons have evolved other adaptive mechanisms to provide for the maintenance of function following injury. These adaptive mechanisms range from activity dependent regulation of gene expression, to modifi cation of synaptic structure, function, and can include actual localized axonal sprouting and new synapse creation. These adaptive mechanisms endow the brain with considerable capacity for structural and functional modifi cation well into adulthood. This plasticity is not only considered to be activity dependent, but also to be reversible with disuse. Plasticity is pronounced within the sensory systems (see Chapter 23), and is quite prominent in the motor systems as well. The molecular mechanisms employed in memory and learning may rely upon very similar processes as those involved in structural and functional plasticity. ORGANIZATION OF THIS TEXT With these overview principles in place, which are detailed more extensively in Section II, we can resume our preview of this book. Another major domain of our fi eld is nervous system development (Section III). ORGANIZATION OF THIS TEXT 7
1. FUNDAMENTALS OF NEUROSCIENCE How does a simple epithelium differentiate into spe- THIS BOOK IS INTENDED FOR A cialized collections of cells and ultimately into distinct BROAD RANGE OF SCHOLARS OF brain structures? How do neurons grow processes tha THE NEUROSCIENCES find appropriate targets some distance away? How do nascent neuronal activity and embryonic experience shape activit and ensor systems and motor systems(Sections Iv science. In preparing it we have focused primarily on graduate students just entering the field, under information from the external world and how move. standing that some of you will have majored in ments and actions are produced(e. g, eye movements biology, some in psychology, some in mathematics and limb movements). These questions range from the or engineering, and even some like me, in German sounds transduced into informative pattern tons, and literature. It is hoped that through the text, the explan- activity? )to the systems and behavioral level(which endings, you will find the book to be both under- brain structures control eye movements and what are standable and enlightening. In many cases,advanced the computations required by each structure? ). undergraduate students will find this book useful An evolutionarily old function of the nervous well system is to regulate respiration, heart rate, sleep and tional clinical correlations that are not provided here to maintain internal homeostasis and to permit dail However, it is hoped that most medical scholars at and longer reproductive cycles. In this area of regula least will be able to use our textbook in conjunction tory systems( Section VD), we explore how organisms hose who have completed their formal education, remain in balance with their environment, ensuring it is hoped that this text can provide you with that they obtain the energy resources needed to survive and reproduce. At the level of cells and molecules, the some useful information and challenging perspec study of regulatory systems concerns the receptors tors tives, whether you are active neuroscientists wishing g pathways by particular horm to learn about areas of the field other than your or neurotransmitters prepare the organism to sleep, to own or individuals who wish to enter from a different area of inquiry. We invite all of you cope with acute stress, or to seek food or reproduce. to join us in the adventure of studying the nervous At the level of brain systems, we ask such questions to create a self-destructive proble Produce thirst or system. as what occurs in brain circuitry to abuse? In recent years, the disciplines of psychology and b iology have increasingly found common ground, and CLINICAL ISSUES IN this convergence of psychology and biology defines THE NEUROSCIENCES the modern topics of behavioral and cognitive neuro- ience( Section VID). These topics concern the so-called Many fields of clinical medicine are directly higher mental functions: perception, attention, lan cerned with the brain. The branches of medicine guage, memory, thinking, and the ability to navigate tied most closely to neuroscience are neurology in space. Work on these problems traditionally ( the study of the diseases of the brain), neurosurgery has drawn on the techniques of neuroanatomy, (the study of the surgical treatment of neurological neurophysiology, neuropharmacology, and behav- disease), and psychiatry(the study of behavioral, ioral analysis. More recently, behavioral and cogni emotional, and mental diseases). Other fields of tive neuroscience has benefited from several new medicine also make important contributions, in- approaches: the use of computers to perform detailed cluding radiology(the use of radiation for such formal analyses of how brain systems operate and how purposes as imaging the brain-initially with X rays cognition is organized; noninvasive neuroimaging and, more recently, with positron emitters and mag techniques, such as positron emission tomography netic waves) and pathology(the study of pathologica and functional magnetic resonance imaging, to obtain tissue). To make connections to the many facets of pictures of the living unai an brain in action: and medicine that are relevant to neuroscience. this book molecular biological methods, such as single gene includes discussion of a limited number of clinical knockouts ice, which can relate genes to brain conditions in the context of basic knowledge in systems and to behavior. neuroscience I. NEUROSCIENCI
8 1. FUNDAMENTALS OF NEUROSCIENCE I. NEUROSCIENCE How does a simple epithelium differentiate into specialized collections of cells and ultimately into distinct brain structures? How do neurons grow processes that fi nd appropriate targets some distance away? How do nascent neuronal activity and embryonic experience shape activity? Sensory systems and motor systems (Sections IV and V) encompass how the nervous system receives information from the external world and how movements and actions are produced (e.g., eye movements and limb movements). These questions range from the molecular level (how are odorants, photons, and sounds transduced into informative patterns of neural activity?) to the systems and behavioral level (which brain structures control eye movements and what are the computations required by each structure?). An evolutionarily old function of the nervous system is to regulate respiration, heart rate, sleep and waking cycles, food and water intake, and hormones to maintain internal homeostasis and to permit daily and longer reproductive cycles. In this area of regulatory systems (Section VI), we explore how organisms remain in balance with their environment, ensuring that they obtain the energy resources needed to survive and reproduce. At the level of cells and molecules, the study of regulatory systems concerns the receptors and signaling pathways by which particular hormones or neurotransmitters prepare the organism to sleep, to cope with acute stress, or to seek food or reproduce. At the level of brain systems, we ask such questions as what occurs in brain circuitry to produce thirst or to create a self-destructive problem such as drug abuse? In recent years, the disciplines of psychology and biology have increasingly found common ground, and this convergence of psychology and biology defi nes the modern topics of behavioral and cognitive neuroscience (Section VII). These topics concern the so-called higher mental functions: perception, attention, language, memory, thinking, and the ability to navigate in space. Work on these problems traditionally has drawn on the techniques of neuroanatomy, neurophysiology, neuropharmacology, and behavioral analysis. More recently, behavioral and cognitive neuroscience has benefi ted from several new approaches: the use of computers to perform detailed formal analyses of how brain systems operate and how cognition is organized; noninvasive neuroimaging techniques, such as positron emission tomography and functional magnetic resonance imaging, to obtain pictures of the living human brain in action; and molecular biological methods, such as single gene knockouts in mice, which can relate genes to brain systems and to behavior. THIS BOOK IS INTENDED FOR A BROAD RANGE OF SCHOLARS OF THE NEUROSCIENCES This textbook is for anyone interested in neuroscience. In preparing it we have focused primarily on graduate students just entering the fi eld, understanding that some of you will have majored in biology, some in psychology, some in mathematics or engineering, and even some like me, in German literature. It is hoped that through the text, the explanatory boxes, and, in some cases, the supplementary readings, you will fi nd the book to be both understandable and enlightening. In many cases, advanced undergraduate students will fi nd this book useful as well. Medical students may fi nd that they need additional clinical correlations that are not provided here. However, it is hoped that most medical scholars at least will be able to use our textbook in conjunction with more clinically oriented material. Finally, to those who have completed their formal education, it is hoped that this text can provide you with some useful information and challenging perspectives, whether you are active neuroscientists wishing to learn about areas of the fi eld other than your own or individuals who wish to enter neuroscience from a different area of inquiry. We invite all of you to join us in the adventure of studying the nervous system. CLINICAL ISSUES IN THE NEUROSCIENCES Many fi elds of clinical medicine are directly concerned with the brain. The branches of medicine tied most closely to neuroscience are neurology (the study of the diseases of the brain), neurosurgery (the study of the surgical treatment of neurological disease), and psychiatry (the study of behavioral, emotional, and mental diseases). Other fi elds of medicine also make important contributions, including radiology (the use of radiation for such purposes as imaging the brain—initially with X rays and, more recently, with positron emitters and magnetic waves) and pathology (the study of pathological tissue). To make connections to the many facets of medicine that are relevant to neuroscience, this book includes discussion of a limited number of clinical conditions in the context of basic knowledge in neuroscience