Studying the Nervous Systems of Humans and Other Animals 9 The term glia(from the Greek word meaning glue")reflects the nine- teenth-century presumption that these cells held the nervous system together in some way. The word has survived, despite the lack of any evi- dence that binding nerve cells together is among the many functions of glial cells. Glial roles that are well-established include maintaining the ionic milieu of nerve cells, modulating the rate of nerve signal propagation, mod- ulating synaptic action by controlling the uptake of neurotransmitters at or near the synaptic cleft, providing a scaffold for some aspects of neural devel pment, and aiding in (or impeding, in some instances) recovery from There are three types of glial cells in the mature central nervous system astrocytes, oligodendrocytes, and microglial cells(see Figure 1.5).Astro- cytes, which are restricted to the brain and spinal cord, have elaborate local processes that give these cells a starlike appearance(hence the prefix astro"). A major function of astrocytes is to maintain, in a variety of ways, an appropriate chemical environment for neuronal signaling. Oligodendro- cytes, which are also restricted to the central nervous system, lay down a aminated, lipid-rich wrapping called myelin around some, but not al axons. Myelin has important effects on the speed of the transmission of elec- trical signals(see Chapter 3). In the peripheral nervous system, the cells that elaborate myelin are called Schwann cells. Finally, microglial cells are derived primarily from hematopoietic pre sor cells(although some may be derived directly from neural precursor cells). They share many properties with macrophages found in other tissues, and are primarily scavenger cells that remove cellular debris from sites of injury or normal cell turnover. In addition, microglia, like their macrophage counterparts, secrete signaling molecules--particularly a wide range of ytokines that are also produced by cells of the immune system-that can modulate local inflammation and influence cell survival or death. Indeed ome neurobiologists prefer to categorize microglia as a type of macrophage Following brain damage, the number of microglia at the site of injury increases dramatically. Some of these cells proliferate from microglia resident area and enter the brain via local disruptions in the cerebral vasculature red in the brain, while others come from macrophages that migrate to the inj Cellular Diversity in the Nervous System Although the cellular constituents of the human nervous system are in many ways similar to those of other organs, they are unusual in their extraordi- nary numbers: the human brain is estimated to contain 100 billion neurons and several times as many supporting cells. More importantly, the nervous system has a greater range of distinct cell types-whether categorized by morphology, molecular identity, or physiological activity-than any other organ system(a fact that presumably explains why so many different genes are expressed in the nervous system; see above). The cellular diversity of any nervous system-including our own-undoubtedly underlies thethe capac ity of the system to form increasingly complicated networks to mediate increasingly sophisticated behaviors For much of the twentieth century, neuroscientists relied on the same set f techniques developed by Cajal and Golgi to describe and categorize the diversity of cell types in the nervous system. From the late 1970s onward, however, new technologies made possible by the advances in cell and mole- cular biology provided investigators with many additional tools to discern the properties of neurons(Figure 1.6). Whereas general cell staining methods
The term glia (from the Greek word meaning “glue”) reflects the nineteenth-century presumption that these cells held the nervous system together in some way. The word has survived, despite the lack of any evidence that binding nerve cells together is among the many functions of glial cells. Glial roles that are well-established include maintaining the ionic milieu of nerve cells, modulating the rate of nerve signal propagation, modulating synaptic action by controlling the uptake of neurotransmitters at or near the synaptic cleft, providing a scaffold for some aspects of neural development, and aiding in (or impeding, in some instances) recovery from neural injury. There are three types of glial cells in the mature central nervous system: astrocytes, oligodendrocytes, and microglial cells (see Figure 1.5). Astrocytes, which are restricted to the brain and spinal cord, have elaborate local processes that give these cells a starlike appearance (hence the prefix “astro”). A major function of astrocytes is to maintain, in a variety of ways, an appropriate chemical environment for neuronal signaling. Oligodendrocytes, which are also restricted to the central nervous system, lay down a laminated, lipid-rich wrapping called myelin around some, but not all, axons. Myelin has important effects on the speed of the transmission of electrical signals (see Chapter 3). In the peripheral nervous system, the cells that elaborate myelin are called Schwann cells. Finally, microglial cells are derived primarily from hematopoietic precursor cells (although some may be derived directly from neural precursor cells). They share many properties with macrophages found in other tissues, and are primarily scavenger cells that remove cellular debris from sites of injury or normal cell turnover. In addition, microglia, like their macrophage counterparts, secrete signaling molecules—particularly a wide range of cytokines that are also produced by cells of the immune system—that can modulate local inflammation and influence cell survival or death. Indeed, some neurobiologists prefer to categorize microglia as a type of macrophage. Following brain damage, the number of microglia at the site of injury increases dramatically. Some of these cells proliferate from microglia resident in the brain, while others come from macrophages that migrate to the injured area and enter the brain via local disruptions in the cerebral vasculature. Cellular Diversity in the Nervous System Although the cellular constituents of the human nervous system are in many ways similar to those of other organs, they are unusual in their extraordinary numbers: the human brain is estimated to contain 100 billion neurons and several times as many supporting cells. More importantly, the nervous system has a greater range of distinct cell types—whether categorized by morphology, molecular identity, or physiological activity—than any other organ system (a fact that presumably explains why so many different genes are expressed in the nervous system; see above). The cellular diversity of any nervous system—including our own—undoubtedly underlies the the capacity of the system to form increasingly complicated networks to mediate increasingly sophisticated behaviors. For much of the twentieth century, neuroscientists relied on the same set of techniques developed by Cajal and Golgi to describe and categorize the diversity of cell types in the nervous system. From the late 1970s onward, however, new technologies made possible by the advances in cell and molecular biology provided investigators with many additional tools to discern the properties of neurons (Figure 1.6). Whereas general cell staining methods Studying the Nervous Systems of Humans and Other Animals 9 Purves01 5/13/04 1:03 PM Page 9
10 Chapter One (E) (G) (O) showed mainly differences in cell size and distribution, antibody stains and probes for messenger RNA added greatly to the appreciation of distinctive types of neurons and glia in various regions of the nervous system. At the same time, new tract tracing methods using a wide variety of tracing sub- stances allowed the interconnections among specific groups of neurons to be
10 Chapter One showed mainly differences in cell size and distribution, antibody stains and probes for messenger RNA added greatly to the appreciation of distinctive types of neurons and glia in various regions of the nervous system. At the same time, new tract tracing methods using a wide variety of tracing substances allowed the interconnections among specific groups of neurons to be (A) (B) (C) (D) (E) (F) (G) (H) (I) (J) (K) (L) (M) (N) (O) (P) Purves01 5/13/04 1:03 PM Page 10
Studying the Nervous Systems of Humans and Other Animals 11 Figure 1.6 Structural diversity in the nervous system demonstrated with cellular and molecular markers. First row: Cellular organization of different brain regions demonstrated with Nissl stains, which label nerve and glial cell bodies. (A) The cerebral cortex at the boundary between the primary and secondary visual areas. The olfactory bulbs. (C) Differences in cell density in cerebral cortical layers. D) sical and modern approaches to seeing individual neurons and their processes. 8 Cortical interneuron labeled by intracellular injection of a fluorescent dye.(H) Reti- nal neurons labeled by intracellular injection of fluorescent dye. Third row: Cellular and molecular approaches to seeing neural connections and systems. I)At top, an antibody that detects synaptic proteins in the olfactory bulb; at bottom, a fluorescent label shows the location of cell bodies. () Synaptic zones and the location of Purk inje cell bodies in the cerebellar cortex labeled with synapse-specific antibodies (green) and a cell body marker(blue).( K) The projection from one eye to the lateral geniculate nucleus in the thalamus, traced with radioactive amino acids(the bright label shows the axon terminals from the eye in distinct layers of the nucleus). (L) The map of the body surface of a rat in the somatic sensory cortex, shown with a marker that distinguishes zones of higher synapse density and metabolic activity Fourth row: Peripheral neurons and their projections (M)An autonomic neuron labeled by intracellular injection of an enzyme marker(N) Motor axons(green)and neuromuscular synapses(orange)in transgenic mice genetically engineered to express fluorescent proteins (O) The projection of dorsal root ganglia to the spinal cord, demonstrated by an enzymatic tracer(P) Axons of olfactory receptor neurons from the nose labeled in the olfactory bulb with a vital fluorescent dye. (G courtesy of L C. Katz; H courtesy of C J Shatz; N,O courtesy of W. Snider and J. Lichtman, all others courtesy of A -S LaMantia and D. Purves. explored much more fully. Tracers can be introduced into either living or fixed tissue, and are transported along nerve cell processes to reveal their origin and termination. More recently, genetic and neuroanatomical meth- ods have been combined to visualize the expression of fluorescent or other tracer molecules under the control of regulatory sequences of neural genes This approach, which shows individual cells in fixed or living tissue in remarkable detail, allows nerve cells to be identified by both their transcrip- tional state and their structure. Finally, ways of determining the molecular identity and morphology of nerve cells can be combined with measurements of their physiological activity, thus illuminating structure-function relation- ships. Examples of these various approaches are shown in Figure 1.6 Neural circuits Neurons never function in isolation; they are organized into ensembles or neural circuits that process specific kinds of information and provide the foundation of sensation, perception and behavior. The synaptic connections that define such circuits are typically made in a dense tangle of dendrites, axons terminals, and glial cell processes that together constitute what is called neuropil(the suffix -pil comes from the Greek word pilos, meaning felt"; see Figure 1.3). The neuropil is thus the region between nerve cell bodies where most synaptic connectivity occurs Although the arrangement of neural circuits varies greatly according to the function being served, some features are characteristic of all such ensem sles. Preeminent is the direction of information flow in any particular circuit, which is obviously essential to understanding its purpose. Nerve cells that
explored much more fully. Tracers can be introduced into either living or fixed tissue, and are transported along nerve cell processes to reveal their origin and termination. More recently, genetic and neuroanatomical methods have been combined to visualize the expression of fluorescent or other tracer molecules under the control of regulatory sequences of neural genes. This approach, which shows individual cells in fixed or living tissue in remarkable detail, allows nerve cells to be identified by both their transcriptional state and their structure. Finally, ways of determining the molecular identity and morphology of nerve cells can be combined with measurements of their physiological activity, thus illuminating structure–function relationships. Examples of these various approaches are shown in Figure 1.6. Neural Circuits Neurons never function in isolation; they are organized into ensembles or neural circuits that process specific kinds of information and provide the foundation of sensation, perception and behavior. The synaptic connections that define such circuits are typically made in a dense tangle of dendrites, axons terminals, and glial cell processes that together constitute what is called neuropil (the suffix -pil comes from the Greek word pilos, meaning “felt”; see Figure 1.3). The neuropil is thus the region between nerve cell bodies where most synaptic connectivity occurs. Although the arrangement of neural circuits varies greatly according to the function being served, some features are characteristic of all such ensembles. Preeminent is the direction of information flow in any particular circuit, which is obviously essential to understanding its purpose. Nerve cells that Studying the Nervous Systems of Humans and Other Animals 11 Figure 1.6 Structural diversity in the nervous system demonstrated with cellular and molecular markers. First row: Cellular organization of different brain regions demonstrated with Nissl stains, which label nerve and glial cell bodies. (A) The cerebral cortex at the boundary between the primary and secondary visual areas. (B) The olfactory bulbs. (C) Differences in cell density in cerebral cortical layers. (D) Individual Nissl-stained neurons and glia at higher magnification. Second row: Classical and modern approaches to seeing individual neurons and their processes. (E) Golgi-labeled cortical pyramidal cells. (F) Golgi-labeled cerebellar Purkinje cells. (G) Cortical interneuron labeled by intracellular injection of a fluorescent dye. (H) Retinal neurons labeled by intracellular injection of fluorescent dye. Third row: Cellular and molecular approaches to seeing neural connections and systems. (I) At top, an antibody that detects synaptic proteins in the olfactory bulb; at bottom, a fluorescent label shows the location of cell bodies. (J) Synaptic zones and the location of Purkinje cell bodies in the cerebellar cortex labeled with synapse-specific antibodies (green) and a cell body marker (blue). (K) The projection from one eye to the lateral geniculate nucleus in the thalamus, traced with radioactive amino acids (the bright label shows the axon terminals from the eye in distinct layers of the nucleus). (L) The map of the body surface of a rat in the somatic sensory cortex, shown with a marker that distinguishes zones of higher synapse density and metabolic activity. Fourth row: Peripheral neurons and their projections. (M) An autonomic neuron labeled by intracellular injection of an enzyme marker. (N) Motor axons (green) and neuromuscular synapses (orange) in transgenic mice genetically engineered to express fluorescent proteins. (O) The projection of dorsal root ganglia to the spinal cord, demonstrated by an enzymatic tracer. (P) Axons of olfactory receptor neurons from the nose labeled in the olfactory bulb with a vital fluorescent dye. (G courtesy of L. C. Katz; H courtesy of C. J. Shatz; N,O courtesy of W. Snider and J. Lichtman; all others courtesy of A.-S. LaMantia and D. Purves.) ▲ Purves01 5/13/04 1:03 PM Page 11
12 Chapter One Muscle 2B 2A Interneuron Motor efferent) 1 Hammer tap stretches 2(A) Sensory neuron synapses (A) Motor neuron conducts 4 ndon, which. in turn with and excites motor action potential to retches sensory euron in the spinal cord receptors in leg extensor muscle fibers, causing muscle B) Sensory neuron also contraction excites spinal interneuron () Interneuron synapse (B) Flexor muscle relaxes inhibits motor neuron because the activity of its to flexor muscles motor neurons has been inhibited Figure 1.7 A simple reflex circuit, the knee-jerk response(more formally, the myotatic reflex), illustrates several carry information toward the brain or spinal cord (or farther centrally within Dints about the functional organization the spinal cord and brain) are called afferent neurons; nerve cells that carry of neural circuits. Stimulation of periph- information away from the brain or spinal cord (or away from the circuit in eral sensors(a muscle stretch receptor in question)are called efferent neurons. Interneurons or local circuit neurons this case)initiates receptor potentials only participate in the local aspects of a circuit, based on the short distances that trigger action potentials that travel over which their axons extend. These three functional classes--afferent neu- entrally along the afferent axons of the rons, efferent neurons, and interneurons -are the basic constituents of all sensory neurons. This information stim- neural circuits ulates spinal motor neurons by means A simple example of a neural circuit is the ensemble of cells that subserves of synaptic contacts. The action poten- the myotatic spinal reflex(the"knee-jerk"reflex; Figure 1.7). The afferent in motor neurons travel peripherally in neurons of the reflex are sensory neurons whose cell bodies lie the dorsal efferent axons, giving rise to muscle con- root ganglia and whose peripheral axons terminate in sensory endings in traction and a behavioral response. One skeletal muscles(the ganglia that serve this same of function for much of the of the purposes of this particular refle head and neck are called cranial nerve ganglia; see Appendix A). The central is to help maintain an upright posture in axons of these afferent sensory neurons enter the the spinal cord where they the face of unexpected changes terminate on a variety of central neurons concerned with the regualtion of muscle tone, most obviously the motor neurons that determine the activity of the related muscles. These neurons constitute the efferent neurons as well as interneurons of the circuit. One group of these efferent neurons in the ventral horn of the spinal cord projects to the flexor muscles in the limb, and the other to extensor muscles. Spinal cord interneurons are the third element of this circuit. The interneurons receive synaptic contacts from sensory afferent neurons and make synapses on the efferent motor neurons that project to the
12 Chapter One carry information toward the brain or spinal cord (or farther centrally within the spinal cord and brain) are called afferent neurons; nerve cells that carry information away from the brain or spinal cord (or away from the circuit in question) are called efferent neurons. Interneurons or local circuit neurons only participate in the local aspects of a circuit, based on the short distances over which their axons extend. These three functional classes—afferent neurons, efferent neurons, and interneurons—are the basic constituents of all neural circuits. A simple example of a neural circuit is the ensemble of cells that subserves the myotatic spinal reflex (the “knee-jerk” reflex; Figure 1.7). The afferent neurons of the reflex are sensory neurons whose cell bodies lie the dorsal root ganglia and whose peripheral axons terminate in sensory endings in skeletal muscles (the ganglia that serve this same of function for much of the head and neck are called cranial nerve ganglia; see Appendix A). The central axons of these afferent sensory neurons enter the the spinal cord where they terminate on a variety of central neurons concerned with the regualtion of muscle tone, most obviously the motor neurons that determine the activity of the related muscles. These neurons constitute the efferent neurons as well as interneurons of the circuit. One group of these efferent neurons in the ventral horn of the spinal cord projects to the flexor muscles in the limb, and the other to extensor muscles. Spinal cord interneurons are the third element of this circuit. The interneurons receive synaptic contacts from sensory afferent neurons and make synapses on the efferent motor neurons that project to the Sensory (afferent) axon Interneuron Motor (efferent) axons Muscle sensory receptor Flexor muscle Extensor muscle 2C 2B 2A 1 3A 3B 4 Hammer tap stretches tendon, which, in turn, stretches sensory receptors in leg extensor muscle Leg extends (C) Interneuron synapse inhibits motor neuron to flexor muscles (B) Sensory neuron also excites spinal interneuron (A) Sensory neuron synapses with and excites motor neuron in the spinal cord (B) Flexor muscle relaxes because the activity of its motor neurons has been inhibited (A) Motor neuron conducts action potential to synapses on extensor muscle fibers, causing contraction 1 2 3 4 Figure 1.7 A simple reflex circuit, the knee-jerk response (more formally, the myotatic reflex), illustrates several points about the functional organization of neural circuits. Stimulation of peripheral sensors (a muscle stretch receptor in this case) initiates receptor potentials that trigger action potentials that travel centrally along the afferent axons of the sensory neurons. This information stimulates spinal motor neurons by means of synaptic contacts. The action potentials triggered by the synaptic potential in motor neurons travel peripherally in efferent axons, giving rise to muscle contraction and a behavioral response. One of the purposes of this particular reflex is to help maintain an upright posture in the face of unexpected changes. Purves01 5/13/04 1:03 PM Page 12
Studying the Nervous Systems of Humans and Other Animals 13 Hammer Figure 1.8 Relative frequency of action (afferent potentials(indicated by individual verti cal lines)in different components of the myotatic reflex as the reflex pathway is Sensory neuron +H++++ activated. Notice the modulatory effect of the interneuron Motor neuron Motor (efferent Interneuron etorneuron +t+++++ flexor muscles; therefore they are capable of modulating the input-output linkage. The excitatory synaptic connections between the sensory afferents and the extensor efferent motor neurons cause the extensor muscles to con- tract;at the same time, the interneurons activated by the afferents are inhibitory, and their activation diminishes electrical activity in flexor efferent motor neurons and causes the flexor muscles to become less active(Figure 8). The result is a complementary activation and inactivation of the syner gist and antagonist muscles that control the position of the leg A more detailed picture of the events underlying the myotatic or any other circuit can be obtained by electrophysiological recording(Figure 1.9).There re two basic approaches to measuring the electrical activity of a nerve cell extracellular recording(also referred to as single-unit recording), where an electrode is placed near the nerve cell of interest to detect its activity; and intracellular recording, where the electrode is placed inside the cell Extracel lular recordings primarily detect action potentials, the all-or-nothing changes in the potential across nerve cell membranes that convey information from one point to another in the nervous system. This sort of recording is particu larly useful for detecting temporal patterns of action potential activity and relating those patterns to stimulation by other inputs, or to specific behavioral events. Intracellular recordings can detect the smaller, graded potential changes that trigger action potentials, and thus allow a more detailed analy- sis of communication between neurons within a circuit. These graded trig- gering potentials can arise at either sensory receptors or synapses and are called receptor potentials or synaptic potentials, respectively. For the myotatic circuit, electrical activity can be measured both extracellu- larly and intracellularly, thus defining the functional relationships between neurons in the circuit. The pattern of action potential activity can be measured for each element of the circuit(afferents, efferents, and interneurons) before during, and after a stimulus(see Figure 1.8). By comparing the onset, dura tion, and frequency of action potential activity in each cell, a functional picture f the circuit emerges. As a result of the stimulus, the sensory neuron is trig- gered to fire at higher frequency (i.e, more action potentials per unit time nis increase triggers a higher frequency of action potentials in both the exten- sor motor neurons and the interneurons. Concurrently, the inhibitory synapses made by the interneurons onto the flexor motor neurons cause the frequency f action potentials in these cells to decline. Using intracellular recording, it is possible to observe directly the potential changes underlying the synaptic con- nections of the myotatic reflex circuit(see Figure 1.9)
flexor muscles; therefore they are capable of modulating the input–output linkage. The excitatory synaptic connections between the sensory afferents and the extensor efferent motor neurons cause the extensor muscles to contract; at the same time, the interneurons activated by the afferents are inhibitory, and their activation diminishes electrical activity in flexor efferent motor neurons and causes the flexor muscles to become less active (Figure 1.8). The result is a complementary activation and inactivation of the synergist and antagonist muscles that control the position of the leg. A more detailed picture of the events underlying the myotatic or any other circuit can be obtained by electrophysiological recording (Figure 1.9). There are two basic approaches to measuring the electrical activity of a nerve cell: extracellular recording (also referred to as single-unit recording), where an electrode is placed near the nerve cell of interest to detect its activity; and intracellular recording, where the electrode is placed inside the cell. Extracellular recordings primarily detect action potentials, the all-or-nothing changes in the potential across nerve cell membranes that convey information from one point to another in the nervous system. This sort of recording is particularly useful for detecting temporal patterns of action potential activity and relating those patterns to stimulation by other inputs, or to specific behavioral events. Intracellular recordings can detect the smaller, graded potential changes that trigger action potentials, and thus allow a more detailed analysis of communication between neurons within a circuit. These graded triggering potentials can arise at either sensory receptors or synapses and are called receptor potentials or synaptic potentials, respectively. For the myotatic circuit, electrical activity can be measured both extracellularly and intracellularly, thus defining the functional relationships between neurons in the circuit. The pattern of action potential activity can be measured for each element of the circuit (afferents, efferents, and interneurons) before, during, and after a stimulus (see Figure 1.8). By comparing the onset, duration, and frequency of action potential activity in each cell, a functional picture of the circuit emerges. As a result of the stimulus, the sensory neuron is triggered to fire at higher frequency (i.e., more action potentials per unit time). This increase triggers a higher frequency of action potentials in both the extensor motor neurons and the interneurons. Concurrently, the inhibitory synapses made by the interneurons onto the flexor motor neurons cause the frequency of action potentials in these cells to decline. Using intracellular recording, it is possible to observe directly the potential changes underlying the synaptic connections of the myotatic reflex circuit (see Figure 1.9). Studying the Nervous Systems of Humans and Other Animals 13 Sensory (afferent) axon Interneuron Motor (efferent) axons Motor neuron (extensor) Interneuron Sensory neuron Hammer tap Leg extends Motor neuron (flexor) Figure 1.8 Relative frequency of action potentials (indicated by individual vertical lines) in different components of the myotatic reflex as the reflex pathway is activated. Notice the modulatory effect of the interneuron. Purves01 5/13/04 1:03 PM Page 13