《医学生理学 Medical Physiology》参考教材资料（PDF电子书籍）Neuroscience in Medicine, Third edition, 2008

Chapter 1/Cytology and Organization of Cell Types cells, neurons possess a cell body, or perikaryon, other type of electrical signal, the synaptic potential which is the metabolic hub of the cell. However, at the postsynaptic site. The unidirectional or polar cellular processes extend from this center and give ized flow of information consists of action potentials the neuron its unique form and ability to receive at the axonal level eliciting synaptic potentials in the and rapidly send signals often over long distances postsynaptic cell, which triggers an action potential in (Fig. 1) that cell and so on. Axons may be as long as 2 m synapses. One neuron forms the presynaptic element, within the circuli stance and rapid communication signals are communicated between neurons at permitting long and the subsequent neuron forms the postsynaptic element.Chemical signals, in the form of neurotrans- 1.3. Diversity in Form Is a Distinctive Property mitters or neuropeptides, are concentrated at the pre- concentration of receptor molecules that are specific Although neuronal form follows the basic plan for each messenger. Presynaptic and postsynaptic 40 um,ensuring precise and directed transmission of them silty in size, shape, and function, which allows elements are separated by a space of only 20 to diver to discriminate the multitude of different types of incoming signals. The detection of commands for muscle contraction is under the control of motor neurons. Information in the form of light. mechanical 1.2. Neuronal Polarity Is a Function of Axons force, or chemical substances is distinguished by sen- and Dendrites sory neurons highly specialized for each particular The two main types of cellular processes are called type of sensation. It is perhaps in this group of neu- dendrites and axons(Fig. 1). Dendrites are usually rons that structural and functional diversity is most postsynaptic and form an enormous receptive sur- apparent. The rigorous demands of sensory discrimi face, which branches extensively. In some neurons, nation have imposed on these neurons the require such as cerebellar Purkinje cells, the dendritic ment to develop specific, highly sensitive detection branches form a characteristic elaborate arboriza- systems that are able to perceive various degrees of tion;others are less distinctive. In addition to their stimulus intensities. a classic example is the olfactory growth during normal development, some of these cell of the male gypsy moth, which can detect a mole- processes remain plastic and can change in length cule of the female's sex attractant, or pheromone, dramatically in the adult. For example, the extent of released a mile away. Equally impressive is the ability arborization of the dendritic tree of male rat motor of the mammalian nasal epithelium to detect and neurons that innervate penile muscles and mediate discriminate more than 10,000 different odiferous copulatory behavior appears to be under steroid hor- substances. In terms of the ability to recognize diverse mone (i.e, androgen) regulation. Stress and stress molecules, olfactory neurons are second only to the hormones appear to decrease dendritic length in the cells of the immune system. The olfactory neuron hippocampus, a brain area involved in memory and however, is markedly different in form and receptor learning and responses to stress. In some dendrites, locale from, for example, the retinal photoreceptor the membranous surfaces are further elaborated to cell. Receptive surfaces consisting of specialized cilia form protrusions called dendritic spines. Chemical on olfactory neurons contain the receptors and are signals received by dendrites and their spines are the primary sites of sensory transduction. In retinal integrated and transduced into an electrical signal, photoreceptor neurons, visual transduction occurs known as the synaptic potential within special cylindrical cellular domains containing The signal triggers the action potential, which is stacks of about 1000 membranous disks in which the propagated along the neuron,s plasma membrane photon receptors called rhodopsin are embedded down an elongated process called the axon. Although Sensory and other types of information enter the axons are not as expansive as dendrites, they branch nervous system by means of a particular neuron, but and may innervate more than one effector. The term- those signals are rarely sent to the effector neuron inal end of an axon is modified to form a bulbous surfaces directly. Rather, the initial signal is sent to a structure, the presynaptic terminal(Fig. 1). The third class of nerve cell, the interneurons. Interneur- incoming action potentials cause the release of neu- ons integrate various inputs from other neurons rotransmitter molecules that bind to complementary before the information, often in a modified form postsynaptic receptors. This binding initiates the reaches its final destination. In this way, various

cells, neurons possess a cell body, or perikaryon, which is the metabolic hub of the cell. However, cellular processes extend from this center and give the neuron its unique form and ability to receive and rapidly send signals often over long distances (Fig. 1). Signals are communicated between neurons at synapses. One neuron forms the presynaptic element, and the subsequent neuron forms the postsynaptic element. Chemical signals, in the form of neurotrans￾mitters or neuropeptides, are concentrated at the pre￾synaptic site. The postsynaptic site contains a high concentration of receptor molecules that are specific for each messenger. Presynaptic and postsynaptic elements are separated by a space of only 20 to 40 mm, ensuring precise and directed transmission of signals. 1.2. Neuronal Polarity Is a Function of Axons and Dendrites The two main types of cellular processes are called dendrites and axons (Fig. 1). Dendrites are usually postsynaptic and form an enormous receptive sur￾face, which branches extensively. In some neurons, such as cerebellar Purkinje cells, the dendritic branches form a characteristic elaborate arboriza￾tion; others are less distinctive. In addition to their growth during normal development, some of these processes remain plastic and can change in length dramatically in the adult. For example, the extent of arborization of the dendritic tree of male rat motor neurons that innervate penile muscles and mediate copulatory behavior appears to be under steroid hor￾mone (i.e., androgen) regulation. Stress and stress hormones appear to decrease dendritic length in the hippocampus, a brain area involved in memory and learning and responses to stress. In some dendrites, the membranous surfaces are further elaborated to form protrusions called dendritic spines. Chemical signals received by dendrites and their spines are integrated and transduced into an electrical signal, known as the synaptic potential. The signal triggers the action potential, which is propagated along the neuron’s plasma membrane down an elongated process called the axon. Although axons are not as expansive as dendrites, they branch and may innervate more than one effector. The term￾inal end of an axon is modified to form a bulbous structure, the presynaptic terminal (Fig. 1). The incoming action potentials cause the release of neu￾rotransmitter molecules that bind to complementary postsynaptic receptors. This binding initiates the other type of electrical signal, the synaptic potential at the postsynaptic site. The unidirectional or polar￾ized flow of information consists of action potentials at the axonal level eliciting synaptic potentials in the postsynaptic cell, which triggers an action potential in that cell and so on. Axons may be as long as 2 m, permitting long-distance and rapid communication within the circuit. 1.3. Diversity in Form Is a Distinctive Property of Neurons Although neuronal form follows the basic plan described above, nerve cells show a tremendous diversity in size, shape, and function, which allows them to discriminate the multitude of different types of incoming signals. The detection of commands for muscle contraction is under the control of motor neurons. Information in the form of light, mechanical force, or chemical substances is distinguished by sen￾sory neurons highly specialized for each particular type of sensation. It is perhaps in this group of neu￾rons that structural and functional diversity is most apparent. The rigorous demands of sensory discrimi￾nation have imposed on these neurons the require￾ment to develop specific, highly sensitive detection systems that are able to perceive various degrees of stimulus intensities. A classic example is the olfactory cell of the male gypsy moth, which can detect a mole￾cule of the female’s sex attractant, or pheromone, released a mile away. Equally impressive is the ability of the mammalian nasal epithelium to detect and discriminate more than 10,000 different odiferous substances. In terms of the ability to recognize diverse molecules, olfactory neurons are second only to the cells of the immune system. The olfactory neuron, however, is markedly different in form and receptor locale from, for example, the retinal photoreceptor cell. Receptive surfaces consisting of specialized cilia on olfactory neurons contain the receptors and are the primary sites of sensory transduction. In retinal photoreceptor neurons, visual transduction occurs within special cylindrical cellular domains containing stacks of about 1000 membranous disks in which the photon receptors called rhodopsin are embedded. Sensory and other types of information enter the nervous system by means of a particular neuron, but those signals are rarely sent to the effector neuron surfaces directly. Rather, the initial signal is sent to a third class of nerve cell, the interneurons. Interneur￾ons integrate various inputs from other neurons before the information, often in a modified form, reaches its final destination. In this way, various Chapter 1 / Cytology and Organization of Cell Types 3

Cohen and pfaff types of inputs(e.g, sensory, hormonal) can be inte- Nevertheless, as eukaryotic cells, they adhere to grated and relayed to other parts of the central ner- basic laws that govern cellular function. In many vous system or to motor or endocrine targets. ways, neurons are not so different from other cells Interneurons contribute to the formation of neural and qualities once ascribed only to neurons may he circuits and are to a great extent responsible for the found elsewhere. Egg membranes, for example, can relatively large size and extraordinary complexity of depolarize during fertilization and release granules in the mammalian nervous system response to Ca entry through specific channels, although the process takes much longer than compar 1.4. Neuronal Polarity Allows the Directed able signaling mechanisms in neurons. Sites of ribo- Flow of Electrical and Chemical Signals somal RNA synthesis, called nucleoli, are found in all A single neuron may receive a multitude of differ- eukaryotic cells but are especially pro rons. because there is a constant need for ribosomes nt inputs from a variety of sources. A motor neuron, fo for example, receives thousands of presynaptic term- for new protein synthesis. It appears that basic cellu inals from many different neurons on its dendritic lar mechanisms are present in nerve cells but that surface and on its somal and nd, to some extent axonal. some of these are amplified to meet the rigorous membranes, which may also bear postsynaptic recep- demands of neuronal form and function tors. This input has to be organized into a cohesive message that can be transmitted to its postsynaptic 2.1. The Nucleus Is the command Center neighbor of the neuron The neuronal plasma membrane plays a key role in The molecular and cellular diversity within and integrating and relaying the information in a directed among neurons reflects a highly controlled differen- manner and with exceptional speed. Information is tial expression of genes. Gene regulation also deter- conducted within neurons in the form of electrical mines nerve cell connectivity, which dictates patterns or shals, which are actually changes in the distribution of stereotyped behaviors. It is also becoming evident Charge distribution is highly regulated in neurons by learning, may require the synthesis of new proteins specific and selective proteins called ion channels which ultimately depends on the expression of parti- embedded in the plasma membrane. These transmem- cular genes. As eukaryotic cells, neurons sequester brane proteins control the flow of ions and, conse- their genome in the nucleus, the largest and most quently, the distribution of positive and negative conspicuous feature of the perikaryon(Fig. 2). The charges across the membrane In resting neurons, the nucleus contains chromosomal dna and the membrane potential is about -60 to -70 mV(i.e, an machinery for synthesizing and processing RNA excess of positive charges outside and negative charges which is subsequently transported to the cytoplasm, inside). When this potential becomes less negative, or where information encoded in the DNA is expressed depolarized, electrical excitation occurs in the mem- as specific proteins. The nucleus is separated from the brane. In axons, this excitation is known as the action rest of the cytoplasm by a porous double membrane potential.The action potential is generated when the the nuclear envelope, consisting of an outer nuclear membrane potential of the axonal membrane is membrane and an inmer muclear membrane: the inner decreased beyond a threshold value. An important and outer membranes are in contact with each other area of the cell body is the axon hillock, the site on at regions called pore membranes, which are described summation of excitatory and inhibitory input Struc- below. Beneath and in intimate contact with the inner turally, it is devoid of organelles, such as rough nuclear membrane is the nuclear lamina, consisting endoplasmic reticulum(see later) and, at the light of intermediate filaments, and which controls such microscopic level, appears as a lightly stained area. functions as the maintenance of nuclear shape, dis- After summation, the membrane potential reaches its assembly and assembly of the nucleus prior to and threshold, thereby generating the action potential following mitosis, organization of the chromatin spacing of nuclear pores, and transcriptional regula 2. MECHANISMS OF NEURONAL FUNCTION tion. At least 13 genetic disorders involving gene encoding some of the laminins have been described ompared with other cells, neurons are unsurpassed and include premature aging syndromes, myopathies in their complexity of form and ability to comm- and neuropathies, and lipodystrophies. The nuclear unicate with lightning speed over long distances. envelope protects the DNa molecules from mechanical

types of inputs (e.g., sensory, hormonal) can be inte￾grated and relayed to other parts of the central ner￾vous system or to motor or endocrine targets. Interneurons contribute to the formation of neural circuits and are to a great extent responsible for the relatively large size and extraordinary complexity of the mammalian nervous system. 1.4. Neuronal Polarity Allows the Directed Flow of Electrical and Chemical Signals A single neuron may receive a multitude of differ￾ent inputs from a variety of sources. A motor neuron, for example, receives thousands of presynaptic term￾inals from many different neurons on its dendritic surface and on its somal and, to some extent axonal, membranes, which may also bear postsynaptic recep￾tors. This input has to be organized into a cohesive message that can be transmitted to its postsynaptic neighbor. The neuronal plasma membrane plays a key role in integrating and relaying the information in a directed manner and with exceptional speed. Information is conducted within neurons in the form of electrical signals, which are actually changes in the distribution of electrical charges across the neuronal membrane. Charge distribution is highly regulated in neurons by specific and selective proteins called ion channels embedded in the plasma membrane. These transmem￾brane proteins control the flow of ions and, conse￾quently, the distribution of positive and negative charges across the membrane. In resting neurons, the membrane potential is about –60 to –70 mV (i.e., an excess of positive charges outside and negative charges inside). When this potential becomes less negative, or depolarized, electrical excitation occurs in the mem￾brane. In axons, this excitation is known as the action potential. The action potential is generated when the membrane potential of the axonal membrane is decreased beyond a threshold value. An important area of the cell body is the axon hillock, the site of summation of excitatory and inhibitory input. Struc￾turally, it is devoid of organelles, such as rough endoplasmic reticulum (see later) and, at the light microscopic level, appears as a lightly stained area. After summation, the membrane potential reaches its threshold, thereby generating the action potential. 2. MECHANISMS OF NEURONAL FUNCTION Compared with other cells, neurons are unsurpassed in their complexity of form and ability to comm￾unicate with lightning speed over long distances. Nevertheless, as eukaryotic cells, they adhere to basic laws that govern cellular function. In many ways, neurons are not so different from other cells, and qualities once ascribed only to neurons may he found elsewhere. Egg membranes, for example, can depolarize during fertilization and release granules in response to Ca+ entry through specific channels, although the process takes much longer than compar￾able signaling mechanisms in neurons. Sites of ribo￾somal RNA synthesis, called nucleoli, are found in all eukaryotic cells but are especially prominent in neu￾rons, because there is a constant need for ribosomes for new protein synthesis. It appears that basic cellu￾lar mechanisms are present in nerve cells but that some of these are amplified to meet the rigorous demands of neuronal form and function. 2.1. The Nucleus Is the Command Center of the Neuron The molecular and cellular diversity within and among neurons reflects a highly controlled differen￾tial expression of genes. Gene regulation also deter￾mines nerve cell connectivity, which dictates patterns of stereotyped behaviors. It is also becoming evident that more complex behaviors, such as memory and learning, may require the synthesis of new proteins, which ultimately depends on the expression of parti￾cular genes. As eukaryotic cells, neurons sequester their genome in the nucleus, the largest and most conspicuous feature of the perikaryon (Fig. 2). The nucleus contains chromosomal DNA and the machinery for synthesizing and processing RNA, which is subsequently transported to the cytoplasm, where information encoded in the DNA is expressed as specific proteins. The nucleus is separated from the rest of the cytoplasm by a porous double membrane, the nuclear envelope, consisting of an outer nuclear membrane and an inner nuclear membrane; the inner and outer membranes are in contact with each other at regions called pore membranes, which are described below. Beneath and in intimate contact with the inner nuclear membrane is the nuclear lamina, consisting of intermediate filaments, and which controls such functions as the maintenance of nuclear shape, dis￾assembly and assembly of the nucleus prior to and following mitosis, organization of the chromatin, spacing of nuclear pores, and transcriptional regula￾tion. At least 13 genetic disorders involving genes encoding some of the laminins have been described and include premature aging syndromes, myopathies and neuropathies, and lipodystrophies. The nuclear envelope protects the DNA molecules from mechanical 4 Cohen and Pfaff

Chapter 1/Cytology and Organization of Cell Types complexes of proteins called transcription factors Each of these proteins possesses special DNA binding domains and requires direct contact with the dna to function. However the long stretch of DNA, which in humans measures about 3 cm long, is folded thousands of times to fit into a nucleus only a few micrometers in diameter. Such compaction cre- ates a potential problem for factors that must gain free access to corresponding binding sites and other regulatory regions on the DNA strand. Another group of proteins, called histones, packs the dNA so that it is folded, coiled, and compressed many times over to form fibers called chromatin visible as fine threads in the interphase nucleus(Fig. 2)and, in Fig. 2. Electron micrograph of a nucleus of a hypothalamic an even more contracted form, as chromosomes in neuron. The nucleus(N) is separated from the cytoplasm by a the dividing cell nuclearenvelope(NE). A conspicuous nucleolus(Nu)signifies In the mature neuron, the nucleus remains in int a great demand for ribosomal RNA by the neuron. Proteins phase. DNA is segregated into morphologically disti called histones associate with DNA to form chromatin, which areas, reflecting the degree of chromatin may appear extended (i.e, euchromatin) or condensed (i.e, which is a function of nuclear activity(Fig. 2).Riboso heterochromatin), depending on the translational activity of mal dNa genes and their products are separately fine fibers of euchromatin(asterisk). Heterochromatin(arrow- packed into a structurall y defined compartment heads) is seen as clumps within the nucleus, on the inner sur- called the nucleolus that is specialized for ribosomal face of the nuclear envelope, or associated with the nucleolus. RNA synthesis. Highly coiled regions for the genome appear as dense, irregularly shaped clumps known as heterochromatin. These areas of condensed chro- perturbations caused by cytoplasmic filaments. More- matin are situated within the nucleus along the inner over, it separates the process of RNA synthesis (i.e, nuclear membrane, in association with the nucleolus transcription)from that of protein synthesis (i. e, trans- or dispersed within the nucleus proper. Other regions lation). This segregation of function has an important of the genome readily available for transcription into advantage over the situation in prokaryotes, in which messenger RNA appear as fine filaments and are transcription and translation occur simultaneously. In known as euchromatin these organisms, protein synthesis begins before the completion of transcription, limiting the opportunity 2.1.1.1. Chromatin Remodeling in Behavior for modifying the RNA. Translation in eukaryotes and in Neural Diseases. The manner in which does not begin until the RNA is transported into the DNA encodes proteins is discussed elsewhere.These cytoplasm. In the nucleus, the RNa may be modified proteins ultimately affect our behavior.However in such a way that specific portions of the RNa mole- novel studies reveal the exciting possibility that our cule are removed (ie, RNA Splicing) or altered. These behavior may modify the genome and that some of complex changes have important implications for cell these changes may become permanent. These changes function. Mechanisms that control variability at the are known as environmental programming and are part level of transcribed rNa allow a single gene to code of the phenomenon of epigenesis, whereby stable and for several different proteins, resulting in the rich diver- heritable alterations in gene expression are not directly sity seen, especially in neurons, in the form of neuro- due to changes in DNA sequences. An example is that peptides, receptors, ion channels, and cytoskeletal of maternal behavior in rats. In rodents materna proteins behavior, such as tactile stimulation by the mother toward the pup, can result in increased amounts of 2.1.1 MATIN STRUCTURE IN THE REGULATION OF GENE ACTIVITY specific second messengers and gene transcription fac- tors. Binding of certain transcription factors to the The degree of complexity of gene expression is further DNA may result in the recruitment of a class of multiplied at another, even more fundamental level of enzymes, called histone acetyltransferases. These gene regulation: the DNA Genes are turned on by enzymes increase histone acetylation, which permits

perturbations caused by cytoplasmic filaments. More￾over, it separates the process of RNA synthesis (i.e., transcription) from that of protein synthesis (i.e., trans￾lation). This segregation of function has an important advantage over the situation in prokaryotes, in which transcription and translation occur simultaneously. In these organisms, protein synthesis begins before the completion of transcription, limiting the opportunity for modifying the RNA. Translation in eukaryotes does not begin until the RNA is transported into the cytoplasm. In the nucleus, the RNA may be modified in such a way that specific portions of the RNA mole￾cule are removed (i.e., RNA splicing) or altered. These complex changes have important implications for cell function. Mechanisms that control variability at the level of transcribed RNA allow a single gene to code for several different proteins, resulting in the rich diver￾sity seen, especially in neurons, in the form of neuro￾peptides, receptors, ion channels, and cytoskeletal proteins. 2.1.1. CHROMATIN STRUCTURE IN THE REGULATION OF GENE ACTIVITY The degree of complexity of gene expression is further multiplied at another, even more fundamental level of gene regulation: the DNA. Genes are turned on by complexes of proteins called transcription factors. Each of these proteins possesses special DNA￾binding domains and requires direct contact with the DNA to function. However, the long stretch of DNA, which in humans measures about 3 cm long, is folded thousands of times to fit into a nucleus only a few micrometers in diameter. Such compaction cre￾ates a potential problem for factors that must gain free access to corresponding binding sites and other regulatory regions on the DNA strand. Another group of proteins, called histones, packs the DNA so that it is folded, coiled, and compressed many times over to form fibers called chromatin, visible as fine threads in the interphase nucleus (Fig. 2) and, in an even more contracted form, as chromosomes in the dividing cell. In the mature neuron, the nucleus remains in inter￾phase. DNA is segregated into morphologically distinct areas, reflecting the degree of chromatin condensation, which is a function of nuclear activity (Fig. 2). Riboso￾mal DNA genes and their products are separately packed into a structurally defined compartment called the nucleolus that is specialized for ribosomal RNA synthesis. Highly coiled regions for the genome appear as dense, irregularly shaped clumps known as heterochromatin. These areas of condensed chro￾matin are situated within the nucleus along the inner nuclear membrane, in association with the nucleolus or dispersed within the nucleus proper. Other regions of the genome readily available for transcription into messenger RNA appear as fine filaments and are known as euchromatin. 2.1.1.1. Chromatin Remodeling in Behavior and in Neural Diseases. The manner in which DNA encodes proteins is discussed elsewhere. These proteins ultimately affect our behavior. However, novel studies reveal the exciting possibility that our behavior may modify the genome and that some of these changes may become permanent. These changes are known as environmental programming and are part of the phenomenon of epigenesis, whereby stable and heritable alterations in gene expression are not directly due to changes in DNA sequences. An example is that of maternal behavior in rats. In rodents, maternal behavior, such as tactile stimulation by the mother toward the pup, can result in increased amounts of specific second messengers and gene transcription fac￾tors. Binding of certain transcription factors to the DNA may result in the recruitment of a class of enzymes, called histone acetyltransferases. These enzymes increase histone acetylation, which permits Fig. 2. Electron micrograph of a nucleus of a hypothalamic neuron. The nucleus (N) is separated from the cytoplasm by a nuclear envelope (NE). A conspicuous nucleolus (Nu) signifies a great demand for ribosomal RNA by the neuron. Proteins called histones associate with DNA to form chromatin, which may appear extended (i.e., euchromatin) or condensed (i.e., heterochromatin), depending on the translational activity of specific regions of the genome. Most of the nucleus contains fine fibers of euchromatin (asterisk). Heterochromatin (arrow￾heads) is seen as clumps within the nucleus, on the inner sur￾face of the nuclear envelope, or associated with the nucleolus. Chapter 1 / Cytology and Organization of Cell Types 5

Cohen and pfaff access of another enzyme, demethylase, allowing along the envelope, the inner and outer membranes demethylation of a promoter to facilitate the recruit- are in continuity around the edges of each pore at a ment of DNA-binding proteins. These proteins, in region called the pore membrane( Fig. 3).The turn, may facilitate the expression of beneficial genes. nuclear pore is not a simple opening. The nuclear Conversely, in the absence of tactile stimulation and pore complex, itself, resembles a megaphone, with increased transcription factor, the promoter will the large opening facing the cytoplasm and the small remain methylated. An example of one of these pro- opening on the nuclear side. The basic structure moters is that for the glucocorticoid receptor, which consists of cytoplasmic fibrils, a central core, and a appears to be involved in modulating stress. Other nuclear cage or basket. Depending upon the organ behavioral studies suggest that handling of newborn ism, from 50 to 100 different proteins, called nucleo- rats decreases the extent of the hormonal response to porins, or Nups, make up the entire structure in adulthood; that is, the rats are less stressed as Irregardless of the organism, however, there are s. Importantly, the experience of tactile stimula- only about 30 distinct nucleoporins Nucleoporins tion by the mother may be converted into a phenotypic are involved in binding large transported molecules variation of the offspring that may be transmitted (displaying diameters of up to 39 nm), called cargo into human behavior, where the kind of parental care trapping the molecules, and terminating the trans- ort reaction. Other proteins, called ka received by children can impact physiologic responses (Kaps), are shuttling transport, or carrier, proteins to stress(resulting, for example, in cognitive and beha- Karyopherins, including importins and exportins viral problems)that persist into adulthood. Epige- recognize muclear localization or export signals on netic modifications can also result in various brain the cargo, which allow entry into or export from the dysfunctions, including Rubinstein-Taybi syndrome nucleus, respectively. The transport is energy and the Coffin-Lowry syndrome, disorders character ized by mental retardation, and the a-thalassemia mental retardation syndrome 2.1.2. NUCLEOLUS AS THE SITE OF RIBOSOMAL RNA A SYNTHESIS The nucleolus is a prominent spherical region of the nucleus(Fig. 2)containing that portion of the genome dedicated to the transcription of ribosomal DNA and the mechanisms for the assembly of ribo- somal subunits, the precursors of mature ribo- somes. Large precursor ribosomal RNA molecules are processed in the nucleus, resulting in the degra dation of almost half of the nucleotide sequences. B two subunits that are independently transported into the cytoplasm, where the mature ribosomes are assembled. The nucleolus is evident only in the interphase nucleus; in other cells that undergo mitosis, it decondenses, ribosomal RNA synthesis stops, and ribosomal DNA genes associate with specific regions of the chromosomes called nucleo- lar organizing regions 2.1.3. NUCLEAR PORE COMPLEX CONTROLS TRAFFIC Fig 3. Electron micrographs of nuclear pores.(A)The BETWEEN THE NUCLEUS AND CYTOPLASM pendicular section of the nuclear envelope(NE) shows the The double membrane comprising the nuclear continuity of the inner and outer nuclear membranes(arrow- heads) around a nuclear pore(arrow)of the nucleus(N).( B)A envelope presents a formidable barrier between the surface view shows the arrangement of nuclear pores in the nucleus and cytoplasm. Macromolecular traffic into nuclear membrane (NM). One of the nuclear pores(arron and out of the nucleus is achieved by perforations, head) shows the octagonal configuration of proteins compris or pores, in the nuclear envelope. At various points ing the nuclear pore complex

access of another enzyme, demethylase, allowing demethylation of a promoter to facilitate the recruit￾ment of DNA-binding proteins. These proteins, in turn, may facilitate the expression of beneficial genes. Conversely, in the absence of tactile stimulation and increased transcription factor, the promoter will remain methylated. An example of one of these pro￾moters is that for the glucocorticoid receptor, which appears to be involved in modulating stress. Other behavioral studies suggest that handling of newborn rats decreases the extent of the hormonal response to stress in adulthood; that is, the rats are less stressed as adults. Importantly, the experience of tactile stimula￾tion by the mother may be converted into a phenotypic variation of the offspring that may be transmitted across generations. This phenomenon may translate into human behavior, where the kind of parental care received by children can impact physiologic responses to stress (resulting, for example, in cognitive and beha￾vioral problems) that persist into adulthood. Epige￾netic modifications can also result in various brain dysfunctions, including Rubinstein-Taybi syndrome and the Coffin-Lowry syndrome, disorders character￾ized by mental retardation, and the a-thalassemia/ mental retardation syndrome. 2.1.2. NUCLEOLUS AS THE SITE OF RIBOSOMAL RNA SYNTHESIS The nucleolus is a prominent spherical region of the nucleus (Fig. 2) containing that portion of the genome dedicated to the transcription of ribosomal DNA and the mechanisms for the assembly of ribo￾somal subunits, the precursors of mature ribo￾somes. Large precursor ribosomal RNA molecules are processed in the nucleus, resulting in the degra￾dation of almost half of the nucleotide sequences. The remaining ribonucleoprotein molecules form two subunits that are independently transported into the cytoplasm, where the mature ribosomes are assembled. The nucleolus is evident only in the interphase nucleus; in other cells that undergo mitosis, it decondenses, ribosomal RNA synthesis stops, and ribosomal DNA genes associate with specific regions of the chromosomes called nucleo￾lar organizing regions. 2.1.3. NUCLEAR PORE COMPLEX CONTROLS TRAFFIC BETWEEN THE NUCLEUS AND CYTOPLASM The double membrane comprising the nuclear envelope presents a formidable barrier between the nucleus and cytoplasm. Macromolecular traffic into and out of the nucleus is achieved by perforations, or pores, in the nuclear envelope. At various points along the envelope, the inner and outer membranes are in continuity around the edges of each pore at a region called the pore membrane (Fig. 3). The nuclear pore is not a simple opening. The nuclear pore complex, itself, resembles a megaphone, with the large opening facing the cytoplasm and the small opening on the nuclear side. The basic structure consists of cytoplasmic fibrils, a central core, and a nuclear cage or basket. Depending upon the organ￾ism, from 50 to 100 different proteins, called nucleo￾porins, or Nups, make up the entire structure. Irregardless of the organism, however, there are only about 30 distinct nucleoporins. Nucleoporins are involved in binding large transported molecules (displaying diameters of up to 39 nm), called cargo, trapping the molecules, and terminating the trans￾port reaction. Other proteins, called karyopherins (Kaps), are shuttling transport, or carrier, proteins. Karyopherins, including importins and exportins, recognize nuclear localization or export signals on the cargo, which allow entry into or export from the nucleus, respectively. The transport is energy Fig. 3. Electron micrographs of nuclear pores. (A) The per￾pendicular section of the nuclear envelope (NE) shows the continuity of the inner and outer nuclear membranes (arrow￾heads) around a nuclear pore (arrow) of the nucleus (N). (B) A surface view shows the arrangement of nuclear pores in the nuclear membrane (NM). One of the nuclear pores (arrow￾head) shows the octagonal configuration of proteins compris￾ing the nuclear pore complex. 6 Cohen and Pfaff

Chapter 1/Cytology and Organization of Cell Types 7 dependent for both import and export. The enzyme 2.2.1. PROTEINS SYNTHESIZED BY NEURONS GTPase or Ran provides energy and cycles between FOR ExPORT a guanosine triphosphate(GTP)- and guanosine Appreciation of the tremendous protein synthetic diphosphate (GDP)-bound state, with Ran GTP nerve being primarily nuclear and Ran GDP primarily tions is relatively recent. Neuronal form and mem- cytoplasmic in location. Small molecules(less than brane properties were the main focus of earlier 40 kDa), ions, and metabolites can cross the nuclear neurobiologists. However, the compelling discovery pore complex by passive diffusion. Some proteins of glandular cells in the spinal cord of fish by Carl th the are thought to be imported both passively and , peidel in 1919 and of neurosecretory cells in the hypothalamus by Ernst Scharrer in 1928 directed actively. Some particles, such as the assembled attention to the great degree of biosynthetic activity mature ribosomes, are too large to gain entrance in the perikaryon. Ernst Scharrer noticed that the through these passageways, ensuring that protein secretory activity of diencephalic neurons was com- synthesis is restricted to the cytoplasm. parable with that seen in endocrine cells. This obser 2.1. 4. DYNAMIC NUCLEAR MORPHOLOGY REFLECTS vation stimulated further interest in finding structural ALTERATIONS IN THE GENOME counterparts of the secretory process in neurons. The mechanisms involved in peptide biosynthesis and Although nuclear events occur on a molecular scale, posttranslational processing are now well-known they may be detected by gross adjustments in nuclear Related molecular and biochemical events are morphology. The overall size and shape of nuclei and detailed in other chapters of this volume. In this nucleoli can change with the metabolic and physiolo- chapter, we describe the structural correlates of demands of the neuron. Depending on transcrip- these functions as they occur in various parts of the tional activity, various segments of the chromatin can nerve cell condense or decondense. resulting in a relative change in the disposition of heterochromatin and euchromatin and altering the general appearance of 2. 2.1.1. Synthesis of Exportable Neuropeptides the nucleus. For example, in the hypothalamus, a on the Rough Endoplasmic Reticulum. Neurons brain area controlling female reproductive behavior. must transmit chemical information and electrical the gonadal steroid hormone estrogen exerts a pro- signals over very long distances. Proteins are synthe found influence on nuclear mophology, altering the sized, packaged, processed, stored, and released in size, shape, and position of heterochromatic regions. difterent domains of the neuron. The synthesis of Nucleolar size is also subject to the physiologic con- bosomal subunits produced in the nucleolus enter the ditions of the cell. Estrogen treatment has a pro nounced effect on precursor ribosomal RNA levels. cytoplasm, where they are assembled and activated to hich are accompanied by a significant increase in form functional ribosomes. In some cases, they attach nucleolar area in the hypothalamus of ovariecto- to membranous cisternae comprising the rough endo- mized animals. Nucleolar hypertrophy Is Followed plasmic reticulum(Fig. 4). The outer nuclear mem- by a massive increase in rough endoplasmic reticulum brane ramifies within the cytoplasm as it encircles the in these neurons nucleus and studded with ribosomes. also becomes part of the protein synthetic apparatus Messenger rnas associated with ribosomes are 2.2. Neurons Are Actively Engaged in Protein translated into precursor proteins. The precursors Synthesis are larger than the biologically active peptides and Information contained within the genome is must be enzymatically cleaved and modified to attain expressed as biologically active peptides in the cell their final form Instructions about whether a given body or perikaryon of the neuron. Some peptides protein is destined for export are also encoded in the are neuron specific, such as some of the neurosecre- DNA of its precursor. A portion of the complemen tory peptides, cytoskeletal proteins, ion channels, and tary messenger RNa is translated into a signal pep- receptors. Others are common to all cells and are tide, which directs ribosomes to the cisternae of the involved in increasing the efficiency of transcriptional rough endoplasmic reticulum. Peptides lacking a and translational events related to the production, signal sequence cannot gain entry to the cisternae transport, and release of these proteins The disposition and extent of rough endoplasmic

dependent for both import and export. The enzyme GTPase or Ran provides energy and cycles between a guanosine triphosphate (GTP)- and guanosine diphosphate (GDP)-bound state, with Ran GTP being primarily nuclear and Ran GDP primarily cytoplasmic in location. Small molecules (less than 40 kDa), ions, and metabolites can cross the nuclear pore complex by passive diffusion. Some proteins associated with the inner nuclear membrane itself are thought to be imported both passively and actively. Some particles, such as the assembled mature ribosomes, are too large to gain entrance through these passageways, ensuring that protein synthesis is restricted to the cytoplasm. 2.1.4. DYNAMIC NUCLEAR MORPHOLOGY REFLECTS ALTERATIONS IN THE GENOME Although nuclear events occur on a molecular scale, they may be detected by gross adjustments in nuclear morphology. The overall size and shape of nuclei and nucleoli can change with the metabolic and physiolo￾gic demands of the neuron. Depending on transcrip￾tional activity, various segments of the chromatin can condense or decondense, resulting in a relative change in the disposition of heterochromatin and euchromatin and altering the general appearance of the nucleus. For example, in the hypothalamus, a brain area controlling female reproductive behavior, the gonadal steroid hormone estrogen exerts a pro￾found influence on nuclear morphology, altering the size, shape, and position of heterochromatic regions. Nucleolar size is also subject to the physiologic con￾ditions of the cell. Estrogen treatment has a pro￾nounced effect on precursor ribosomal RNA levels, which are accompanied by a significant increase in nucleolar area in the hypothalamus of ovariecto￾mized animals. Nucleolar hypertrophy is followed by a massive increase in rough endoplasmic reticulum in these neurons. 2.2. Neurons Are Actively Engaged in Protein Synthesis Information contained within the genome is expressed as biologically active peptides in the cell body or perikaryon of the neuron. Some peptides are neuron specific, such as some of the neurosecre￾tory peptides, cytoskeletal proteins, ion channels, and receptors. Others are common to all cells and are involved in increasing the efficiency of transcriptional and translational events related to the production, transport, and release of these proteins. 2.2.1. PROTEINS SYNTHESIZED BY NEURONS FOR EXPORT Appreciation of the tremendous protein synthetic activity of the nerve cell and its functional implica￾tions is relatively recent. Neuronal form and mem￾brane properties were the main focus of earlier neurobiologists. However, the compelling discovery of glandular cells in the spinal cord of fish by Carl Speidel in 1919 and of neurosecretory cells in the hypothalamus by Ernst Scharrer in 1928 directed attention to the great degree of biosynthetic activity in the perikaryon. Ernst Scharrer noticed that the secretory activity of diencephalic neurons was com￾parable with that seen in endocrine cells. This obser￾vation stimulated further interest in finding structural counterparts of the secretory process in neurons. The mechanisms involved in peptide biosynthesis and posttranslational processing are now well-known. Related molecular and biochemical events are detailed in other chapters of this volume. In this chapter, we describe the structural correlates of these functions as they occur in various parts of the nerve cell. 2.2.1.1. Synthesis of Exportable Neuropeptides on the Rough Endoplasmic Reticulum. Neurons must transmit chemical information and electrical signals over very long distances. Proteins are synthe￾sized, packaged, processed, stored, and released in different domains of the neuron. The synthesis of exportable proteins begins in the perikaryon. Preri￾bosomal subunits produced in the nucleolus enter the cytoplasm, where they are assembled and activated to form functional ribosomes. In some cases, they attach to membranous cisternae comprising the rough endo￾plasmic reticulum (Fig. 4). The outer nuclear mem￾brane ramifies within the cytoplasm as it encircles the nucleus and, studded with ribosomes, also becomes part of the protein synthetic apparatus. Messenger RNAs associated with ribosomes are translated into precursor proteins. The precursors are larger than the biologically active peptides and must be enzymatically cleaved and modified to attain their final form. Instructions about whether a given protein is destined for export are also encoded in the DNA of its precursor. A portion of the complemen￾tary messenger RNA is translated into a signal pep￾tide, which directs ribosomes to the cisternae of the rough endoplasmic reticulum. Peptides lacking a signal sequence cannot gain entry to the cisternae. The disposition and extent of rough endoplasmic Chapter 1 / Cytology and Organization of Cell Types 7