Physiology_Levy

Physiology_Levy. These pathways ensure that the cellular response to external signals is specific, amplified, tightly regulated, and coordinated. 2. There are two classes of GTP-binding proteins: monomeric G proteins and heterotrimeric G proteins composed of α, β, and γ subunits. Monomeric G proteins regulate actin cytoskeleton organization, cell cycle progression, intracellular vesicular transport, and gene expression. Heterotrimeric G proteins regulate ion channels, adenylyl cyclase and the cAMP-PKA signaling pathway, phosphodiesterases (which also regulate cAMP and cGMP signaling pathways), and Cheung E, Kraus WL. Genomic analyses of hormone signaling and gene regulation. Annu Rev Physiol. 2010;72:191-218. Huang P, Chandra V, Rastinejad F. Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu Rev Physiol. 2010;72:247-272. Levin ER. Extranuclear steroid receptors are essential for steroid hormone actions. Annu Rev Med. 2015;66:271-280.


Physiology_Levy

Physiology_Levy. Levin ER. Extranuclear steroid receptors are essential for steroid hormone actions. Annu Rev Med. 2015;66:271-280. Riccardi D, Kemp P. The calcium-sensing receptor beyond extracellular calcium homeostasis: conception, development, adult physiology, and disease. Annu Rev Physiol. 2012;74:271-297. Wu H. Higher-order assemblies in a new paradigm of signal transduction. Cell. 2013;153:287-292. phospholipases, which regulate the production of prostaglandins, prostacyclins, and thromboxanes. 3. There are four subtypes of enzyme-linked receptors that mediate the cellular response to a wide variety of signals, including ANP, nitric oxide, TGF-β, PDGF, insulin, and interleukins. 4. There are two types of nuclear receptors: (1) one type that in the absence of ligand is located in the cytoplasm and when bound to ligand translocates to the nucleus and (2) another type that permanently resides in the nucleus. Both classes of receptors regulate gene transcription.


Physiology_Levy

Physiology_Levy. Cantley L. Signal transduction. In: Boron WF, Boulpaep EL, eds. Medical Physiology. 3rd ed. Philadelphia: Elsevier; 2016 [Chapter 3]. Caplan MJ. Functional organization of the cell. In: Boron WF, Boulpaep EL, eds. Medical Physiology. 3rd ed. Philadelphia: Elsevier; 2016 [Chapter 2]. Heald R. Cell signaling. In: Alberts B, Johnson A, Lewis J, et al., eds. Molecular Biology of the Cell. 6th ed. New York: Garland Science; 2015 [Chapter 15]. Igarashi P. Regulation of gene expression. In: Boron WF, Boulpaep EL, eds. Medical Physiology. 3rd ed. Philadelphia: Elsevier; 2016 [Chapter 4]. SECTION 2The Nervous System ERIC J. LANG AND KALMAN RUBINSON Chapter 4 The Nervous System: Introduction to Cells and Systems Chapter 5 Generation and Conduction of Action Potentials The Somatosensory System The Special Senses Organization of Motor Function Chapter 10 Integrative Functions of the Nervous System Chapter 11 The Autonomic Nervous System and Its Central Control


Physiology_Levy

Physiology_Levy. The Somatosensory System The Special Senses Organization of Motor Function Chapter 10 Integrative Functions of the Nervous System Chapter 11 The Autonomic Nervous System and Its Central Control Upon completion of this chapter the student should be able to answer the following questions: 1. What are the major cell types of the central and peripheral nervous systems? 2. What are the major components of a neuron, and what are their functional roles? 3. What are the functional roles of the major glial cell types? 4. What are the main divisions of the central nervous system? 5. How and where is the cerebrospinal fluid formed, and how does it circulate and exit the ventricular system? 6. How is axon transport related to the response of the axon to transection?


Physiology_Levy

Physiology_Levy. 5. How and where is the cerebrospinal fluid formed, and how does it circulate and exit the ventricular system? 6. How is axon transport related to the response of the axon to transection? he nervous system is a communications and control network that allows an organism to interact rapidly and adaptively with its environment, where environment includes both the external environment (the world outside the body) and the internal environment (the components and cavities of the body). To carry out its function the nervous system takes in sensory information from a variety of sources using specialized sensors (receptors), integrates this information with previously obtained information stored as memories and with the intrinsic goals and drives of the organism that have been embedded in its nervous system through evolution, decides on a course of action, and then issues commands to the effector organs (muscles and glands) to execute the chosen behavioral response.


Physiology_Levy

Physiology_Levy. Moreover, almost all behavioral responses require the coordination of many body parts. For example, even a simple reaching movement of the arm may require coactivation of axial muscles and possibly muscles in the lower extremity to maintain posture and balance, which themselves may be monitored by up to three different sensory systems (vision, vestibular, and proprioceptive) whose information has to be integrated. Furthermore, movements can alter the internal environment and thus can require compensatory changes in heart and breathing rates, blood vessel diameters, and other internal processes. All these variables are monitored and controlled by various specialized subsystems of the nervous system, all of which must work together for the organism to perform movements and more generally to survive. The succeeding chapters will describe these major subsystems individually; however, it should be remembered that in reality their activity is integrated to generate normal behavior.


Physiology_Levy

Physiology_Levy. To begin, it is useful to divide the nervous system into central and peripheral parts. The central nervous system (CNS) consists of the brain and spinal cord. The peripheral nervous system (PNS) consists of nerves and ganglia (small groups of neurons) that innervate all parts of the body and provide an interface between the environment and the CNS. The transition between the CNS and PNS occurs on the dorsal and ventral rootlets near to where they emerge from the spinal cord and on the cranial nerve fibers near to where they arise from the brain. Cellular Components of the Nervous System


Physiology_Levy

Physiology_Levy. Cellular Components of the Nervous System The nervous system is made up of cells, connective tissue, and blood vessels. The major cell types are neurons (nerve cells) and glia (neuroglia = “nerve glue”). In its most general form a neuron’s function can be defined as generation of signals (to be sent to other neurons or effector cells [e.g., muscle cells]) based on an integration of its own electrical properties with electrochemical signals from other neurons. The points where specific neuron-to-neuron communication occurs are known as synapses, and the process of synaptic transmission is critical to neuronal function (see ). Neuroglia, or just glia, traditionally have been characterized as supportive cells that sustain neurons both metabolically and physically, isolate individual neurons from each other, and help maintain the internal milieu of the nervous system; however, it is now known that they also have important roles in shaping the flow of activity through the nervous system.


Physiology_Levy

Physiology_Levy. The typical neuron consists of three main cellular compartments: a cell body (also referred to as a perikaryon or CHAPTER 4 The Nervous System: Introduction to Cells and Systems •Fig. 4.1 Schematicdiagramofanidealizedneuronanditsmajorcomponentsandconnections.A,Afferentinputfromaxonsofothercellsterminatesinsynapsesonthedendritesandcellbody.Theinitialsegmentoftheaxonattachesattheaxonhillock.Thisaxonismyelinated,asindicatedbythebluestructuresthatencapsulatesegmentsoftheaxon.Theaxonterminatesontwopostsynapticneuronsbyformingsynapticterminals.B,NodesofRanvierarethegapsbetweenthemyelinsegmentswheretheaxonmembraneisexposedtotheextracellularspace.C,Higher-magnificationviewofsynapse.(RedrawnfromBlumenfeldH.Neuroanatomy Through Clinical Cases. 2nded.Sunderland,MA:SinauerAssociates;2010.) soma), a variable number of processes that extend from the soma called dendrites, and an axon (


Physiology_Levy

Physiology_Levy. Fig. 4.1 ). A tremendous number of morphological variants of this basic template exist, including cases where dendrites or an axon may be absent ( Fig. 4.2 ). These variations do not occur randomly but rather relate to the distinct functional properties of each neuronal class. Indeed, neurons with similar morphologies often characterize specific regions of the CNS and reflect the distinct neuronal processing performed in each CNS region.


Physiology_Levy

Physiology_Levy. The cell body is the main genetic and metabolic center of the neuron. Correspondingly it contains the nucleus and nucleolus of the cell and also possesses a well-developed biosynthetic apparatus for manufacturing membrane constituents, synthetic enzymes, and other chemical substances needed for the specialized functions of nerve cells. The neuronal biosynthetic apparatus includes Nissl bodies, which are stacks of rough endoplasmic reticulum, and a prominent Golgi apparatus. The soma also contains numerous mitochondria and cytoskeletal elements, including neurofilaments and microtubules.


Physiology_Levy

Physiology_Levy. The cell body is also a region in which the neuron receives synaptic input (i.e., electrical and chemical signals from other neurons). Although quantitatively the synaptic input to the soma is usually much less than that to dendrites, it often differs qualitatively from dendritic inputs, and by virtue of the closeness of the soma to the axon, inputs to the soma can override those to the dendrites (see


Physiology_Levy

Physiology_Levy. Dendrites are tapering and branching extensions of the soma and are the main direct recipients of signals from other neurons. They can be thought of as a way to expand and specialize the surface area of a neuron, and indeed, they may account for more than 90% of the surface area available for synaptic contact (soma plus dendrites). Dendrites can be divided into primary dendrites (those that extend directly from the soma) and higher-order dendrites (daughter branches extending from a more proximal branch, in •Fig. 4.2 A,Purkinjecell.B,Pyramidalcell.C,Golgicell.D,Granulecell.E,Inferiorolivecells.F,Bipolarcells.(A,CourtesyofBorisBarbour.B,CourtesyofT.F.Fletcher,from http://vanat.cvm.umn.edu/ neurHistAtls/pages/neuron3.html .C,FigurewasprovidedbyCourtHullandWadeRegehr,DepartmentofNeurobiology,HarvardMedicalSchool.D,FromDelvendahlIetal.Front Cell Neurosci 2015;9:93,Fig.1A.E,FromMathyA,ClarkBA.In:MantoMetal[eds].Handbook of the Cerebellum and Cerebellar Disorders.


Physiology_Levy

Physiology_Levy. Cell Neurosci 2015;9:93,Fig.1A.E,FromMathyA,ClarkBA.In:MantoMetal[eds].Handbook of the Cerebellum and Cerebellar Disorders. Dordrecht,Netherlands:SpringerScience+BusinessMediaDordrecht;2013.F,FromLiW,DeVriesSH.Nat Neurosci 2006;9:669-675,Fig.2.) which proximal refers to closeness to the soma). The main cytoplasmic organelles in dendrites are microtubules and neurofilaments; however, the primary dendrites can also contain Nissl bodies and parts of the Golgi apparatus.


Physiology_Levy

Physiology_Levy. A neuron’s set of dendrites is termed its dendritic tree. Dendritic trees differ tremendously between different types of neurons in terms of the size, number, and spatial organization of the dendrites. A dendritic tree can consist of just a few unbranched dendrites or of many highly ramified dendrites. Individual dendrites can be longer than 1 mm or only 10 to 20 µm in length. Another major morphological variation is whether or not a dendrite has spines, which are small mushroomor lollipop-shaped protrusions from the main dendrite. Spines are sites specialized for synaptic contact (usually, but not always) from excitatory inputs. The shape and size of the dendritic tree, as well as the population and distribution of channels in the dendritic membrane, are all important determinants of how the synaptic input will affect the neuron (see Chapter 6).


Physiology_Levy

Physiology_Levy. Chapter 6). The axon is an extension of the cell that conveys the output of the cell to other neurons or, in the case of a motor neuron, to muscle cells as well. In general, each neuron has only one axon, and it is usually of uniform diameter. The length and diameter of axons vary with the neuronal type. Some axons do not extend much beyond the length of the dendrites, whereas others may be a meter or more long. Axons may have orthogonal branches en passant, but they often end in a spray of branches called a terminal arborization (represented by the four terminal branches and their synaptic terminals in


Physiology_Levy

Physiology_Levy. Fig. 4.1A ). The size, shape, and organization of the terminal arborization determine which other cells it will contact. The first part of the axon is known as the initial segment and arises from the soma (or sometimes from a proximal dendrite) in a specialized region called the axon hillock. The axon differs from the soma and proximal dendrites in that it lacks rough endoplasmic reticulum, free ribosomes, and a Golgi apparatus. The initial segment is usually the site where action potentials (spikes) that are propagated down the axon are initiated (see ). An axon may terminate in a synapse and/or it may make synapses along its length. Synapses will be described in detail in


Physiology_Levy

Physiology_Levy. CHAPTER 4 The Nervous System: Introduction to Cells and Systems •Fig. 4.3 Axonaltransport.Schematicofneuronandenlargementofaxonaltransportmechanism.Axonaltransportdependsonmovementofmaterialalongtransportfilamentssuchasmicrotubules.Transportedcomponentsattachtotransportfilamentsbymeansofcross-bridges.Differentobjectsaretransportedanterogradely(fromcellbodytoaxonterminal)andothersretrogradely(towardthecellbody).Thedirectionoftransport—retrogradeandanterograde—isdeterminedbyspecificproteinssuch asdyneinandkinesin,respectively.


Physiology_Levy

Physiology_Levy. Neurons are special because of their ability to control and respond to electricity. Moreover, the response and control mechanisms of each part of a neuron are distinct from those in other parts. This intraneuronal specialization is a consequence of the particular morphology and the ion channel composition of each part of the neuron. For example, dendrites have ligand gated ion channels that allow neurons to respond to chemicals released by other neurons, and their characteristic branching pattern allows for integration of multiple input signals. In contrast the axon typically has a long length and high concentration of voltage-gated channels that allows it to convey electrical signals (action potentials) rapidly over long distances without alteration.


Physiology_Levy

Physiology_Levy. Because the soma is the metabolic engine of the neuron, substances needed to support axonal and synaptic function are synthesized there. These substances must be distributed to replenish secreted or inactivated materials along the axon and especially to the presynaptic terminals. Most axons are too long to allow efficient movement of substances from the soma to the synaptic endings by simple diffusion. Thus special axonal transport mechanisms have evolved to accomplish this task ( Fig. 4.3). A consequence of this metabolic dependency is that axons degenerate when disconnected from the cell body, a fact that has been used by scientists tracing out neuronal pathways; they would cut an axonal pathway and then determine where the degenerating axons distal to the cut projected to.


Physiology_Levy

Physiology_Levy. Several types of axonal transport exist. Membrane-bound organelles and mitochondria are transported relatively rapidly by fast axonal transport. Substances that are dissolved in cytoplasm (e.g., proteins) are moved by slow axonal transport. In mammals, fast axonal transport proceeds as rapidly as 400 mm/day, whereas slow axonal transport occurs at about 1 mm/day. Synaptic vesicles, which travel by fast axonal transport, can travel from the soma of a motor neuron in the spinal cord to a neuromuscular junction in a person’s foot in about 2.5 days. In comparison the movement of some soluble proteins over the same distance can take nearly 3 years. Axonal transport requires metabolic energy and involves calcium ions. Microtubules provide a system of guidewires along which membrane-bound organelles move (see Fig.


Physiology_Levy

Physiology_Levy. Axonal transport requires metabolic energy and involves calcium ions. Microtubules provide a system of guidewires along which membrane-bound organelles move (see Fig. 4.3 ). Organelles attach to microtubules through a linkage similar to that between the thick and thin filaments of skeletal muscle fibers. Ca++ triggers movement of the organelles along the microtubules. Special microtubule-associated motor proteins called kinesin and dynein are required for axonal transport. Axonal transport occurs in both directions. Transport from the soma toward the axonal terminals is called anterograde axonal transport. This process involves kinesin, and it allows replenishment of synaptic vesicles and enzymes responsible for the synthesis of neurotransmitters in synaptic terminals. Transport in the opposite direction, which is driven by dynein, is called retrograde axonal transport. This process returns recycled synaptic vesicle membrane to the soma for lysosomal degradation.


Physiology_Levy

Physiology_Levy. Certainvirusesandtoxinscanbeconveyedbyaxonaltransportalongperipheralnerves.Forexample,herpeszoster,thevirusofchickenpox,invadesdorsalrootganglioncells.Thevirusmaybeharboredbytheseneuronsformanyyears.However,eventuallythevirusmaybecomeactivebecauseofachangeinimmunestatus.Thevirusmaythenbetransportedalongthesensoryaxonstotheskin,causingshingles,averypainfuldisease.Anotherexampleistheaxonaltransportoftetanustoxin.Clostridium tetani bacteriamaygrowinadirtywound,andifthepersonhadnotbeenvaccinatedagainsttetanustoxin,thetoxincanbetransportedretrogradelyintheaxonsofmotorneurons.Thetoxincanescapeintotheextracellularspaceofthespinalcordventralhornandblockthesynapticreceptorsforinhibitoryaminoacids.Thisprocesscanresultintetanicconvulsions. The major nonneuronal cellular elements of the nervous system are the glia (


Physiology_Levy

Physiology_Levy. The major nonneuronal cellular elements of the nervous system are the glia ( Fig. 4.4 ). Glial cells in the human CNS outnumber neurons by an order of magnitude: there are about 1013 glia and 1012 neurons. Glial cells in the CNS include astrocytes, oligodendrocytes, microglia, and ependymal cells (see Fig. 4.4 ); in the PNS the glial cells are Schwann cells and satellite cells. Traditionally, glial cells were thought of as supportive cells, and consistent with that conception, their functions include regulation of the microenvironment and myelination of axons. Glial cells are now also recognized to be important determinants of the flow of signals through neuronal circuits, and related to that they act to modulate synaptic and nonsynaptic transmission and have important roles in synaptogenesis and maintenance.


Physiology_Levy

Physiology_Levy. Astrocytes (named for their star shape) help regulate the microenvironment of the CNS, both under normal conditions and in response to damage to the nervous system. Astrocytes have a cell body from which several main branches arise. Through repeated branching these main processes give rise to hundreds to thousands of branchlets. Astrocyte processes contact neurons and surround synaptic endings, isolating them from adjacent synapses and the general extracellular space. Astrocytes also have foot •Fig. 4.4 SchematicrepresentationofcellularelementsintheCNS.Twoastrocytesareshownendingonasomaanddendritesofaneuron.Astrocytesalsocontactthepialsurfaceorcapillariesorboth.Anoligodendrocyteprovidesthemyelinsheathsforaxons.Alsoshownaremicrogliaandependymalcells. N,neuron.(RedrawnfromWilliamsPL,WarwickR.Functional Neuroanatomy of Man. Edinburgh:ChurchillLivingstone;1975.) processes that contact the capillaries and connective tissue at the surface of the CNS, the pia mater (see


Physiology_Levy

Physiology_Levy. Fig. 4.4 ). These foot processes may help mediate the entry of substances into the CNS. Astrocytes can actively take up K+ ions and neurotransmitter substances, which they metabolize, biodegrade, or recycle. Thus astrocytes serve to buffer the extracellular environment of neurons with respect to both ions and neurotransmitters. The cytoplasm of astrocytes contains glial filaments that provide mechanical support for CNS tissue. After injury the astrocytes undergo a variety of changes to become reactive astrocytes. One example is a class of reactive astrocytes that act to form a glial scar around an area of focal damage, which segregates the damaged tissue and thereby allows inflammatory processes to act selectively at the site of damage, minimizing the impact on surrounding normal tissue. Astrocytes can also affect the properties of synaptic transmission, which is discussed in


Physiology_Levy

Physiology_Levy. Oligodendrocytes and Schwann cells are critical for the function of axons. Many axons are surrounded by a myelin sheath, which is a spiral multilayered wrapping of glial cell membrane ( Fig. 4.5A–B ). In the CNS, myelin is formed by the oligodendrocytes, whereas in the PNS Schwann cells form myelin. Myelin increases the speed of action potential conduction, in part by restricting the


Physiology_Levy

Physiology_Levy. CHAPTER 4 The Nervous System: Introduction to Cells and Systems •Fig. 4.5 Axonal/glialassociations.A,MyelinatedaxonsintheCNS.Asingleoligodendrocyte(G)emitsseveralprocesses,eachofwhichwindsinaspiralfashionaroundanaxontoformamyelinsegment.Theaxonisshownincutaway.Themyelinfromasingleoligodendrocyteendsbeforethenextwrappingfromanotheroligodendrocyte.ThebareaxonbetweenthemyelinatedsegmentsisthenodeofRanvier(N).B,ElectronmicrographofmyelinatedaxoninthePNSshownincrosssection.Theaxon(Ax)isseenatthecenterwithinasheathconsistingofmultiplewrappingsoftheSchwanncell’scytoplasmicmembrane.TheSchwanncellsoma(SC)isattheupperright.mes,mesaxon,internalandexternal.C,Electronmicro-graphofunmyelinatedaxonsinPNS.Nineaxons(asterisks) cutincrosssectionareseenembeddedinaSchwanncellwhosenucleusisatthecenter(N).Atlowerrightaportionofamyelinatedaxonisvisible.(B,FromPetersAetal.The Fine Structure of the Nervous System. NewYork:OxfordUniversityPress;1991,Fig.6.5.C,FromPanneseE.Neurocytology.


Physiology_Levy

Physiology_Levy. Fine Structure of the Nervous System. NewYork:OxfordUniversityPress;1991,Fig.6.5.C,FromPanneseE.Neurocytology. 2nded.Basel,Switzerland:SpringerInternational;2015.)


Physiology_Levy


Physiology_Levy

Physiology_Levy. flow of ionic current to small unmyelinated portions of the axon between adjacent glial cells, the nodes of Ranvier (see ). Although both act to increase the speed of conduction, there are several important differences in the relationship between axons and either oligodendrocytes or Schwann cells. One major difference is that a single oligodendrocyte typically helps myelinate multiple axons in the CNS, whereas each Schwann cell helps myelinate only a single axon in the PNS. A second difference is that in the CNS, unmyelinated axons are bare, whereas in the PNS, unmyelinated axons are not. Rather, they are surrounded by Schwann cell processes; the Schwann cell, however, does not form a multilayered covering (i.e., myelin), but instead extends processes that surround parts of several axons (the Schwann cell with its set of unymyelinated axons is called a Remak bundle) (see Fig. 4.5C


Physiology_Levy

Physiology_Levy. Fig. 4.5C Satellite cells encapsulate dorsal root and cranial nerve ganglion cells and regulate their microenvironment in a fashion similar to that of astrocytes. Microglia are derived from erythromyeloid stem cells that migrate into the CNS early in development. They play an important role in immune responses within the CNS. When the CNS is damaged, microglia help remove the cellular products of the damage by phagocytosis. They are assisted by other glia and by other phagocytes that invade the CNS from the circulation. In addition to their role in immune responses, recent evidence suggests they are also active in healthy brain tissue and may have important roles in normal brain development and function, including pruning of excess synapses that are formed during development and synaptic plasticity.


Physiology_Levy

Physiology_Levy. Ependymal cells form the epithelium lining the ventricular spaces of the brain, which contain (cerebrospinal fluid) CSF. CSF is secreted in large part by specialized ependymal cells of the choroid plexuses located in the ventricular system. Many substances diffuse readily across the ependyma, which lies between the extracellular space of the brain and the CSF.


Physiology_Levy

Physiology_Levy. The Peripheral Nervous System The PNS provides an interface between the environment and the CNS, both for sensory information flowing to the CNS and for motor commands issued from the CNS. It includes sensory (or primary afferent) neurons, somatic motor neurons, and autonomic motor neurons. Sensory pathways into the nervous system start with a receptor, which may simply be a specialized part of an axon in the PNS or may include additional cells. Each sensory receptor is organized so that it transduces a specific type of energy into an electrical signal. Thus they can be classified in terms of the type of energy they transduce (e.g., photoreceptors transduce light, mechanoreceptors transduce displacement and force). They may also be classified according to the source of the input (e.g., exteroceptors signal external events, proprioceptors signal the state of a body part such as the angle of elbow, and interoceptors signal the distension of the gut).


Physiology_Levy

Physiology_Levy. The transduction process leads to an electrical response in the primary afferent called a receptor potential, which triggers action potentials in the primary afferent fibers innervating the receptor. These action potentials contain information about the sensory stimulus that is conveyed to the CNS via the primary afferent. Somatic and autonomic motor neurons convey signals from the CNS to their respective effector targets. The somatic motor neurons innervate the skeletal muscles throughout the body. Their cell bodies lie in the ventral horn (or equivalent brainstem nuclei) and project out of the CNS via a ventral root or cranial nerve. The details of their relationship to muscles is covered in . The autonomic motor pathway is responsible for controlling the functioning of organs, smooth muscle, and glands. It is actually a two-neuron pathway, and its properties are covered in Chapter 11. The Central Nervous System


Physiology_Levy

Physiology_Levy. Chapter 11. The Central Nervous System The CNS is built from the cellular elements just described and includes the spinal cord and brain ( Fig. 4.6A ). These cellular elements are connected in a variety of complex ways to form the subsystems that underlie the multitude of functions performed by the CNS. The physiology of these systems is covered in ; however, a basic knowledge of CNS anatomy is needed to understand systems physiology and will be briefly discussed here.


Physiology_Levy

Physiology_Levy. Regions of the CNS containing high concentrations of axon pathways (and very few neurons) are called white matter because the axonal myelin sheaths of the axons are highly refractive to light. Regions containing high concentrations of neurons and dendrites are by contrast called gray matter. Note that axons are also present in gray matter. These axons may be related to local processing (i.e., either originating from local neurons or terminating on them) or may be fibers of passage. Thus effects of damage to an area may reflect either loss of local function or disconnection CHAPTER 4 The Nervous System: Introduction to Cells and Systems pallidus Fimbria of Temporal (fornix) Caudate Inferior horn nucleus of lateral (tail) Mammillary body ventricle


Physiology_Levy

Physiology_Levy. CHAPTER 4 The Nervous System: Introduction to Cells and Systems pallidus Fimbria of Temporal (fornix) Caudate Inferior horn nucleus of lateral (tail) Mammillary body ventricle OpticB Cerebral peduncle of hypothalamus tract Hippocampus •Fig. 4.6 A,SchematicofthemajorcomponentsoftheCNSasshowninalongitudinalmidlineview.B–F,Representativesectionsthroughthebrainandspinalcord,withthemajorlandmarkslabeled.B,Cerebrumandthalamus;C,midbrain;D,pons;E,medulla;F,cervicalspinalcord.Notethatmanypathways(e.g.,corticospinalfibers)crosssides(decussate)astheytravelthroughtheCNS,butthesedescussationsarenotindicatedinthefigure(seeChapters7and9fordetailsonthemotorandsensorypathwaycrossings).(A,FromHainesDE[ed].Fundamental Neuroscience for Basic and Clinical Applications. 3rded.Philadelphia:ChurchillLivingstone;2006.) of remote regions that had been linked by fibers of passage through the area that was damaged.


Physiology_Levy

Physiology_Levy. In the CNS, axons often travel in bundles or tracts. The names applied to tracts usually describe their origin and termination. For example, the spinocerebellar tracts convey information from the spinal cord to the cerebellum. The term pathway is similar to tract but is generally used to suggest a particular function (e.g., the auditory pathway: a series of neuron-to-neuron links across several synapses that convey and process auditory information). Gray matter exists in two main configurations in the CNS. A nucleus is a group of neurons in the CNS (in the PNS such a grouping is called a ganglion). Examples include the thalamic, cerebellar, and cranial nerve nuclei. A cortex is neurons that are organized into layers and usually found on the surface of the CNS. The most prominent are the cerebral and cerebellar cortices, which cover the surface of the cerebral hemispheres and the cerebellum, respectively ( Fig. 4.7


Physiology_Levy

Physiology_Levy. Fig. 4.7 In most nuclei and cortices, one can classify neurons into two broad categories: projection cells and local interneurons. Projection cells are neurons that send their axon to another region and thus are the origins of the various tracts of the nervous system. In contrast, local interneurons have axons that terminate in the same neural structure as their cell of origin and are involved with local computations rather than conveying signals from one region to another. These categories are not exclusive; many neurons have axons that both give off local branches and project to one or more distant regions. • Fig. 4.7 Lateral view of the human brain showing the left cerebral hemisphere, cerebellum, pons, and medulla. Note the division of the lobes of the cerebrum (frontal, parietal, occipital, and temporal) and the two major fissures (lateral and central). (From Nolte J, Angevine J. The Human Brain in Photographs and Diagrams. 2nd ed. St Louis: Mosby; 2000.)


Physiology_Levy

Physiology_Levy. Regional Anatomy of the CNS The spinal cord can be subdivided into a series of regions (see Fig. 4.6A ), each composed of a number of segments named for the vertebrae where their nerve roots enter or leave: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal. Each portion maintains its tubular appearance, although its lumen, the spinal canal, may not remain patent. Within the gray matter the dorsal horn receives and processes sensory information from the dorsal roots, whereas the ventral horn is primarily a motor structure and contains the motor neurons whose axons project out via the ventral roots ( Fig. 4.8 The surrounding white matter consists of many tracts interconnecting spinal cord levels and for communication with the brain. Three major ones are the lateral corticospinal tract (motor), spinothalamic tract/anterolateral system (sensory), and dorsal column-medial lemniscus pathway (sensory) (see Fig. 4.6F


Physiology_Levy

Physiology_Levy. Fig. 4.6F The brainstem consists of the medulla, pons, and midbrain ( Fig. 4.9 Fig. 4.6 ). In addition to the longitudinal pathways interconnecting with the spinal cord, the brainstem contains nuclei and many additional pathways that vary by level. These structures have many functions, some of which are analogous to those of the spinal cord (e.g., conveying basic sensory information and motor commands) and others related to a variety of other brain functions, such as cardiac control and state of consciousness. The brainstem also receives input and sends motor output via cranial nerves ( Table 4.1 The cerebellum sits dorsal to the pons and medulla. It receives inputs from spinal cord, brainstem, and cerebral cortex and projects back to many of these same structures. The cerebellum is critical for motor coordination but is increasingly recognized as having key roles in other cognitive functions.


Physiology_Levy

Physiology_Levy. • Fig. 4.8 Diagram of the spinal cord, spinal roots, and spinal nerve. The spinal nerve begins where the dorsal and ventral roots fuse, and has multiple branches (rami), the first few of which are represented. A primary afferent neuron is shown with its cell body in the dorsal root ganglion and its central and peripheral processes distributed, respectively, to the spinal cord gray matter and to a sensory receptor in the skin. An α motor neuron is shown to have its cell body in the spinal cord gray matter and to project its axon out the ventral root to innervate a skeletal muscle fiber. CHAPTER 4 The Nervous System: Introduction to Cells and Systems Massa intermedia of Thalamus Interventricular foramen Fornix Anterior commissure Infundibular recess Lamina terminalis


Physiology_Levy

Physiology_Levy. CHAPTER 4 The Nervous System: Introduction to Cells and Systems Massa intermedia of Thalamus Interventricular foramen Fornix Anterior commissure Infundibular recess Lamina terminalis Choroid plexus of third ventricle •Fig. 4.9 Midsagittalviewofthebrainshowingthethirdandfourthventricles,thecerebralaqueductofthemidbrain,andthechoroidplexus.TheCSFformedbythechoroidplexusinthelateralventriclesentersthiscirculationviatheinterventricularforamen.Notealsothelocationofthecorpuscallosumandothercommissures.(FromHainesDE[ed]:Fundamental Neuroscience for Basic and Clinical Applications. 3rded.Philadelphia:ChurchillLivingstone;2006.) The thalamus sits at the upper end of the brainstem and is enclosed by the cerebrum with which it is highly interconnected (see


Physiology_Levy

Physiology_Levy. The thalamus sits at the upper end of the brainstem and is enclosed by the cerebrum with which it is highly interconnected (see Fig. 4.6B ). With a few exceptions, ascending information first reaches the thalamus, which conveys it to the cerebral cortex. These structures play a major role in many functions, including conscious awareness, volition, memory, and language. In addition to the cortex, the cerebrum contains a group of deep nuclei, the basal ganglia, that are interconnected with the cortex and thalamus and whose function will be described in The major functions of the different parts of the CNS are listed in Table 4.1


Physiology_Levy

Physiology_Levy. The major functions of the different parts of the CNS are listed in Table 4.1 CSF fills the ventricular system, a series of interconnected spaces within the brain, and the subarachnoid space directly surrounding the brain. The intraventricular CSF reflects the composition of the brain’s extracellular space via free exchange across the ependyma, and the brain “floats” in the subarachnoid CSF to minimize the effect of external mechanical forces. The volume of CSF within the cerebral ventricles is approximately 30 mL, and that in the sub-arachnoid space is about 125 mL. Because about 0.35 mL of CSF is produced each minute, CSF is turned over more than three times daily. CSF is a filtrate of capillary blood formed largely by the choroid plexuses, which comprise pia mater, invaginating capillaries, and ependymal cells specialized for transport. The choroid plexuses are located in the lateral, third, and fourth ventricles (see


Physiology_Levy

Physiology_Levy. Fig. 4.9 ). The lateral ventricles are situated within the two cerebral hemispheres. They each connect with the third ventricle through one of the inter-ventricular foramina (of Monro). The third ventricle lies in the midline between the diencephalon on the two sides. The cerebral aqueduct (of Sylvius) traverses the midbrain and connects the third ventricle with the fourth ventricle. The fourth ventricle is a space defined by the pons and medulla below and the cerebellum above. The central canal of the spinal cord continues caudally from the fourth ventricle, although in adult humans the canal is not fully patent and continues to close with age.


Physiology_Levy

Physiology_Levy. CSF escapes from the ventricular system through three apertures or foramina (a medial foramen of Magendie and two lateral foramina of Luschka) located in the roof of the fourth ventricle. After leaving the ventricular system, CSF circulates through the subarachnoid space that surrounds the brain and spinal cord. Regions where these spaces are expanded are called subarachnoid cisterns. An example is the lumbar cistern, which surrounds the lumbar and sacral spinal roots below the level of termination of the spinal cord. The lumbar cistern is the target for lumbar puncture, a clinical procedure to sample CSF. A large part of CSF is removed by bulk flow through the valvular arachnoid granulations into the dural venous sinuses in the cranium.


Physiology_Levy

Physiology_Levy. Because the extracellular fluid within the CNS communicates with the CSF, the composition of the CSF is a useful indicator of the composition of the extracellular environment of neurons in the brain and spinal cord. The main constituents of CSF in the lumbar cistern are listed in Table 4.2. For comparison the concentrations of the same constituents in blood are also given. CSF has a lower concentration of K+ , glucose, and protein but a greater concentration of Na+ and Cl− than blood does. Furthermore, CSF contains practically no blood cells. The increased concentration of Na+ and Cl− enables CSF to be isotonic to blood. The pressure in the CSF column is about 120 to 180 mm H2O when a person is recumbent. The rate at which CSF is formed is relatively independent of the pressure in the Na+ (mEq/L)148136–145K+ (mEq/L)2.93.5–5Cl− (mEq/L)120–130100–106Glucose(mg/dL)50–7570–100Protein(mg/dL)15–456.8× 103pH7.3 FromWillisWD,GrossmanRG.Medical Neurobiology. 3rded.StLouis:Mosby;1981.


Physiology_Levy

Physiology_Levy. Na+ (mEq/L)148136–145K+ (mEq/L)2.93.5–5Cl− (mEq/L)120–130100–106Glucose(mg/dL)50–7570–100Protein(mg/dL)15–456.8× 103pH7.3 FromWillisWD,GrossmanRG.Medical Neurobiology. 3rded.StLouis:Mosby;1981. ventricles and subarachnoid space, as well as systemic blood pressure. However, the absorption rate of CSF is a direct function of CSF pressure. ObstructionofthecirculationofCSFleadstoincreasedCSFpressureandhydrocephalus,anabnormalaccumulationoffluidinthecranium.Inhydrocephalustheventriclesbecomedistended,andiftheincreaseinpressureissustained,brainsubstanceislost.Whentheobstructioniswithintheventricularsystemorintheforaminaofthefourthventricle,theconditioniscalledanoncommunicating hydrocephalus. Iftheobstructionisinthesubarachnoidspaceorthearachnoidvilli,itisknownasacommunicating hydrocephalus. The Blood-Brain Barrier


Physiology_Levy

Physiology_Levy. The Blood-Brain Barrier The local environment of most CNS neurons is controlled such that neurons are normally protected from extreme variations in the composition of the extracellular fluid that bathes them. Part of this control is provided by the presence of a blood-brain barrier (other mechanisms are the buffering functions of glia, regulation of CNS circulation, and exchange of substances between the CSF and extracellular fluid of the CNS). Movement of large molecules and highly charged ions from blood into the brain and spinal cord is severely restricted. The restriction is at least partly due to the barrier action of the capillary endothelial cells of the CNS and the tight junctions between them. Astrocytes may also help limit the movement of certain substances. For example, astrocytes can take up potassium ions and thus regulate [K+] in the extracellular space. Some pharmaceutical agents, such as penicillin, are removed from the CNS by transport mechanisms.


Physiology_Levy

Physiology_Levy. Nervous Tissue Reactions to Injury Injury to nervous tissue elicits responses by neurons and glia. Severe injury causes cell death. Except in specific instances, once a neuron is lost it cannot be replaced because, in general, CHAPTER 4 The Nervous System: Introduction to Cells and Systems 63 The blood-brain barrier can be disrupted by pathology of the brain. For example, brain tumors may allow substances that are otherwise excluded to enter the brain from the circulation. Radiologists can exploit this by introducing a substance into the circulation that normally cannot penetrate the blood-brain barrier. If the substance can be imaged, its leakage into the region occupied by the brain tumor can be used to demonstrate the distribution of the tumor. neurons are postmitotic cells. In animals, two exceptions are olfactory bulb and hippocampal neurons; however, in humans, only for the hippocampus has evidence been found for significant levels of neurogenesis in the adult CNS.


Physiology_Levy

Physiology_Levy. When an axon is transected, the soma of the neuron may show chromatolysis, or “axonal reaction.” Normally, Nissl bodies stain well with basic aniline dyes, which attach to the RNA of ribosomes ( Fig. 4.10A ). After injury to the Fig. 4.10B), the neuron attempts to repair the axon by making new structural proteins, and the cisterns of the rough endoplasmic reticulum become distended with the products of protein synthesis. The ribosomes appear to be disorganized, and the Nissl bodies are stained weakly by basic aniline dyes. This process, called chromatolysis, alters the staining pattern (see Fig. 4.10C ). In addition, the soma may swell and become rounded, and the nucleus may assume an eccentric position. These morphological changes reflect the cytological processes that accompany increased protein synthesis. Because it cannot synthesize new protein, the axon distal to the transection dies (see


Physiology_Levy

Physiology_Levy. Because it cannot synthesize new protein, the axon distal to the transection dies (see Fig. 4.10C ). Within a few days the axon and all the associated synaptic endings disintegrate. If the axon had been a myelinated axon in the CNS, the myelin sheath would also fragment and eventually be removed by phagocytosis. However, in the PNS the Schwann cells that had formed the myelin sheath remain viable, and in fact they undergo cell division. This sequence of events was originally described by Waller and is called wallerian degeneration.


Physiology_Levy

Physiology_Levy. If the axons that provide the sole or predominant synaptic input to a neuron or to an effector cell are interrupted, the • Fig. 4.10 A, Normal motor neuron innervating a skeletal muscle fiber. B, A motor axon has been severed, and the motor neuron is undergoing chromatolysis. C, This is associated in time with sprouting and, in D, with regeneration of the axon. The excess sprouts degenerate. E, When the target cell is reinnervated, chromatolysis is no longer present. and even death. The best known example of this is atrophy of skeletal muscle fibers after their innervation by motor neurons has been interrupted. However, if only one or a few of the innervating axons are removed, the other surviving axons may sprout additional terminals, thereby taking up the synaptic space of the damaged axons and increasing their influence on the postsynaptic cell.


Physiology_Levy

Physiology_Levy. In the PNS, after an axon is lost through injury, many neurons can regenerate a new axon. The proximal stump of the damaged axon develops sprouts (see Fig. 4.10C ), these sprouts elongate, and they grow along the path of the original nerve if this route is available (see Fig. 4.10D ). The Schwann cells in the distal stump of the nerve not only survive the wallerian degeneration but also proliferate and form rows along the course previously taken by the axons. Growth cones of the sprouting axons find their way along these rows of Schwann cells, and they may eventually reinnervate the original peripheral target structures (see Fig. 4.10E ). The Schwann cells then remyelinate the axons. The rate of regeneration is limited by the rate of slow axonal transport to about 1 mm/day.


Physiology_Levy

Physiology_Levy. Fig. 4.10E ). The Schwann cells then remyelinate the axons. The rate of regeneration is limited by the rate of slow axonal transport to about 1 mm/day. In the CNS, transected axons also sprout. However, proper guidance for the sprouts is lacking, in part because the oligodendroglia do not form a path along which the sprouts can grow. This limitation may be a consequence of the fact that a single oligodendroglial cell myelinates many central axons, whereas a single Schwann cell provides myelin for only a single axon in the periphery. In addition, different chemical signals may affect peripheral and central attempts at regeneration differently. Other obstacles to successful CNS regeneration include formation of a glial scar by astrocytes and lack of trophic influences that guided axonal trajectories during development. 1. The functions of the nervous system include excitability, sensory detection, information processing, and behavior. 2.


Physiology_Levy

Physiology_Levy. 1. The functions of the nervous system include excitability, sensory detection, information processing, and behavior. 2. The CNS includes the spinal cord and brain. The brain includes the medulla, pons, cerebellum, midbrain, thalamus, hypothalamus, basal ganglia, and cerebral cortex. 3. The neuron is the functional unit of the nervous system. Neurons have three major compartments: the dendrites, cell body, and axon. The first two receive and integrate signals, and the axon conveys the output signals of the neuron to other cells. 4. The PNS includes primary afferent neurons and the sensory receptors they innervate, the axons of somatic motor neurons, and autonomic neurons. 5. Information is conveyed through neural circuits by action potentials in the axons of neurons and by synaptic transmission between axons and the dendrites and somas of other neurons or between axons and effector cells. 6.


Physiology_Levy

Physiology_Levy. 6. Different types of neurons are specialized as a consequence of their individual morphology and the ion channel distribution in the cell membrane of their soma, dendrites, and axons. 7. Sensory receptors include exteroceptors, interoceptors, and proprioceptors. Stimuli are environmental events that excite sensory receptors, responses are the effects of stimuli, and sensory transduction is the process by which stimuli are detected by transforming their energy into electrical signals. 8. Sensory receptors can be classified in terms of the type of energy they transduce or by the source of the input. Central pathways are usually named by their origin and termination or for the type of information conveyed. 9. Chemical substances are distributed along the axons by fast or slow axonal transport. The direction of axonal transport may be anterograde or retrograde. 10.


Physiology_Levy

Physiology_Levy. 9. Chemical substances are distributed along the axons by fast or slow axonal transport. The direction of axonal transport may be anterograde or retrograde. 10. Glial cells include astrocytes (regulate the CNS microenvironment), oligodendroglia (form CNS myelin), Schwann cells (form PNS myelin), ependymal cells (line the ventricles), and microglia (CNS macrophages). Myelin sheaths increase the conduction velocity of axons. 11. The choroid plexus forms CSF. CSF differs from blood in having a lower concentration of K+ , glucose, and protein and a higher concentration of Na+ and Cl−; CSF normally lacks blood cells. 12. The extracellular fluid composition of the CNS is regulated by CSF, the blood-brain barrier, and astrocytes. 13. Damage to the axon of a neuron causes an axonal reaction (chromatolysis) in the cell body and wallerian degeneration of the axon distal to the injury. Regeneration of PNS axons is more likely than regeneration of CNS axons.


Physiology_Levy

Physiology_Levy. Squire L, Berg D. Fundamental Neuroscience. 4th ed. Waltham, MA: Kiernan JA, Rajakumar N. Barr’s The Human Nervous System: An Academic Press; 2012. Anatomical Viewpoint. 10th ed. Philadelphia: Lippincott Williams Vanderah T, Gould D. Nolte’s The Human Brain: An Introduction to its & Wilkins; 2013. Functional Anatomy. 7th ed. St. Louis: Mosby; 2015. Upon completion of this chapter, the student should be able to answer the following questions: 1. How is a nerve membrane’s response to small-amplitude stimuli like a passive electric circuit comprising batteries, resistors, and capacitors? 2. What factors determine the time and length constants of a nerve membrane? How do these constants shape the electric responses of the nerve membrane? 3. How does an action potential differ from the subthreshold responses of a membrane (i.e., the passive and local responses)? 4. What is the sequence of conductances that underlies the action potential? 5.


Physiology_Levy

Physiology_Levy. 4. What is the sequence of conductances that underlies the action potential? 5. How are the responses of Na+ and K+ channels to membrane depolarization similar? How does the presence of the Na+ channel inactivation gate cause the responses to differ? 6. How do the gating properties of Na+ and K+ channels relate to the absolute and relative refractory periods of the action potential? 7. How is the action potential propagated without decrement? What are the factors that determine its propagation velocity? 8. What are the structural properties of myelin that underlie its ability to increase conduction velocity? 9. Given the all-or-none nature of action potentials, how are the characteristics of different stimuli distinguished by the central nervous system?


Physiology_Levy

Physiology_Levy. n action potential is a rapid, all-or-none change in the membrane potential, followed by a return to the resting membrane potential. This chapter describes how action potentials are generated by voltage-dependent ion channels in the plasma membrane and propagated with the same shape and size along the length of an axon. The influences of axon geometry, ion channel distribution, and myelin are discussed and explained. The ways in which information is encoded by the frequency and pattern of action potentials in individual cells and in groups of nerve cells are also described. Finally, because the nervous system provides important information about the external world through specific sensory receptors, general principles of sensory transduction and coding are introduced. More detailed information about these sensory mechanisms and systems is provided in other chapters.


Physiology_Levy

Physiology_Levy. When a microelectrode (tip diameter <0.5 µm) is inserted through the plasma membrane of a neuron, a difference in potential is observed between the tip of the microelectrode inside the cell and an electrode placed outside the cell. The internal electrode is approximately 70 mV negative with regard to the external electrode, and this difference is referred to as the resting membrane potential or, simply, the resting potential (see for details on the basis of the resting potential). (By convention, membrane potentials are expressed as the intracellular potential minus the extracellular potential.) Neurons have a resting potential that typically is around −70 mV.


Physiology_Levy

Physiology_Levy. One of the signature features of neurons is their ability to change their membrane potential rapidly from rest in response to an appropriate stimulus. Two such classes of responses are action potentials and synaptic potentials, which are described in this chapter and the next, respectively. Current knowledge about the ionic mechanisms of action potentials comes from experiments with many species. One of the most studied is the squid because the large diameter (up to 0.5 mm) of the squid giant axon makes it an excellent model for electrophysiological research with intracellular electrodes. The Passive Response


Physiology_Levy

Physiology_Levy. To understand how an action potential is generated and why it is needed, it is necessary to understand the passive electrical properties of the nerve cell membrane. The term passive properties refers to the fact that components of the cell membrane behave very similarly to some of the passive elements of electric circuits, including batteries, resistors, and capacitors. This is very useful because the properties of these elements are well understood. In particular, a piece of membrane containing ion channels responds to changes in voltage across it much as a circuit containing a resistor and capacitor in parallel (parallel RC circuit) would: The ion channels correspond to the resistor, and the lipid bilayer acts as a capacitor. When a battery is first connected across the two terminals of a parallel RC circuit, all of the current flows through the branch of the circuit with the capacitor, causing the voltage across it to begin changing (recall that for a capacitor, I ˜ dV/dt). Over


Physiology_Levy

Physiology_Levy. of a parallel RC circuit, all of the current flows through the branch of the circuit with the capacitor, causing the voltage across it to begin changing (recall that for a capacitor, I ˜ dV/dt). Over time, however, the current flow through the capacitor decreases, whereas that through the resistor increases. As this happens, the rate of voltage change across the capacitor (and resistor) slows, and the voltage approaches a steady-state value. This change in voltage has an exponential time course whose specific characteristics depend on the resistance (R) and capacitance (C) of the resistor and capacitor. Moreover, a time constant, τ, for this circuit can be defined by the equation τ= R * C, and it equals the time it takes for the voltage to rise (or fall) exponentially by approximately 63% of the difference between its initial and final values.


Physiology_Levy

Physiology_Levy. With regard to how an axon actually responds to electrical stimulation, Fig. 5.1 illustrates the results of an experiment in which the membrane potential of an axon is altered by passing rectangular pulses of depolarizing (upward-going 1.0 0.89 0.44 0.22 0.11 –0.11 –0.22 –0.44 –0.89 –1.0 0 5 10 15 20 25 Change in Voltage from baseline (mV)


Physiology_Levy

Physiology_Levy. Slope ˜ 4.6 MegaOhms Linear range Upward deviation due to activation of Na conductance 1.0 0.0 –1.0 –1.0 –0.5 0.0 0.5 1.0 •Fig. 5.1 (A) Voltageresponsesofanaxontorectangularpulsesofhyperpolarizingcurrent(negativenumbers)ordepolarizingcurrent(positivenumbers)asinjectedandrecordedfromanintracellularelectrode.Thechangesintransmembranepotentialaremirrorimagesofthesmallamplitudepulses.Atthethresholdlevel(current= 1.0),thereisa50:50chanceofreturningtorestingpotentialorofgeneratinganactionpotential.Forclarity,onlytherisingphaseoftheactionpotentialisshown.B, Current-voltage(I-V)plotderivedfromdatainA.Currentpulseamplitudeisplottedonthex-axis,andvoltageresponse(measuredatdottedline)isplottedonthey-axis.Notethedeviationfromlinearitywithlargedepolarizations,whichisduetoactivationofvoltage-gatedconductances.(RedrawnfromHodgkinAL,RushtonWAH:Theelectricalconstantsofacrustaceannervefibre.Proc R Soc Lond B Biol Sci. 1946;133:444-479.) pulses) or hyperpolarizing (downward-going pulses) current across


Physiology_Levy

Physiology_Levy. R Soc Lond B Biol Sci. 1946;133:444-479.) pulses) or hyperpolarizing (downward-going pulses) current across its cell membrane. The injection of positive charge is depolarizing because it makes the cell less negative (i.e., decreases the potential difference across the cell membrane). Conversely, the injection of negative charge makes the membrane potential more negative, and this change in potential is called hyperpolarization. The larger the current that is injected, the greater the change in the membrane potential will be. The responses to hyperpolarizing and small-amplitude depolarizing current pulses (see


Physiology_Levy

Physiology_Levy. Fig. 5.1A ) all have the same fundamental shape because of the passive properties of the membrane. In contrast, the shapes of the responses to the larger depolarizing stimulus pulses differ from those to hyperpolarizing and small-amplitude depolarizing current pulses because the larger stimuli activate nonpassive elements in the membrane. For the responses to hyperpolarizing current pulses, once a long enough time has elapsed from the start of the current pulse to allow the membrane voltage to plateau (essentially several times τ), virtually all of the injected current is flowing through the membrane resistance. If the difference between the initial and steady-state voltages is plotted against the amplitude of the current pulse (see Fig. 5.1B ), a linear relationship is observed for the hyperpolarizing pulses, which is exactly what is expected from Ohm’s law (V = I *


Physiology_Levy

Physiology_Levy. Fig. 5.1B ), a linear relationship is observed for the hyperpolarizing pulses, which is exactly what is expected from Ohm’s law (V = I * R) for current flowing through a resistor. The slope of this line (ΔV/ΔI) is referred to as the input resistance of the cell (Rin) and is determined experimentally, exactly as just described. Rin is related to the membrane resistance (rm) of the cell, but the exact relationship depends on the geometry of the cell and is complex in most cases. Next, note that although the current is injected as rectangular pulses, with vertical rising and falling edges, the shape of the membrane voltage responses just after the starts and ends of the pulses have slower rises and falls. Moreover, with regard to only the responses to hyperpolarizing and small-amplitude depolarizing current pulses (see


Physiology_Levy

Physiology_Levy. Fig. 5.1A ), the fall and rise in the membrane voltage have exponential shapes. This shows that the membrane is responding to these current pulses as a parallel RC circuit would; that is, the stimulus causes no change in membrane resistance or capacitance (cm), and thus the time course of the rise and fall in voltage is the same in all cases because it is governed by the same membrane time constant (τ).


Physiology_Levy

Physiology_Levy. The relationships between voltage and current just described show that within a certain range of stimulation, the cell membrane in one region of the axon can be modeled by a passive RC circuit. However, this model circuit, with only a single resistor and capacitor, takes no account of the fact that axons are spatially extended structures and that because of this, the resistance of the intracellular space is a significant factor in how electrical events in one region affect other regions. That is, if axons had no intracellular resistance, their intracellular space would be isoelectric, and voltage changes, like those just described, across one part of the axonal membrane would occur across all regions instantaneously. In this case, there would be no need for a


Physiology_Levy

Physiology_Levy. CHAPTER 5 Generation and Conduction of Action Potentials special mechanism (i.e., the action potential) to propagate signals actively down the axon. In actuality, axons (and neurons in general) are spatially extended structures with significant resistance to current flow between different regions (this is one reason the relationship of Rin and rm is complicated). Therefore, it is important to understand how current injected at one point along the axon affects the membrane potential at other points because this both helps explain why action potentials are needed and helps explain some of their characteristics. When current pulses that elicit only passive responses are passed across the plasma membrane, the size of the change in potential recorded depends on the distance of the recording electrode from the point of passage of the current ( Fig. 5.2).


Physiology_Levy

Physiology_Levy. Fig. 5.2). The closer the recording electrode is to the site of current passage, the larger and steeper the change in potential is. The magnitude of the change in potential decreases exponentially with distance from the 0.0 mm 0.5 mm Change of membrane potential 1.0 mm (mV) 1.5 2.0 2.5 mm 4.5mV •Fig. 5.2 Responsesofanaxonofashorecrabtoasubthresholdrectangularcurrentpulsebyanextracellularelectrodeappliedcloselytoitssurfaceandlocatedatdifferentdistancesfromthecurrent-passingelectrode.Astherecordingelectrodeismovedfartherfromthepointofstimulation,theresponseofthemembranepotentialisslowerandsmaller.(RedrawnfromHodgkinAL,RushtonWAH:Theelectricalconstantsofacrustaceannervefibre.Proc R Soc Lond B Biol Sci. 1946;133:444-479.) site of passage of the current, and the change in potential is said to reflect passive or electrotonic conduction. Such passively conducted changes in potential do not spread very far along the membrane before they become insignificant. As shown in


Physiology_Levy

Physiology_Levy. Fig. 5.2 , an electrotonically conducted signal dies away over a distance of a few millimeters. The distance over which the change in potential decreases to 1/e (37%) of its maximal value is called the length constant or space constant (where e is the base of natural logarithms and is equal to 2.7182). A length constant of 1 to 3 mm is typical for mammalian axons, which can be more than a meter long, which makes obvious the need for a mechanism to propagate information about electrical events generated at the soma to the far end of the axon.


Physiology_Levy

Physiology_Levy. The length constant can be related to the electrical properties of the axon according to cable theory because nerve fibers have many of the properties of an electrical cable. In a perfect cable, the insulation surrounding the core conductor prevents all loss of current to the surrounding medium, so that a signal is transmitted along the cable with undiminished strength. If an unmyelinated nerve fiber (discussed later) is compared to an electrical cable, the plasma membrane equates to the insulation and the cytoplasm as the core conductor, but the plasma membrane is not a perfect insulator. Thus the spread of signals depends on the ratio of the membrane resistance to the axial resistance of the axonal cytoplasm (ra). When the ratio of rm to ra is high, less current is lost across the plasma membrane per unit of axonal length, the axon can function better as a cable, and the distance that a signal can be conveyed electrotonically without significant decrement is longer. A useful analogy


Physiology_Levy

Physiology_Levy. membrane per unit of axonal length, the axon can function better as a cable, and the distance that a signal can be conveyed electrotonically without significant decrement is longer. A useful analogy is to think of the axon as a garden hose with holes poked in it. The more holes there are in the hose, the more water leaks out along its length (analogous to more loss of current when rm is low) and the less water is delivered to its nozzle. According to cable theory, the length constant can be related to axonal resistance and is equal to rm/ra . This relationship can be used to determine how changes in axonal diameter affect the length constant and, hence, how the decay of electrotonic potentials varies. An increase in the diameter of the axon reduces both ra and rm. However, rm is inversely proportional to diameter (because it is related to the circumference of the axon), whereas ra varies inversely to the diameter squared (because it is related to the cross-sectional area of the axon).


Physiology_Levy

Physiology_Levy. proportional to diameter (because it is related to the circumference of the axon), whereas ra varies inversely to the diameter squared (because it is related to the cross-sectional area of the axon). Thus ra decreases more rapidly than rm does as axonal diameter increases, and the length constant therefore increases (


Physiology_Levy

Physiology_Levy. Fig. 5.3 ˜ = Distance over which response decays to 1 or ~ 37% of original size (Vo) Vo/e Vo/e Vo/e Vo/e Large-diameter axon ra is lowra is high˜Vo ˜˜˜˜ = 3 mm ˜ = 1 mm 1. 2. •Fig. 5.3 Comparison of the Length Constant to Axon Diameter. Notethattheincreaseindiameterisassociatedwithadecreaseinaxialresistanceoftheaxonalcytoplasm(ra)andanincreaseinthelengthconstant(λ).(RedrawnfromBlankenshipJ.Neurophysiology. Philadelphia:Mosby;2002.) CHAPTER 5 Generation and Conduction of Action Potentials In sum, in the passive domain, the membrane response to electrical stimuli is essentially identical to that of a circuit composed of passive electrical elements, and it can thus be characterized by the length and time constants of the membrane, which will determine how far and how rapidly electrical signals at one point in the cell spread to other parts. The Local Response With regard to the experiment shown in


Physiology_Levy

Physiology_Levy. The Local Response With regard to the experiment shown in Fig. 5.1, if larger depolarizing current pulses are injected, the voltage response of the membrane no longer resembles that of a passive RC circuit. This is most easily observed with pulses that elicit depolarizations either just below or to the threshold membrane potential for an action potential but fail to evoke an action potential (tracings 0.89 and 1.0; the threshold membrane potential can be defined as the voltage at which the probability of evoking an action potential is 50%). In these cases, the voltage response shape is altered from that of the passive responses because the stimulus has changed the membrane potential sufficiently to cause the opening of significant numbers of voltage-sensitive Na+ channels (described later). Also, note the upward deviation from linearity for the corresponding points in the I-V curve (see


Physiology_Levy

Physiology_Levy. Also, note the upward deviation from linearity for the corresponding points in the I-V curve (see Fig. 5.1B ). Opening of these voltage-sensitive channels changes the membrane’s resistance and allows Na+ to enter more easily, driven by its electrochemical gradient. This entry of positive charge (Na+ current) enhances the depolarization by adding to the current pulse delivered by the electrode. The resulting depolarization is called a local response. The local response results from active changes in membrane properties (specifically, its Na+ conductance), whereas in a passive electrotonic response, the conductance to various ions remains constant. Nevertheless, the local response is not self-regenerating but, again, decreases in amplitude with distance. The change in membrane properties is insufficient for what is needed to generate an action potential. Suprathreshold Response: The Action Potential


Physiology_Levy

Physiology_Levy. Suprathreshold Response: The Action Potential Local responses will increase in size as the amplitude of the depolarizing current pulse is increased, until the threshold membrane potential is reached, at which point a different sort of response, the action potential (or spike), can occur. The threshold value is typically near −55 mV. Normally, when the membrane potential exceeds this value, an action potential is always triggered.


Physiology_Levy

Physiology_Levy. Fig. 5.4 shows the typical shape of an action potential. When the membrane is depolarized past threshold, the depolarization becomes explosive and overshoots in such a way that the membrane potential reverses from negative to positive and approaches, but does not reach, the Nernst equilibrium potential for Na+ (ENa; see ). The membrane potential then returns toward the resting membrane potential (repolarizes) almost as rapidly as it was depolarized, and in general, it hyperpolarizes beyond its resting potential (the afterhyperpolarization). The main phase of the action potential (from the onset to the return to the resting potential) typically has a duration of 1 to 2 msec, but the afterhyperpolarization, it can persist •Fig. 5.4 Components of the Action Potential With Regard to Time and Voltage.


Physiology_Levy

Physiology_Levy. return to the resting potential) typically has a duration of 1 to 2 msec, but the afterhyperpolarization, it can persist •Fig. 5.4 Components of the Action Potential With Regard to Time and Voltage. Markersindicatetheabsoluteandrelativerefractoryperiods.Notethatthetimescaleforthefirstfewmillisecondshasbeenexpandedforclarity.RMP,restingmembranepotential.(RedrawnfromBlankenshipJ.Neurophysiology. Philadelphia:Mosby;2002.) from a few to 100 msec, depending on the particular type of neuron.


Physiology_Levy

Physiology_Levy. The action potential differs from the subthreshold and passive responses in three important ways: (1) It is a response of much larger amplitude, in which the polarity of the membrane potential actually overshoots 0 mV (the cell interior becomes positive in relation to the exterior). (2) The action potential is generally propagated down the entire length of the axon without decrement (i.e., it maintains its size and shape because it is regenerated as it travels along the axon). (3) It is an all-or-none response, which means that a stimulus normally either produces a full-sized action potential or fails to produce one. This all-or-none nature is in contrast both to the graded nature of the passive and local responses described previously and to synaptic responses (see Ionic Basis of Action Potentials


Physiology_Levy

Physiology_Levy. Ionic Basis of Action Potentials Recall that the resting membrane potential is determined primarily by the weighted average of the Nernst potentials for Na+ (ENa) and K+ (EK), as defined by the chord conductance equation (see ). The weighting factors are the conductance (g = 1/resistance) to each ion. At rest the conductance to K+ (gK) is high in relation to that for Na+ (gNa), and so the resting membrane potential (Vr) is closer to EK (Vr ≅−70 mV). If, however, the relative conductances to these ions were to change, this would cause a corresponding change in the membrane potential. For example, an increase in gK would hyperpolarize the membrane, whereas a decrease in gK would depolarize the membrane because EK is approximately −100 mV. Conversely, an increase in gNa would depolarize the membrane and, if of sufficient magnitude, even a lead to reversal in membrane polarity because ENa is approximately +65 mV.


Physiology_Levy

Physiology_Levy. An axonic action potential is, in fact, the result of a rapid sequence of transient changes in gNa or gK, or both. In all axons there is a brief rise in gNa, followed by a decline back to baseline levels. In some axons, this change in gNa occurs against a fixed resting gK (because of leak channels, which are not voltage-gated; discussed later). In many other cases, however, both gNa and gK change. Thus as with the resting membrane potential, the action potential depends on the opposing tendencies of (1) the Na+ gradient to bring the resting membrane potential toward the Nernst potential for Na+ and (2) the K+ gradient to bring the resting membrane potential toward the Nernst potential for K+; but in contrast to when the neuron is at rest, the gK/gNa ratio is not constant but is changing continuously. One additional difference is that because the membrane potential is changing, a capacitative current also exists, and this must also be taken into account to describe the membrane


Physiology_Levy

Physiology_Levy. continuously. One additional difference is that because the membrane potential is changing, a capacitative current also exists, and this must also be taken into account to describe the membrane potential quantitatively during an action potential (as a corollary, note that the chord conductance equation is valid only when the membrane potential is constant because then there is no capacitative current).


Physiology_Levy

Physiology_Levy. The early phase of the action potential (the positive deflection of the membrane potential toward ENa) is a result of a rapid increase in gNa and thus of the Na+ current (INa). These changes cause the membrane potential to move toward the equilibrium potential for Na+ . The peak of the action potential does not reach ENa because the rise in gNa is not infinite (i.e., the gK/gNa ratio does not fall to zero).


Physiology_Levy

Physiology_Levy. Because of the nature of the underlying Na+ channels (described later), the rise in gNa with depolarization is transient. Moreover, in many cases, the depolarization leads to a rise in gK. These two factors cause the gK/gNa ratio to stop falling and start increasing; as a result, the membrane potential is driven back toward EK and thus repolarizes toward its resting value. In cases in which the repolarization involves a rise in gK, the membrane potential hyperpolarizes temporarily beyond its normal rest value (if gK does not change, the drop in gNa causes the membrane simply to return to its resting potential). This afterhyperpolarization occurs because gK remains elevated for a period of time after the action potential. As gK returns to its baseline level, the membrane potential returns to its rest value. These changes in conductance can be explained by the properties of Na+ and K+ ion channels, which are described next.


Physiology_Levy

Physiology_Levy. These changes in conductance can be explained by the properties of Na+ and K+ ion channels, which are described next. Early studies of the mechanism underlying action potentials indicated that ion currents pass through separate Na+ and K+ channels, each with distinct characteristics, in the cell membrane. Subsequent research has supported this interpretation. The amino acid sequences of the channel proteins and many of the functional and structural characteristics of the channels are now known in detail. The structure of a voltage-gated Na+ channel (


Physiology_Levy

Physiology_Levy. The structure of a voltage-gated Na+ channel ( Fig. 5.5 ) consists of four α subunits and two β subunits. The α subunit has four repeated motifs each of six transmembrane helices that surround a central ion pore. The pore walls are partly formed by the six helices in each motif. Most voltage-gated K+ channels are composed of four separate subunits, each consisting of a polypeptide with six membrane-spanning segments, similar to the motifs that make up the α subunit of the Na+ channel. An important characteristic of some channels, such as those that underlie the action potential, is that they are gated by the membrane voltage. These voltage-gated channels sense the potential across the membrane and then act to either open or close the pore according to the membrane potential. The gates are formed by groups of charged amino acid residues, and the voltage dependence of the Na+ and K+ channel gates can account for the complex changes in gNa and gK that occur during an action potential.


Physiology_Levy

Physiology_Levy. The Characteristics of the Na+ and K+ Channels Explain the Conductance Changes During the Action Potential Use of standard intracellular recording along with voltage-clamp techniques enabled investigators to characterize the underlying ionic currents and conductance changes


Physiology_Levy

Physiology_Levy. CHAPTER 5 Generation and Conduction of Action Potentials 71 •Fig. 5.5 A Model of the Voltage-Gated Na+ Channel. A, Thelargeredelementsrepresentthefourα subunitsandthetwoyellowelementsareβ subunitswiththereceptorsitesforα scorpiontoxin(ScTX)andtetrodotoxin(TTX)indicated.B, β1andβ2subunitsflankinganα subunitareshownwiththeirtransmembranehelices.(RedrawnfromCatterallWA:Structureandfunctionofvoltage-gatedsodiumchannelsatatomicresolution.Exp Physiol. 2014;99:35-51.) associated with the action potential. Detailed statistical analyses of these recordings also allowed remarkable inferences to be made about the nature of the channels that passed these Na+ and K+ currents. The development of the patch recording, however, enabled direct observation of the behavior of individual channels. In this technique, a specially shaped microelectrode is placed against the surface of a cell, and suction is applied to the microelectrode. As a result, a high-resistance seal is formed between the mem brane and


Physiology_Levy

Physiology_Levy. a specially shaped microelectrode is placed against the surface of a cell, and suction is applied to the microelectrode. As a result, a high-resistance seal is formed between the mem brane and the tip of the microelectrode (Fig. 5.6A ), which allows recording of the activity of whatever channels happen to be in the patch of membrane that is inside the seal. Under ideal conditions only one or a few ion channels of a single type are present in the membrane patch.


Physiology_Levy

Physiology_Levy. Patch recordings show that many ion channels flip spontaneously between open and closed conductance states as if they have gates that open and close the entrance to their pore. In the case of voltage-gated channels, the gate is sensitive to the voltage across the membrane, and thus the time a gate spends in each state is a probabilistic function of the membrane potential. A patch recording of a K+ channel demonstrates this probabilistic behavior (see Fig. 5.6B ). As the membrane potential is clamped to more depolarized levels, the channel spends more time in its open state, which reflects the voltage dependence of the probability that the channel will open (see Fig. 5.6C ). Also, the amplitude of the current in the open state increases with the level of depolarization; this is because the driving force for K+ is greater at more depolarized levels (i.e., the membrane potential is farther from the K+ Nernst potential).


Physiology_Levy

Physiology_Levy. The behavior of a Na+ channel is more complex than that of the K+ channel. Like the K+ channel, it has a 72 SECTION2Berne & Levy Physiology X˜X˜X˜X˜X˜Cytosol Pipette solution Patch pipette Ground Operational amplifier Feedback resistor Micropipette Cell membrane Ion channel A 1.0 0.8 0.6 0.4 0.2 C Po °80 °60 °40 °20 200 mV D Time (1ms/division)B ˜°°50 0 50 Membrane potential (mV) °1.0 0 Na+ current density (mA/cm2)


Physiology_Levy

Physiology_Levy. CHAPTER 5 Generation and Conduction of Action Potentials •Fig. 5.6 A, Amicropipetteisappliedtothecellmembraneandsufficientsuctionisappliedtoelectricallyisolateasinglechannelatthetip.Anamplifierrecordsthecurrentthatpassesthroughthechannel.B, EachlineshowsthecurrentpassedthroughaK+ channelasitopensspontaneously.Notethatasthetransmembranevoltageisprogressivelydepolarized(fromtoptobottom),boththeprobabilitythatthechannelwillopenandtheamplitudeofthecurrentareincreased.C, Agraphoftheprobabilitythatthechannelwillopenversusmembranedepolarization.D, Agraphoftransmembranevoltage(lowertracing,right-sidedscale)andthecurrentdensityfromapopulationofNa+ channels(uppertracing,left-sidedscale)isolatedinapatchsimilartothatinA (exceptthatitcontainsseveralNa+ channels).Initially,atrestingpotential,thereisnocurrentflow.Withdepolarizationto0mV,thereisaninwardNa+


Physiology_Levy

Physiology_Levy. (exceptthatitcontainsseveralNa+ channels).Initially,atrestingpotential,thereisnocurrentflow.Withdepolarizationto0mV,thereisaninwardNa+ currentthatiscurtailedevenwhilethedepolarizationcontinues.Thisisduetotheclosingofthechannels’inactivationgates.Afterabriefreturntorestingpotential,anotherdepolarizationto0mVevokesinwardcurrentflow,butitissmallerandbrieferbecausetherehasnotbeenenoughtimeformostoftheslowinactivationgatestoreopen.(B, C, andD areredrawnfrom http://www.physiologymodels.info/electrophysiology voltage-sensitive gate (activation gate) whose probability of being open increases with depolarization. However, unlike K+ channels, with maintained depolarization, Na+ channels open only at the onset of the depolarization and then remain closed. This suggests that Na+ channels have a second gate (inactivation gate) whose probability of being open goes down as the membrane is depolarized. Thus any Na+ current conducted by these channels will be transient (see


Physiology_Levy

Physiology_Levy. Fig. 5.6D ), because the same stimulus (depolarization) increases both the probabilities that the activation gate will open and that the inactivation gate will close. Note that the Na+ channel thus has two closed states, one in which the activation gate is closed, and the channel is said to be “closed,” and one in which the inactivation gate is closed, and the channel is referred to as “inactivated.” The reason the channel is called “inactivated” when the second gate closes is that once this gate closes, it will remain so until the membrane is repolarized. The activation gate, in contrast, can open and close at all membrane potentials, just with differing probabilities.


Physiology_Levy

Physiology_Levy. With the knowledge of the Na+ and K+ channel gating behavior just discussed, we can understand how the action potential is generated by the interaction of these channels (in the following, we assume that both gNa and gK change during the action potential). As stated previously, the action potential starts with a rapid increase in Na+ conductance (gNa; Fig. 5.7 ). This increase in Na+ conductance reflects the opening of many Na+ channels in response to the depolarization. The open channels allow the influx of Na+ ions, and the effect of this current is to depolarize the membrane further. Note that this is a positive feedback loop, which accounts for the explosive nature of the action potential: the Na+ current depolarizes the membrane, which causes more Na+ channels to open, which in turn increases the Na+ current. In sum, the voltage-dependent opening of Na+ channels and the depolarizing action of the Na+ current account for the rising phase of the action potential.


Physiology_Levy

Physiology_Levy. The end of the rising phase and the subsequent falling (repolarization) phase of the action potential is the result of two processes: a reduction in gNa and an increase in gK. The rise in gK is simply a consequence of membrane depolarization, which increases the probability that the K+ channel will be open. The decrease in gNa results from two •Fig. 5.7 The Action Potential and the Conductance and Currents That Underlie the Action Potential With Regard to Time. NotethattheincreasedconductanceforNa+ (gNa),aswellasitsinwardflow,isassociatedwiththerisingphaseoftheactionpotential,whereastheslowerincreaseinconductanceforK+ (gK),aswellasitsoutwardflow,isassociatedwithrepolarizationofthemembraneandwithafterhyperpolarization.ThereductionintheNa+ current(INa)beforethepeakoftheactionpotential(eventhoughgNaisstillhigh)isduetoinactivationoftheNa+ channels.(RedrawnfromSquiresLR,etal:Fundamental Neuroscience. 2nded.SanDiego,CA:AcademicPress;2002.) factors. First, Na+ channels are inactivated as a


Physiology_Levy

Physiology_Levy. channels.(RedrawnfromSquiresLR,etal:Fundamental Neuroscience. 2nded.SanDiego,CA:AcademicPress;2002.) factors. First, Na+ channels are inactivated as a result of the closing of the inactivation gate with depolarization. Unlike the activation gate, which can flip between states even when the membrane is depolarized, the inactivation gate, once closed, remains closed until significant repolarization occurs. Second, as the gK/gNa ratio increases (as a result of both inactivation of Na+ channels and opening of K+ channels), the membrane begins to repolarize, and this repolarization acts to shut the activation gate of the Na+ channel. The closure of both voltage-gated Na+ and K+ channels during the falling phase brings the membrane back to its resting state. If only Na+ channels had opened during the action potential (as is the case for some axons), the membrane would simply return to its rest potential. If voltage-gated K+ channels also had opened during the action potential, an


Physiology_Levy

Physiology_Levy. during the action potential (as is the case for some axons), the membrane would simply return to its rest potential. If voltage-gated K+ channels also had opened during the action potential, an afterhyperpolarization would be present because these K+ channels close slowly in response to hyperpolarization.


Physiology_Levy


Physiology_Levy

Physiology_Levy. When a nerve is depolarized very slowly, the normal threshold may be passed without the firing of an action potential; this phenomenon is called accommodation. Both Na+ and K+ channels are involved in accommodation. In response to membrane depolarization, gNa first increases and then, a short time later, decreases. This is due to the opening of the activation gates and closing of the inactivation gates of the Na+ channels. Normally, membrane depolarization to threshold or beyond triggers an action potential; however, the explosive depolarization of the action potential can occur only if a critical number of Na+ channels are recruited. Thus if a cell is slowly depolarized, Na+ channels can become inactivated even without the occurrence of an action potential, and the pool of available noninactivated Na+ channels (i.e., channels in the closed state) can be reduced to the point at which a stimulus to may not be able to recruit a sufficient number of Na+ channels to generate an action


Physiology_Levy

Physiology_Levy. Na+ channels (i.e., channels in the closed state) can be reduced to the point at which a stimulus to may not be able to recruit a sufficient number of Na+ channels to generate an action potential. An additional factor in causing accommodation is that K+ channels open slowly in response to the depolarization. The increased gK tends to oppose depolarization of the membrane, which makes it even less likely to fire an action potential.


Physiology_Levy

Physiology_Levy. When a cell is refractory, it is either completely unable to fire an action potential or it requires a much stronger stimulation than usual. During much of the action potential, the cell is completely refractory because it will not fire another action potential no matter how strongly it is stimulated. This absolute refractory period (see Fig. 5.4 ) occurs when a large fraction of the Na+ channels are inactivated and therefore cannot be reopened until the membrane is repolarized. During this period, the critical number of Na+ channels required to produce an action potential cannot be recruited.


Physiology_Levy

Physiology_Levy. During the latter part of the action potential, and during the afterhyperpolarization period, the cell is able to fire a second action potential, but a stimulus stronger than normal is required. This period is called the relative refractory period. Early in the relative refractory period, before the


Physiology_Levy

Physiology_Levy. CHAPTER 5 Generation and Conduction of Action Potentials membrane potential has returned to the resting potential level, some Na+ channels are still voltage inactivated, but there are enough in the closed state (and therefore have the potential to open when the membrane is depolarized) to support the generation of an action potential if they are stimulated to open. However, a stimulus stronger than normal is necessary to recruit the critical number of Na+ channels needed to trigger an action potential (i.e., the reduction in the total number of available Na+ channels is countered by increasing the probability of opening). Throughout the relative refractory period, conductance to K+ is elevated, which opposes depolarization of the membrane. This increase in K+ conductance continues throughout the afterhyperpolarization and accounts for most of the duration of the relative refractory period. Conduction of Action Potentials


Physiology_Levy

Physiology_Levy. Conduction of Action Potentials Fundamental to nervous system function is the transmission of information along neuronal pathways. To accomplish this, neurons generate action potentials that propagate down the length of their axon without decrement in size in order to trigger neurotransmitter release from the presynaptic terminals. How action potentials propagate down an axon and how the characteristics of the axon affect this propagation are discussed in this section. How they trigger transmitter release is covered in Action Potential as a Self-Reinforcing Signal


Physiology_Levy

Physiology_Levy. Passive conduction will not transport a signal from one end of an axon to the other unless the axon is very short (i.e., on the order of its length constant) because passively conducted signals decrease in size rapidly with distance from their origin. Neurons with such short axons exist; for example, in the retina of the eye, the distance from one neuron to the next is so small that electrotonic (passive) conduction is sufficient. However, in most cases, axons are many times longer than their length constant. In fact, they can be up to 1 m or more in length (e.g., those of motor neurons) and thus hundreds of times their length constant. Nonetheless, if researchers were to record from points along a typical axon, they would find that as the action potential arrives at successive points traveling along the axon, its shape and size remain constant. This is because the action potential regenerates itself as it is conducted along the fiber and thus is said to be actively propagated.


Physiology_Levy

Physiology_Levy. Fig. 5.8 shows how in a local response the current that flows in through one part of the membrane acts to depolarize the neighboring membrane. The same thing happens when the Na+ channels are opened by an action potential at one site along the axon, except that in this case, the current will be large enough to depolarize the areas on either side past threshold and thus generate action potentials in these neighboring areas. The inward Na+ current in these areas can then provide the current to depolarize their neighbors past threshold so that they in turn generate action potentials, •Fig. 5.8 Mechanism of Electrotonic Spread of Depolarization. A, Thereversalofmembranepolaritythatoccurswithlocaldepolariza-tion.B, Thelocalcurrentsthatflowtodepolarizeadjacentareasofthemembraneandallowconductionofthedepolarization.B + – + – + – + – + – + – + – + – + – + – + – + – + – + – – + – + – + + – + – + – – + – + – + – + – + – + – + – + – + – + – + – + – + – + and so on. In short, action potential


Physiology_Levy

Physiology_Levy. + – + – + – + – + – + – + – + – + – + – + – + – + – + – – + – + – + + – + – + – – + – + – + – + – + – + – + – + – + – + – + – + – + – + and so on. In short, action potential propagation along an axon involves recurring cycles of depolarization to provide sufficient local current flow for generation of an action potential in an adjacent region of the cell membrane. Thus the action potential is said to be propagated down the axon, with “new” action potentials being generated along its length. In this way, the action potential can propagate down the entire length of the axon while retaining the same size and shape.


Physiology_Levy

Physiology_Levy. Normally, action potentials are first generated at the axon’s initial segment (i.e., where the axon is attached to the neuron cell body or proximal dendrite) and then conducted to the terminal end. The reason for this is that the initial segment has a very high density of voltage-gated Na+ channels, and thus it has a lower threshold for spiking than does the soma or dendrites. However, axons are not inherently unidirectional conductors. For example, as implied by the local circuits shown in Fig. 5.8 , an action potential generated by a depolarization in the middle of an axon is conducted in both directions from its initiation site simultaneously.


Physiology_Levy

Physiology_Levy. Why does a spike that starts at the initial segment not propagate in both directions? In fact, it does. In addition to propagating down the axon, the current flowing from the initial segment back to the soma can cause a spike to be generated in the soma because the soma also has voltage-gated Na+ channels. Additional “backpropagating” spikes from the axon do not occur, however, nor does the somatic spike cause the initial segment of the axon to fire a second time (and thereby send another spike down the axon and start a repeating cycle). This does not happen because the refractory period of the membrane makes any area that has already spiked unable to fire a second spike for a short time. Thus for a spike that started at the initial segment and has begun traveling down the axon, current flowing in at the site of the spike depolarizes the membrane on both sides of that site. However, the side closer to the cell body, which has recently fired a spike, cannot respond to this


Physiology_Levy

Physiology_Levy. current flowing in at the site of the spike depolarizes the membrane on both sides of that site. However, the side closer to the cell body, which has recently fired a spike, cannot respond to this depolarization because its Na+ channels are still inactivated. By the time Na+ channels are de-inactivated (have returned to their closed state and would be able to open) the depolarization of membrane at that site has ended (because the action potential lasts only for ≈1 msec). Thus the inactivation gate of the Na+ channel not only helps determine the duration of the action potential but it also is responsible for its singular and unidirectional propagation from its origin at the initial segment.


Physiology_Levy

Physiology_Levy. The speed of conduction in a nerve fiber is determined by the electrical properties of the cytoplasm and the plasma membrane that surrounds the fiber, as well as by its geometry. In nonmyelinated fibers, conduction velocity is proportional to the square root of the cross-sectional diameter (Fig. 5.9 ). This effect is related to the changes in ra and rm with diameter. As the diameter of a fiber increases, ra decreases with the square of the diameter, and rm increases only linearly with diameter; as a result, resistance to current •Fig. 5.9 Conductionvelocitiesofunmyelinated(blue) andmyelinated(red) felineaxonsasfunctionsofaxondiameter.Solid lines representmeasureddata.Dotted lines representextrapolationsthatshowtheadvantageofmyelinationoversimplyincreasingaxondiameterasamechanismforincreasedconductionvelocity.(FromSchmidt-Nielsen K.


Physiology_Levy

Physiology_Levy. K. Animal Physiology: Adaptation and Environment. 5thed.Cambridge,UK:CambridgeUniversityPress;1997.) flow down the axon decreases more than it does to current flow across the membrane. This increases the length constant (see Fig. 5.3 ), which means that a greater amount of the current entering at one site is delivered to neighboring regions of the axon, which brings those regions to threshold more quickly, and thus the action potential is conducted faster along fibers with large diameters. However, increasing the diameter also increases the surface area of the plasma membrane over which inner negative and outer positive charges are held to each other. Discharging this increased capacitance tends to slow conduction and mitigate the increase in conduction velocity gained by increasing diameter.


Physiology_Levy

Physiology_Levy. In vertebrates, many nerve fibers are coated with myelin, and such fibers are said to be myelinated. Myelin consists of the plasma membranes of Schwann cells (in the peripheral nervous system) or oligodendroglia (in the central nervous system [CNS]), which wrap around and insulate the nerve fiber ( Fig. 5.10A and B ). The myelin sheath consists of several to more than 100 layers of glial cell plasma membrane. Gaps about 1-2 µm wide, known as nodes of Ranvier, separate the contribution of one Schwann cell (or oligodendrocyte) from that of another. For all but the axons of smallest diameter, a myelinated axon has much greater conduction velocity than does an unmyelinated fiber of the same caliber because the myelin sheath increases the effective membrane resistance of the axon, decreases the capacitance of the axon membrane, and limits the generation of action potentials to the nodes of Ranvier. In short, myelination greatly alters the electrical properties of the axon.


Physiology_Levy

Physiology_Levy. Because the many wrappings of membrane around the axon increase the effective membrane resistance rm/ra and the length constant are much greater. The increased membrane resistance means that less current is lost through the membrane per length of axon, and thus the amplitude of a conducted signal decreases less with distance along the axon and needs to be regenerated (by opening of Na+ channels) less often.


Physiology_Levy

Physiology_Levy. In addition, the thicker myelin-wrapped membrane results in a much larger separation of charges across it than exists across the bare membrane of an axon, so that the charges across it are much less tightly bound to each other. This is analogous to when the plates of a capacitor are moved apart and reduce its capacitance. Because the effect of membrane capacitance is to slow the rate at which the membrane potential can be changed, the reduced capacitance of myelinated axons means that the depolarization occurs more rapidly. For all these reasons, conduction velocity is greatly increased by myelination, and the current generated at one node of Ranvier is conducted at great speed to the next (see Fig. 5.10 In myelinated axons, the Na+ channels that bring about generation of an action potential are highly concentrated


Physiology_Levy

Physiology_Levy. Fig. 5.10 In myelinated axons, the Na+ channels that bring about generation of an action potential are highly concentrated CHAPTER 5 Generation and Conduction of Action Potentials •Fig. 5.10 A, Schematicillustrations,incrosssectionandlongitudinalsectionthroughanodeofRanvier,ofaSchwanncellwrappedaroundanaxontoformmyelin.NotethattheaxonisexposedtotheextracellularspaceonlyatthenodeofRanvier.B, Viewoftwonodesandtheinterveninginternodeofmyelin.C, Saltatoryconductioninamyelinatedaxonwithaplotoftheactionpotentiallocationalongtheaxon(x-axis)versustime(y-axis).Notetheshorttimetakenfortheactionpotentialtotraversethelargedistancebetweennodes(shallow sloped lines ontheplot)becauseofthehighresistanceandlowcapacitanceoftheinternodalregion.Incontrast,theactionpotentialslowsasitcrosseseachnode(steep sloped line segments). (B, RedrawnfromSquiresLRetal:Fundamental Neuroscience. 2nded.SanDiego,CA:AcademicPress;2002.C, RedrawnfromBlankenshipJ:Neurophysiology. Philadelphia: