Neurons and Nervous Systems

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1 44 Neurons and Nervous Systems On a dark, moonless winter night a mouse scurries across the icy forest floor. With an almost imperceptible whoosh, an owl swoops down, grabs the mouse in its talons, and rises back into the forest canopy. How did the owl locate the mouse so precisely that it could seize it while flying? It heard the mouse, of course. But place yourself in that same dark forest. If you heard a scratching sound, how accurate do you think you would be at instantly shining your flashlight on the mouse making the sound? Yet your nervous system and the owl s are exposed to the same environmental information. How do nervous systems derive directional information from sound? Sound is converted into simple electric signals in the inner ear. These signals are produced by nerve cells, or neurons, and carried by long extensions of those neurons to the brain. Different neurons in the ear respond to different pitches or frequencies of sound, and the rate of the electric signals can convey information about the intensity of the sound. Neurons in the owl s brain, and in ours to a lesser degree, are able to detect these tiny differences in the electric signals they receive and integrate that information to decide where the sound is coming from. The brain and nervous system are capable of many amazing feats such as this. In this chapter and the three that follow, we will learn how nervous systems accomplish these feats. In this chapter, we start by describing the cells of the nervous system, how they generate electric signals, conduct those signals from place to place in the body, and communicate those signals from cell to cell. Listening in the Dark In total darkness, a long-eared owl (Asio otus) catches a mouse by using directional information in the sounds the mouse makes as it moves. Such precise analysis of limited information shows the amazing capabilities of complex nervous systems. Nervous Systems: Cells and Functions Nerve cells, or neurons, are specialized to receive information, encode it, and transmit it to other cells. Neurons and their specialized supportive cells, called glial cells, make up nervous systems. Animals receive various kinds of information from both inside and outside their bodies. This information is received and converted, or transduced, by sensory cells (also called receptor cells) into electric signals that

2 NEURONS AND NERVOUS SYSTEMS 845 can be transmitted and processed by neurons. To cause behavioral or physiological responses, a nervous system communicates these signals to effectors, such as muscles and glands. Nervous systems process information Simple animals such as sea anemones can process information with simple networks of neurons that do little more than provide direct lines of communication from sensory cells to effectors (Figure 44.1a). The anemone s nerve net is most developed around the tentacles and the oral opening, where it facilitates detection of food or danger and causes tentacles to extend or retract. Bilaterally symmetrical animals, such as earthworms, that move more rapidly through their environments need to process and integrate larger amounts of information. This need is met by clusters of neurons called ganglia (Figure 44.1b). Ganglia serving different functions may be distributed around the body, as in the earthworm or the squid (Figure 44.1c). Frequently one pair of ganglia is larger and more central than the others and is therefore given the designation of brain. In vertebrates, most of the cells of the nervous system are found in the brain and the spinal cord, the sites of most information processing, storage, and retrieval (Figure 44.1d). Therefore, the brain and spinal cord are called the central nervous system (CNS). Information is transmitted from sensory cells to the CNS and from the CNS to effectors via neurons that extend or reside outside of the brain and the spinal cord; these neurons and their supporting cells are called the peripheral nervous system. Vertebrates differ greatly in their behavioral complexity and in their physiological specializations. Even the smaller and simpler nervous systems of invertebrates can be remarkably complex. Consider the nervous systems of small spiders that have programmed within them the thousands of precise movements necessary to construct a beautiful web without prior experience. Neurons are the functional units of nervous systems Although nervous systems vary enormously in structure and function, neurons function similarly in animals as different as squids and humans. Their plasma membranes generate electric signals called nerve impulses or action potentials and conduct these signals from one location on a neuron to the 44.1 Nervous Systems Vary in Size and Complexity As we compare animals that have increasingly complex sensory and behavioral abilities, we find that information processing is increasingly centralized in ganglia (collections of neurons) or in a brain. most distant reaches of that cell a distance that can be more than a meter in a human and many meters in a whale. Most neurons have four regions a cell body, dendrites, an axon, and axon terminals (Figure 44.2a) but the variation among different types of neurons is considerable (Figure 44.2b). The cell body contains the nucleus and most of the cell s organelles. Many projections may sprout from the cell body. Most of these projections are bushlike dendrites (from the Greek dendron, tree ), which bring information from other neurons or sensory cells to the cell body. The degree of branching of the dendrites differs among different types of neurons. In most neurons, one projection is much longer than (a) Nerve net (c) A nerve net serves simple behaviors such as contraction and relaxation. Brain Nerves to gut Ganglion Squid (Mollusca) Sea anemone (Cnidaria) Visual ganglion Nerves to muscles In squid, more complex behaviors are served by collections of neurons in specialized ganglia. (d) (b) Segmental nerve Brain Earthworm (Annelida) In the earthworm, ganglia in each segment coordinate movement and an anterior brain controls more complex behavior. The human brain and spinal cord are the central nervous system which communicates to the cells and organs of the body via the peripheral nervous system. Human (Chordata) Ganglion in ventral nerve cord

3 846 CHAPTER FORTY-FOUR (a) Generalized neuron anatomy (b) Specialized neurons Neurons with bushy dendrites collect information from many other cells. Neurons with fewer dendrites process fewer inputs. Dendrites receive infor-mation from other neurons. Dendrites The cell body contains the nucleus and most cell organelles. Cell body Retina Base of axon (axon hillock) integrates information collected by dendrites and initiates nerve impulses. Cerebellum The axon conducts nerve impulses away from the cell body. Some neurons branch over a broad area. terminals synapse with a target cell. Cell body Target cell 44.2 Neurons (a) A generalized diagram of a neuron. (b) Neurons from different parts of the mammalian nervous system are specifically adapted to their functions. Cerebral cortex Cell body Some neurons provide local links to a small number of cells. Some communicate long distances via long axons. Spinal cord the others, and is called the axon. s usually carry information away from the cell body. The length of the axon also differs among different types of neurons some axons are remarkably long, such as those that run from the spinal cord to the toes. s are the telephone lines of the nervous system. Information received by the dendrites can cause the cell body to generate a nerve impulse, which is then conducted along the axon to the cell that is its target. At the target cell which can be another neuron, a muscle cell, or an endocrine cell the axon divides into a spray of fine nerve endings. At the tip of each of these tiny nerve endings is a swelling, called an axon terminal, that comes very close to the target cell. Where an axon terminal comes close to another cell, the membranes of both cells are modified to form a synapse. In most cases, a space only about 25 nm wide separates the two membranes. A nerve impulse arriving at an axon terminal causes an increase of chemical messenger molecules called neurotransmitters stored in the axon terminal to be released. The released neurotransmitters diffuse across the space and bind to receptors on the plasma membrane of the target cell. We will discuss this process of synaptic transmission in more detail later in the chapter. Thousands of synapses impinge on most individual neurons. Integration of information in the nervous system is possible because a neuron can receive information (synaptic inputs) from many sources before producing nerve impulses that travel down its single axon to target cells. Glial cells are also important components of nervous systems Neurons are not the only type of cell in the nervous system. In fact, there are more glial cells than neurons in the human brain. Like neurons, glial cells come in several forms and have a diversity of functions. Some glial cells physically support and orient the neurons and help them make the right contacts during embryonic development. Other glial cells insulate axons. In the peripheral nervous system, Schwann cells wrap around the axons of neurons, covering them with concentric layers of insulating plasma membrane (Figure 44.3). Other glial cells called oligodendrocytes perform a similar function in the central nervous system. Myelin is the covering produced by Schwann cells and oligodendrocytes, and it gives many parts of the nervous system a glistening white appearance. Later in this chapter we will see how the electrical

4 (a) Myelin-producing Schwann cell NEURONS AND NERVOUS SYSTEMS 847 Site and direction of myelin growth Nucleus of Schwann cell (b) Myelin layers thousand or more synapses; thus, there may be as many as synapses in the human brain. Therein lies the incredible ability of the human brain to process information. This astronomical number of neurons and synapses is divided into thousands of distinct but interacting networks that function in parallel. But before we can understand how even one of these networks works, we must understand the properties of individual neurons that allow them to generate and conduct nerve impulses. Multiple layers of plasma membrane (myelin) insulate the axon Wrapping Up an (a) Schwann cells wrap axons in the peripheral nervous system with layers of myelin, a type of plasma membrane that provides electrical insulation. (b) A myelinated axon, seen in cross section through an electron microscope. insulation provided by myelin increases the speed with which axons can conduct nerve impulses. Glial cells are well known for the many supportive roles they play. Some supply neurons with nutrients; others consume foreign particles and cell debris. Glial cells also help maintain the proper ionic environment around neurons. Although they have no axons and do not generate or conduct nerve impulses, some glial cells communicate with one another electrically through gap junctions, a special type of connection that enables ions to flow between cells. Glial cells called astrocytes (because they look like stars) contribute to the blood brain barrier, which protects the brain from toxic chemicals in the blood. Blood vessels throughout the body are very permeable to many chemicals, including toxic ones, which would reach the brain if this special barrier did not exist. Astrocytes help form the blood brain barrier by surrounding the smallest, most permeable blood vessels in the brain. The barrier is not perfect, however. Since it consists of plasma membranes, it is permeable to fat-soluble substances such as anesthetics and alcohol. Neurons function in networks As we learn more about the properties of neurons, it is important to keep in mind that nervous systems depend on neurons working together. The simplest neuronal network consists of three cells: a sensory neuron connected to a motor neuron connected to a muscle cell. Most of the neuronal networks that carry out the functions of the human nervous system are much more complex and consist of many more neurons. The human brain contains an estimated neurons, and most of those neurons receive information from a Neurons: Generating and Conducting Nerve Impulses The insides of cells are electrically negative in comparison to the outsides. The difference in electric potential, or voltage, across the plasma membrane of a cell is called its membrane potential. In an unstimulated neuron, this voltage difference is called a resting potential. Membrane potentials can be measured with electrodes. An electrode can be made from a glass pipette pulled to a very sharp tip and filled with a solution containing ions that conduct electric charges. Using such electrodes, we can record very tiny local electrical events. If a pair of electrodes is placed one on each side of the plasma membrane of a resting axon, they measure a voltage difference of about 60 millivolts (mv) (Figure 44.4). The resting potential provides a means for neurons to respond to a stimulus. A neuron is sensitive to any chemical or physical factor that causes a change in the resting potential across a portion of its plasma membrane. The most extreme change in membrane potential is an action potential, which is a sudden and rapid reversal in the voltage across a portion of the plasma membrane. For 1 or 2 milliseconds, a bioelectric current crosses the membrane and the inside of the cell becomes more positive than the outside. Nerve impulses are action potentials that move along axons. Simple electrical concepts underlie neuronal function Voltage (potential or electric charge difference) is the tendency for electrically charged particles such as electrons or ions to move between two points. Voltage is to the flow of electrically charged particles what pressure is to the flow of water. If the negative and the positive poles of a battery are connected by a copper wire, electrons flow from negative to positive because there is a voltage difference between them. This flow of electrons is an electric current, and it can be used to do work, just as a current of water can be used to do work such as turning a turbine. Electric current is carried by electrons in wires, but in solutions and across cell membranes, it is carried not by electrons, but by charged ions. The major ions that carry electric

5 RESEARCH METHOD Neuron 3 Two electrodes, one inside and one outside the axon, detect a difference in electric charge in an unstimulated neuron. 4 The small difference is amplified Outside axon 2 and connected with a wire to an amplifier. 5 and displayed on an oscilloscope. 1 An electrode, made from a glass pipette pulled to a sharp tip, is filled with an electrical conducting solution Inside axon Plasma membrane Outside axon Inside axon Outside axon Amplifier mv 0 60 Oscilloscope screen Time 44.4 Measuring the Resting Potential The difference in electric charge across the plasma membrane of a neuron can be measured using two electrodes, one inside and one outside the cell. In an unstimulated neuron, this difference is constant (about 60 mv), and is known as the resting potential. 6 The constant difference of 60 mv between outside and inside is the resting potential. charges across the plasma membranes of neurons are sodium ( ), chloride (Cl ), potassium ( ), and calcium (Ca 2+ ). It is also important to remember that ions with opposite charges attract one another, and those with like charges repel one another. With these basics of bioelectricity in mind, we can ask how the resting potential of the neuronal plasma membrane is created and how the flow of ions through membrane channels is turned on and off to generate action potentials. extracellular fluid, and the concentration of inside the cell less than that of the extracellular fluid. The concentration differences established by the pump mean that would diffuse out of the cell and would diffuse in if the ions could cross the lipid bilayer. Ion channels are pores formed by proteins in the lipid bilayer (see Chapter 5). These water-filled pores allow ions to pass through a membrane, but they are generally selective they allow some types of ions to pass through more easily than others (Figure 44.5b). Thus, there are potassium chan- Ion pumps and channels generate resting and action potentials The plasma membranes of neurons, like those of all other cells, are lipid bilayers that are impermeable to ions. However, these impermeable lipid bilayers contain many protein molecules that serve as ion channels and ion pumps (see Chapter 5). Ion pumps and channels are responsible for resting and action potentials. Ion pumps use energy to move ions or other molecules against their concentration gradients. A major ion pump in the plasma membranes of neurons (and of all other cells) is the sodium potassium pump. The action of this pump expels ions from inside the cell, exchanging them for ions from outside the cell (Figure 44.5a; see also Figure 5.13). The sodium - potassium pump keeps the concentration of inside the cell greater than that of the (a) pump Outside of cell Inside of cell The pump moves and ions against their concentration gradients Ion Pumps and Channels (a) The sodium potassium pump actively moves ions to the inside of a neuron and ions to the outside. (b) Ion channels allow specific ions to diffuse down their concentration gradient; ions tend to leave neurons when potassium channels are open, and ions tend to enter neurons when sodium channels are open. (b) and channels Na channel + channel (open) channel (closed) and ions tend to diffuse down their concentration gradients through ion-specific channels.

6 NEURONS AND NERVOUS SYSTEMS 849 nels, sodium channels, chloride channels, and calcium channels, and there are many different kinds of each. Ions move through channels by diffusion, and can move in either direction. The direction and magnitude of net movement of ions through a channel depends on the concentration gradient of that ion type across the plasma membrane, as well as the voltage across that membrane. Potassium channels are the most common open channels in the plasma membranes of resting (non-stimulated) neurons. As a consequence, resting neurons are more permeable to than to any other ion. As Figure 44.6 shows, this characteristic explains the resting potential. Because the potassium channels make the plasma membrane permeable to, and because the sodium potassium pump keeps the concentration of inside the cell much higher than that outside the cell, tends to diffuse out of the cell through the channels. As positively charged ions diffuse out of the cell, they leave behind unbalanced negative charges (mostly Cl ions and protein molecules), generating an electric potential across the membrane that tends to pull positively charged ions back into the cell. The membrane potential at which the tendency of ions to diffuse out of the cell is balanced by the negative electric potential pulling them back in is called the potassium equilibrium potential. The value of the potassium equilibrium potential can be calculated from the concentrations of on the two sides of the membrane using an equation called the Nernst equation, which is derived from the laws of physical chemistry (Figure 44.7). In general, the resting potential is a bit less negative than this equation predicts because resting neurons are also slightly permeable to other ions, such as and Cl. Outside of cell channel Cl Inside of cell Negatively charged protein mv 0 60 The tendency of ions to diffuse out leaves an excess of negative charges inside the cell, creating the resting potential. Oscilloscope screen Resting potential Milliseconds 44.6 Open Potassium Channels Create the Resting Potential Open potassium channels allow ions to diffuse out of the cell, leaving unbalanced negative charges behind (mostly on Cl ions and protein molecules). 1 ions diffuse out of the neuron creating a negative potential across the plasma membrane. 3 Outside cell Inside cell channel The diffusional force causing to leave the neuron is RT ln [K+ ] out [ ] in R = universal gas constant T = absolute temperature E = voltage difference across membrane zf = number of electric charges carried by a mole of ln [K+ ] natural logarithm of the ratio out = [ of concentrations on the ] in two sides of the membrane 4 The resulting electrical force is EzF. Deriving the Nernst equation: At equilibrium the electrical force equals the diffusional force, or 5 The equilibrium potential is that [ ] membrane potential that EzF = RT ln out counteracts the tendency of [ ] in Rearranging this equality, we get an expression of the Nernst equation for the potassium equilibrium potential: RT [ ] E out K = ln zf [ ] in The equation can be made simpler by combining the constants, assuming the temperature is 20 C, and converting the natural logarithm to base 10 logarithm: E K = (58 mv)log RESEARCH METHOD [ ] out [ ] in 2 The resulting negative potential tends to pull back into the cell. the ions to diffuse out. mv Resting potential Time Applying the Nernst equation: The concentration of ions inside a mammalian neuron is about 140 mm; outside the neuron the concentration is about 5 mm. Putting these numbers into the Nernst equation gives us a predicted resting potential of about 84 mv Amplifier Oscilloscope screen 44.7 The Nernst Equation The Nernst equation calculates membrane potential when only one type of ion can cross a membrane that separates solutions with different concentrations of that ion. A resting neuron comes close to that situation because its permeability to ions is high and its permeability to all other ions is low.

7 850 CHAPTER FORTY-FOUR Ion channels can alter membrane potential Many ion channels in the plasma membranes of neurons behave as if they contain a gate that opens under some conditions, but closes under other conditions. Voltage-gated channels open or close in response to a change in the voltage across the plasma membrane. Chemically gated channels open or close depending on the presence or absence of a specific molecule that binds to the channel protein, or to a separate receptor that in turn alters the channel protein. Both voltage-gated and chemically gated channels play important roles in neuronal function. Changes in gated channels may perturb the resting potential. Imagine what happens, for example, if sodium channels in the plasma membrane open. ions diffuse into the neuron because of their higher concentration on the outside, plus they are attracted to the inside of the cell by its negative charge. As a result of the entry of ions, the inside of the cell becomes less negative. When the inside of a neuron becomes less negative (or more positive) in comparison to its resting condition, its plasma membrane is said to be depolarized (Figure 44.8a). An opposite change in the resting potential occurs if gated Cl channels open. The concentration of Cl ions is normally greater in the extracellular fluid than inside the neuron. This difference is large enough so that the opening Membrane potential (mv) (a) channel channel open Resting potential channel voltage gate open Gated channel open channel open flowing into the cell depolarizes it. Voltage gate closed (b) Cl channel K + channel open Cl channel voltage gate open Cl Gated Cl channel open channel open Cl flowing into the cell hyperpolarizes it. Time Time 44.8 Membranes Can Be Depolarized or Hyperpolarized The resting potential is produced by open channels. (a) A shift from the resting potential to a less negative membrane potential, as occurs when enters the cell through a gated sodium channel, is called depolarization. (b) Hyperpolarization occurs when the membrane potential becomes more negative, as when Cl enters the cell through a gated chloride channel. Voltage gate closed of Cl channels causes Cl to enter the cell, even though the membrane potential is negative. The entry of negative charges causes the membrane potential to become even more negative. When the inside of a neuron becomes more negative in comparison to its resting condition, its plasma membrane is said to be hyperpolarized (Figure 44.8b). The opening and closing of ion channels, which result in changes in the polarity of the plasma membrane, are the basic mechanisms by which neurons respond to electrical, chemical, or other stimuli, such as touch, sound, and light. How does a neuron use a change in its resting membrane potential to process and transmit information? A change in resting potential may result from input at a synapse. This input, however, is a very local event that affects only a small patch of plasma membrane. How can that information be passed to other parts of the cell? A local perturbation of the resting potential causes a flow of electrically charged ions, which tends to spread the change in membrane potential to adjacent regions of the membrane. This flow of electrically charged ions is an electric current. For example, if positively charged ions enter the cell through open sodium channels at one location, that positively charged area on the inside of the membrane attracts negative charges from surrounding areas, and thus there is a rapid flow of electric current. However, this local flow of electric current does not spread very far before it diminishes and disappears. The reason why these electric currents do not travel very far is that cell membranes are not completely impermeable to ions. An electric current traveling along a membrane is like water flowing through a leaky hose. The flow of electric current along plasma membranes is useful for transmitting signals over only very short distances. Therefore, axons do not transmit information as a continuous flow of electric current (as telephone wires do). However, the local flow of electric current is an important part of the mechanism that generates the signals that axons do transmit over long distances: action potentials. Sudden changes in ion channels generate action potentials An action potential is a sudden and major change in membrane potential that lasts for only 1 or 2 milliseconds. Action potentials are conducted along the axon of a neuron at speeds of up to 100 meters

8 NEURONS AND NERVOUS SYSTEMS 851 per second, which is equivalent to running the length of a football field in a second. If we place the tips of a pair of electrodes on either side of the plasma membrane of a resting axon and measure the voltage difference, the reading is about 60 mv, as we saw in Figure If these electrodes are in place when an action potential travels down the axon, they register a rapid change in membrane potential, from 60 mv to about +50 mv. The membrane potential then rapidly returns to its resting level of 60 mv as the action potential passes (Figure 44.9). Neuron Voltage-gated sodium channels in the plasma membrane of the axon are responsible for action potentials. At the resting potential, most of these channels are closed. They are called voltage-gated channels because depolarization of the membrane causes them to open. For example, if synaptic input to some part of a neuron is sufficiently strong to cause the plasma membrane of its cell body to depolarize, that depolarization can spread by local current flow to the base of the axon (see Figure 44.2), where there are voltage-gated sodium channels. When the plasma membrane in this area is depolarized, the channels open briefly for less than a millisecond. The concentration is much higher outside the Amplifier Oscilloscope screen 44.9 The Course of an Action Potential Action potentials result from rapid changes in voltage-gated sodium and potassium channels. Outside axon Inside axon Outside axon The action potential is a sudden, brief reversal of charge in the membrane potential. Membrane potential (mv) Threshold Resting potential The membrane potential at any given time depends on how many and which channels are open channel Gated channel Voltage-gated channel Time Inactivated channels 1 Open channels create the resting potential. 2 Activation gates of some channels open, depolarizing the cell to threshold. 3 Additional voltage-gated channel activation gates open, causing a rapid spike of depolarization an action potential. 4 channel inactivation gates close; gated channels open, repolarizing and even hyperpolarizing the cell. 5 All gated channels close. The cell returns to its resting potential. inactivation gates open

9 852 CHAPTER FORTY-FOUR axon than inside, so when the channels open, ions rush into the axon. The entering makes the inside of the plasma membrane electrically positive. When the membrane is depolarized about 5 to 10 mv from the resting potential, a threshold is reached, and a large number of sodium channels open, causing a large, sudden depolarization: an action potential (see Figure 44.9). What causes the depolarized axon to return to resting potential? There are two contributing factors: The voltage-gated sodium channels close, and voltage-gated potassium channels open. The voltage-gated potassium channels open more slowly than the sodium channels and stay open longer, allowing to carry excess positive charges out of the axon. As a result, the voltage across the membrane returns to its resting level. Another feature of the voltage-gated sodium channels is that once they open and close, they cannot respond again until after a short delay of 1 to 2 milliseconds. This property can be explained by the assumption that they have two voltage-sensitive gates, an activation gate and an inactivation gate (see Figure 44.9). Under resting conditions, the activation gate is closed and the inactivation gate is open. Depolarization of the membrane to the threshold level causes both gates to change state, but the activation gate responds faster. As a result, the channel is open for a brief time between the opening of the activation gate and the closing of the inactivation gate. The inactivation gate remains closed for 1 2 milliseconds before it spontaneously opens again, thus explaining why the membrane has a refractory period before it can fire another action potential. When the inactivation gate finally opens, the activation gate is closed, and the membrane is poised to respond once again to a depolarizing stimulus by firing another action potential. Another contribution to the refractory period is the duration of the opening of the voltage-gated potassium channels. Because the potassium channels are open and the sodium channels are closed immediately following an action potential, the membrane potential briefly falls below the normal resting potential. This dip in the membrane potential is called the afterhyperpolarization. The difference in the concentration of across the plasma membrane and the negative resting potential constitute the battery that drives action potentials. How rapidly does the battery run down? It might seem that a substantial number of and ions would have to cross the membrane for the membrane potential to change from 60 mv to +50 mv and back to 60 mv again. In fact, only a vanishingly small percentage of the ions concentrated outside the plasma membrane move through the channels during the passage of an action potential. Thus the effect of a single action potential on the concentration gradients of and is very small, and it is possible in most cases for the sodium potassium pump to keep the battery charged, even when the neuron is generating many action potentials every second. Action potentials are conducted down axons without loss of signal Action potentials can travel over long distances with no loss of signal. If we place two pairs of electrodes at two different locations along an axon, we can record an action potential at those two locations as it travels down the axon (Figure 44.10a). The magnitude of the action potential does not change between the two recording sites. This constancy is possible because an action potential is an all-or-nothing, selfregenerating event. An action potential is all-or-nothing because of the interaction between the voltage-gated sodium channels and the membrane potential. If the membrane is depolarized slightly, some voltage-gated sodium channels open. Some ions cross the plasma membrane and depolarize it even more, opening more voltage-gated sodium channels, and so on, until the membrane reaches threshold and generates an action potential. This positive feedback mechanism ensures that action potentials always rise to their maximum value. An action potential is self-regenerating because it spreads by local current flow to adjacent regions of the plasma membrane. The resulting depolarization brings those neighboring areas of membrane to threshold. So when an action potential occurs at one location on an axon, it stimulates the adjacent region of axon to generate an action potential, and so on down the length of the axon. We can initiate an action potential by using a stimulating electrode to deliver an electric current that depolarizes the membrane enough to reach threshold. Now we can observe the changes in membrane potential associated with the passage of that action potential past the recording electrodes (Figure 44.10b). At the site of the action potential, positive ions flood into the neuron. Once inside, those positive ions spread by current flow to adjacent regions of the axon plasma membrane, making those regions less negative. As this depolarization of the adjacent membrane brings it to threshold, an action potential is generated. Because an action potential always brings the adjacent area of membrane to threshold, the action potential propagates itself along the axon. The action potential normally propagates itself in only one direction, away from the cell body. It cannot reverse itself because the region of membrane it came from is in its refractory period. Action potentials do not travel along all axons at the same speed. They travel faster in large-diameter axons than in

10 (a) Electric stimulus NEURONS AND NERVOUS SYSTEMS 853 Oscilloscope screen Point A Point B Amplifier Electrode 1 Outside axon Inside axon Outside axon Inside axon Amplifier Electrode Outside axon + Electrode pair 1 (point A) Outside axon + Electrode pair 2 (point B) Time (b) Electric stimulus 1 Voltage-gated channels open in response to the electric stimulus, generating an action potential. 2 A depolarizing current spreads down the axon, opening neighboring voltage-gated channels. channel channel Time = 0 Point A Point B Point C 3 Upstream Na+ channels inactivate, making the membrane 4 refractory. Voltage-gated channels open, repolarizing the axon. Spreading depolarization causes neighboring channels to open, renewing the action potential. Time = 1 5 The process is repeated, propagating the action potential along the axon. Time = Action Potentials Travel along s (a) There is no loss of signal as an action potential travels along an axon. (b) When an action potential occurs in one region of membrane, electric current flows to adjacent areas of membrane and depolarizes them. As voltage-gated channels in those areas reach threshold, they generate an action potential. In this way, an action potential continuously regenerates itself along the axon.

11 854 CHAPTER FORTY-FOUR RESEARCH METHOD small-diameter axons. In invertebrates, the axon diameter determines the rate of conduction, and axons that transmit messages involved in escape behavior are very large. The giant axons that enable squids to escape predators are almost 1 mm in diameter. Recording pipette A recording pipette filled with a conducting solution is placed in contact with a neuron s membrane. Ion channels and their properties can be studied directly The size of the squid giant axon made it possible for the British neurophysiologists A. L. Hodgkin and A. F. Huxley to study the electrical properties of axonal membranes almost 70 years ago. They used electrodes to measure voltage differences across the plasma membrane of the squid giant axon and to pass electric current into the axon to change its resting potential. They also changed the concentrations of and ions both inside and outside the axon and measured the resulting changes in membrane potential. On the basis of their many careful experiments, Hodgkin and Huxley developed the story we have discussed so far. However, they could only hypothesize the existence of ion channels and their properties, since they were working long before technology enabled the actual demonstration of their existence. Hodgkin and Huxley received the Nobel prize in With a technique called patch clamping, developed in the 1980s by Bert Sakmann and Erwin Neher, neurobiologists can record currents caused by the openings and closings of single ion channels. Using a fine pipette and slight suction, patch clamping isolates a small patch of plasma membrane. Using the pipette as an electrode, voltage differences due to movements of ions through channels in the isolated patch can be recorded (Figure 44.11). Frequently, a patch will contain only one or a few ion channels; thus the electrical recording from that patch can show individual channels opening and closing. Sakmann and Neher received the Nobel prize in Action potentials can jump down axons In vertebrate nervous systems, increasing the speed of action potentials by increasing the diameter of axons is not feasible because of the huge number of axons in these organisms. Each of our eyes, for example, has about a million axons extending from it. Evolution has increased action potential velocity in vertebrate axons in a way that does not require large size. When we described glial cells earlier in the chapter, we saw that certain glial cells wrap themselves around axons, covering them with concentric layers of myelin (see Figure 44.3). These myelin wrappings are not continuous along the length of the axon, but have regularly spaced gaps, called nodes of Ranvier, where the axon is not covered (Figure 44.12). Myelin electrically insulates the axon; that is, charged ions cannot cross the regions of the plasma membrane that are Mild suction Retract pipette Closed Open Slight suction clamps a patch of the membrane to the pipette tip. Retracting the pipette removes the membrane patch, often with one or more ion channels in it. The opening and closing of ion channels can be recorded through the pipette. Oscilloscope tracing of ionic current Patch Clamping The patch clamping technique can record the opening and closing of a single ion channel. wrapped in myelin. Additionally, ion channels are clustered at the nodes of Ranvier. Thus an axon can fire an action potential only at a node, and that action potential cannot be propagated through the adjacent patch of membrane covered with myelin. The positive charges that flow into the axon at the node, however, spread down the inside of the axon. When the spread of current causes the plasma membrane at the next node to depolarize to threshold, an action potential is fired at that node. Action potentials therefore appear to jump from node to node down the axon. The speed of conduction is increased in these myelinwrapped axons because electric current flows very fast through the cytoplasm in comparison to the time required for channels to open and close. This form of impulse propagation is called saltatory ( jumping) conduction and is much quicker than continuous propagation of action potentials down an unmyelinated axon.

12 NEURONS AND NERVOUS SYSTEMS 855 Neuron Nodes of Ranvier 1 channels open, generating 2 Spreading current from the upstream node brings an action potential. the membrane at the next node to threshold. Myelin sheath Time = 0 Point A 3 Upstream channels inactivate, making the membrane refractory. channels open, repolarizing the axon. Point B 4 The action potential jumps quickly to the new node and Point C Time = 1 5 continues from node to node. Time = Saltatory Action Potentials Action potentials appear to jump from node to node in myelinated axons. Neurons, Synapses, and Communication The most remarkable abilities of nervous systems stem from interactions among neurons. It is these interactions that process and integrate information. Our nervous systems can orchestrate complex behaviors, deal with complex concepts, and learn and remember because large numbers of neurons interact with one another. The mechanisms of these interactions depend on synapses between cells. Synapses, as we saw above, are structurally specialized junctions where one cell influences another cell directly through the transfer of an electrical or chemical message. The cell that sends the message is the presynaptic cell, and the cell that receives it is the postsynaptic cell. The most common type of synapse in the nervous system is the chemical synapse one in which chemical messages released by a presynaptic cell induce changes in a postsynaptic cell.

13 856 CHAPTER FORTY-FOUR The neuromuscular junction is a classic chemical synapse Neuromuscular junctions are synapses between muscle cells and the neurons that innervate them. They are excellent models for how chemical synaptic transmission works. The neurons that innervate muscles cells are called motor neurons. Like most other neurons, a motor neuron has only one axon, but that axon can have many branches, each with an axon terminal that forms a neuromuscular junction with a muscle cell. At each axon terminal is an enlarged knob or buttonlike structure that contains many vesicles filled with neurotransmitters. The neurotransmitter used by all vertebrate motor neurons is acetylcholine. The portion of the axon terminal plasma membrane that forms a synapse with a muscle cell is called the presynaptic membrane. Acetylcholine is released by exocytosis when the membrane of a vesicle fuses with the presynaptic membrane. Where does the neurotransmitter come from? Some neurotransmitters, like acetylcholine, are synthesized in the axon terminal and packaged in vesicles. The enzymes required for acetylcholine biosynthesis, however, are produced in the cell body of the motor neuron and are transported down the axon to the terminals along microtubules. Other kinds of neurotransmitters, such as peptide neurotransmitters, are produced in the cell body and transported down the axon to the terminals. Motor neuron Muscle fiber Synaptic Transmission Begins with the Arrival of a Nerve Impulse This diagram shows the sequence of events involved in synaptic transmission at the neuromuscular junction, a typical chemical synapse.the events shown here for acetylcholine are similar for other neurotransmitters. Presynaptic cell (motor neuron) Nerve impulse Myelin 1 An action potential arrives and initiates synaptic transmission. 8 After synaptic transmission, acetylcholine and vesicles are recycled. 2 channels open, depolarizing the axon terminal membrane. Plasma membranes 3 Depolarization of the terminal membrane causes voltagegated Ca 2+ channels to open. Action potential 4 Ca 2+ enters the cell and triggers fusion of acetylcholine vesicles with the presynaptic membrane. Ca 2+ terminal Acetyl CoA + choline Action potential 5 Acetylcholine molecules diffuse across the synaptic cleft and bind to receptors on the postsynaptic membrane. Acetylcholinesterase 6 Activated receptors open chemically gated channels and depolarize the postsynaptic membrane. The spreading depolarization fires an action potential in the postsynaptic membrane. Acetylcholine receptors Synaptic cleft Postsynaptic cell (muscle cell) 7 Acetylcholine in the synaptic cleft is broken down by the enzyme acetylcholinesterase and the components are taken back up by the presynaptic cell for resynthesis.

14 NEURONS AND NERVOUS SYSTEMS 857 The postsynaptic membrane of the neuromuscular junction is a modified part of the muscle cell plasma membrane called a motor end plate. The space between the presynaptic membrane and the postsynaptic membrane is called the synaptic cleft. In chemical synapses, the synaptic cleft is, on average, about nm wide. Neurotransmitter released into the cleft by the presynaptic cell diffuses across to the postsynaptic membrane (Figure 44.13). The motor end plate contains acetylcholine receptor proteins. These receptors are chemically gated channels that allow both and to pass through. Since the resting membrane of the postsynaptic cell is already permeable to, the major change that occurs when these channels open is the movement of into the cell. When a receptor binds acetylcholine, the pore of its channel opens, and moves across the membrane, depolarizing the motor end plate (Figure 44.14). The arrival of a nerve impulse causes the release of neurotransmitter The acetylcholine receptor-mediated channel is normally closed. Outside of cell Inside of cell ACh receptor ACh When ACh binds at specific sites on the receptor, the channel opens, allowing to enter the postsynaptic cell. ACh Postsynaptic cell depolarizes Acetylcholinesterase breaks down ACh, causing the receptor-mediated channel to close. Acetylcholinesterase The Acetylcholine Receptor Is a Chemically Gated Channel The motor end plate contains acetylcholine (ACh) receptors, which are chemically gated ion channels. When one of these receptors binds ACh, its channel pore opens, and ions move into the postsynaptic cell, depolarizing its plasma membrane. An enzyme called acetylcholinesterase breaks down ACh in the synapse, closing the channel; the breakdown products are then resynthesized into more ACh. What causes the presynaptic membrane to release neurotransmitter? Neurotransmitter is released when a nerve impulse arrives at the axon terminal. The presynaptic membrane contains voltage-gated calcium channels. When a nerve impulse depolarizes the axon terminal, it causes these channels to open (see Figure 44.13). Because Ca 2+ concentration is greater outside the cell than inside the cell, Ca 2+ enters the axon terminal near the synaptic vesicles. The increase in Ca 2+ inside the axon terminal causes the vesicles containing acetylcholine to fuse with the presynaptic membrane and empty their contents into the synaptic cleft. The acetylcholine molecules diffuse within the cleft, and some bind to acetylcholine receptors on the motor end plate. The postsynaptic membrane integrates synaptic input The postsynaptic membrane of the neuromuscular junction differs from the presynaptic membrane in an important way. Motor end plates have very few voltage-gated sodium channels; therefore, they do not fire action potentials. This is true not only of motor end plates on muscle cells, but also of most dendrites and most regions of neuronal cell bodies. The binding of acetylcholine to receptors at the motor end plate and the opening of chemically gated ion channels produce a change in the membrane potential of the postsynaptic membrane. This local change in membrane potential spreads to neighboring regions of the plasma membrane of the postsynaptic cell. The entire plasma membrane of a muscle cell, except for the motor end plates, contains voltage-gated sodium channels. If the axon terminal of a motor neuron releases sufficient amounts of acetylcholine to depolarize a motor end plate enough, that spreading depolarization will reach an area of plasma membrane that contains voltagegated sodium channels. When that area of membrane is depolarized to threshold, an action potential is fired. This action potential is then conducted throughout the muscle cell s system of membranes, causing the cell to contract. (We ll learn more about muscle membrane action potentials and the contraction of muscle cells in Chapter 47.) How much neurotransmitter is enough? Neither a single acetylcholine molecule nor the contents of an entire vesicle (about 10,000 acetylcholine molecules) are enough to bring the plasma membrane of a muscle cell to threshold. However, a single action potential in an axon terminal releases the contents of about 100 vesicles, which is enough to fire an action potential in the muscle cell and cause it to contract. Synapses between neurons can be excitatory or inhibitory In vertebrates, the synapses between motor neurons and muscle cells are always excitatory; that is, motor end plates always re-

15 858 CHAPTER FORTY-FOUR spond to acetylcholine by depolarizing the postsynaptic membrane. Synapses between neurons, however, are not always excitatory. Recall that a neuron may have many dendrites. terminals from many other neurons may form synapses with those dendrites and with the cell body. The axon terminals of different presynaptic neurons may store and release different neurotransmitters, and the plasma membrane of the dendrites and cell body of a postsynaptic neuron may have receptors for a variety of neurotransmitters. Thus, at any one time, a postsynaptic neuron may receive a variety of different chemical messages. If the postsynaptic neuron s response to a neurotransmitter is depolarization, as at the neuromuscular junction, the synapse is excitatory; if its response is hyperpolarization, the synapse is inhibitory. How do inhibitory synapses work? In vertebrates, the two most common inhibitory neurotransmitters are gammaaminobutyric acid (GABA) and glycine. The postsynaptic membranes at inhibitory synapses that bind these neurotransmitters have receptors that are chemically gated chloride channels. When these channels bind their neurotransmitter and open, they hyperpolarize the postsynaptic membrane. Thus the release of neurotransmitter at an inhibitory synapse makes the postsynaptic cell less likely to fire an action potential. Neurotransmitters that depolarize the postsynaptic membrane are excitatory; they Dendrites bring about an excitatory postsynaptic potential (EPSP). Neurotransmitters that hyperpolarize the postsynaptic membrane are inhibitory; they bring about an inhibitory postsynaptic potential (IPSP). axon hillock is not insulated by glial cells and has many voltage-gated channels. Excitatory and inhibitory postsynaptic potentials from synapses anywhere on the dendrites or the cell body spread to the axon hillock by local current flow. If the resulting combined potential depolarizes the axon hillock to threshold, the axon fires an action potential. Because postsynaptic potentials decrease in strength as they spread from the site of the synapse, all postsynaptic potentials do not have equal influences on the axon hillock. A synapse at the tip of a dendrite has less influence than a synapse on the cell body near the axon hillock. Excitatory and inhibitory postsynaptic potentials can be summed over space or over time. Spatial summation adds up the simultaneous influences of synapses at different sites on the postsynaptic cell (Figure 44.15a). Temporal summation adds up postsynaptic potentials generated at the same site in a rapid sequence (Figure 44.15b). All the neuron-to-neuron synapses that we have discussed up to this point are between the axon terminals of a presynaptic cell and the cell body or dendrites of a postsynaptic cell. Synapses can also form between the axon terminals of one neuron and the axon terminals of another neuron. Such a synapse can modulate how much neurotransmitter the second neuron releases in response to action potentials traveling down Excitatory synapses hillock The postsynaptic cell sums excitatory and inhibitory input Individual neurons can decide whether or not to fire an action potential by summing excitatory and inhibitory postsynaptic potentials. This summation ability is the major mechanism by which the nervous system integrates information. Each neuron may receive a thousand or more synaptic inputs, but it has only one output: an action potential in a single axon. All the information contained in all the inputs a neuron receives is reduced to the rate at which that neuron generates nerve impulses in its axon. For most neurons, the critical area for decision making is the axon hillock, the region of the cell body at the base of the axon (see Figure 44.2). The plasma membrane of the (a) Membrane potential (mv) Neuron Resting potential Spatial summation occurs when several excitatory postsynaptic potentials (EPSPs) arrive at the axon hillock simultaneously. EPSPs Threshold Synapse number Action potential (b) Temporal summation means that postsynaptic potentials created at the same synapse in rapid succession can be summed Milliseconds The Postsynaptic Neuron Sums Information Individual neurons sum excitatory and inhibitory postsynaptic potentials over space (a) and time (b). When the sum of the potentials depolarizes the axon hillock to threshold, the neuron generates an action potential.