To produce a behavior, a stretch reflex for example, each participating sensory and motor nerve cell must generate four different signals in sequence, each at different site within the cell: an input signal, a trigger signal, a conducting signal, and an output signal. Regardless of cell size and shape, transmitter biochemistry, or behavioral function, almost all neurons can be described by a model neuron that has four functional components that generate the four types of signals: a receptive component, a summing or integrative component, a long-range signaling component, and a secretory component (Figure 2–9). This model neuron is the physiological expression of Ramón y Cajal's principle of dynamic polarization.
Most neurons, regardless of type, have four functional regions in which different types of signals are generated.
Thus the functional organization of most neurons can be represented schematically by a model neuron. The input, integrative, and conductive signals are all electrical and integral to the cell, whereas the output signal is a chemical substance ejected by the cell into the synaptic cleft. Not all neurons share all these features; for example, local interneurons often lack a conductive component.
The different types of signals generated in a neuron are determined in part by the electrical properties of the cell membrane. Every cell, including a neuron, maintains a certain difference in the electrical potential on either side of the plasma membrane when the cell is at rest. This is called the resting membrane potential. In a typical resting neuron the voltage of the inside of the cell is about 65 mV more negative than the voltage outside the cell. Because the voltage outside the membrane is defined as zero, we say the resting membrane potential is–65 mV. The resting potential in different nerve cells ranges from–40 to–80 mV; in muscle cells it is greater still, about–90 mV. As we shall see in Chapter 6, the resting membrane potential results from two factors: the unequal distribution of electrically charged ions, in particular the positively charged Na+ and K+ ions, and the selective permeability of the membrane.
The unequal distribution of positively charged ions on either side of the cell membrane is maintained by two main mechanisms. Intracellular Na+ and K+ concentrations are largely controlled by a membrane protein that actively pumps Na+ out of the cell and K+ back into it. This Na + -K + pump, about which we shall learn more in Chapter 6, keeps the Na+ concentration in the cell low (about one-tenth the concentration outside the cell) and the K+ concentration high (about 20 times the concentration outside). The extracellular concentrations of Na+ and K+ are maintained by the kidneys.
The cell membrane is selectively permeable to K+ because the otherwise impermeable membrane contains proteins that form pores called ion channels. The channels that are active when the cell is at rest are highly permeable to K+ but considerably less permeable to Na+. The K+ ions tend to leak out of these open channels, down the ion's concentration gradient. As K+ ions exit the cell, they leave behind a cloud of unneutralized negative charge on the inner surface of the membrane, so that the net charge inside the membrane is more negative than that outside.
A cell, such as nerve and muscle, is said to be excitable when its membrane potential can be quickly and significantly altered. This change serves as a signaling mechanism. In some neurons reducing the membrane potential by 10 mV (from–65 to–55 mV) makes the membrane much more permeable to Na+ than to K+. The resultant influx of positively charged Na+ neutralizes the negative charge inside the cell and causes a brief and explosive change in membrane potential to +40 mV. This action potential is conducted down the cell's axon to the axon's terminal, where it initiates an elaborate chemical communication with other neurons or muscle cells. The action potential is actively propagated along the axon so that its amplitude does not diminish by the time it reaches the axon terminal. An action potential typically lasts approximately 1 ms, after which the membrane returns to its resting state, with its normal separation of charges and higher permeability to K+ than to Na+.
We shall learn more about the mechanisms underlying the resting potential and action potential in Chapters 6 to 7. In addition to the long distance signals represented by the action potential, nerve cells also produce local signals—receptor potentials and synaptic potentials—that are not actively propagated and that typically decay within just a few millimeters.
The change in membrane potential that generates long-range and local signals can be either a decrease or an increase from the resting potential. The resting membrane potential therefore provides the baseline on which all signaling occurs. A reduction in membrane potential is called depolarization. Because depolarization enhances a cell's ability to generate an action potential, it is excitatory. In contrast, an increase in membrane potential is called hyperpolarization. Hyperpolarization makes a cell less likely to generate an action potential and is therefore inhibitory.
The Input Component Produces Graded Local Signals
In most neurons at rest no current flows from one part of the cell to another, so the resting potential is the same throughout. In sensory neurons current flow is typically initiated by a physical stimulus, which activates specialized receptor proteins at the neuron's receptive surface. In our example of the knee-jerk reflex, stretching of the muscle activates specific ion channels that open in response to stretch of the sensory neuron membrane, as we shall learn in Chapter 5. The opening of these channels when the cell is stretched permits the rapid influx of Na+ ions into the sensory cell. This ionic current changes the membrane potential, producing a local signal called the receptor potential.
The amplitude and duration of a receptor potential depend on the intensity of the muscle stretch: The larger or longer-lasting the stretch, the larger or longer-lasting the resulting receptor potential (Figure 2–10A). Thus, unlike the action potential, which is all or none, receptor potentials are graded. Most receptor potentials are depolarizing (excitatory). However, hyperpolarizing (inhibitory) receptor potentials are found in the retina.
Each of the neuron's four signaling components produces a characteristic signal.
The figure shows a sensory neuron activated by stretching of a muscle, which the neuron senses through a specialized receptor, the muscle spindle.
A. The input signal, called a receptor potential, is graded in amplitude and duration, proportional to the amplitude and duration of the stimulus.
B. The trigger zone sums the depolarization generated by the receptor potential. An action potential is generated only if the receptor potential exceeds a certain voltage threshold. Once this threshold is surpassed, any further increase in amplitude of the receptor potential can only increase the frequency with which the action potentials are generated, because action potentials have a constant amplitude. The duration of the receptor potential determines the duration of the train of action potentials. Thus the graded amplitude and duration of the receptor potential is translated into a frequency code in the action potentials generated at the trigger zone. All action potentials produced are propagated faithfully along the axon.
C. Action potentials are all-or-none. Because all action potentials have a similar amplitude and duration, the frequency and duration of firing represents the information carried by the signal.
D. When the action potential reaches the synaptic terminal, it initiates the release of a neurotransmitter, the chemical substance that serves as the output signal. The frequency of action potentials determines exactly how much neurotransmitter is released by the cell.
The receptor potential is the first representation of stretch to be coded in the nervous system. This signal spreads passively, however, and therefore does not travel much farther than 1 to 2 mm. In fact, 1 mm down the axon the amplitude of the signal is only about one-third what it was at the site of generation. To be carried successfully to the central nervous system, the local signal must be amplified —it must generate an action potential. In the knee-jerk reflex the receptor potential in the sensory neuron must reach the first node of Ranvier in the axon. If it is large enough, the signal triggers an action potential that then propagates without failure to the axon terminals in the spinal cord (Figure 2–10C). At the synapse between the sensory neuron and a motor neuron, the action potential produces a chain of events that results in an input signal to the motor neuron.
In the knee-jerk reflex the action potential in the presynaptic terminal of the sensory neuron initiates the release of a chemical substance, or neurotransmitter, into the synaptic cleft (Figure 2–10D). After diffusing across the cleft, the transmitter binds to receptor proteins in the postsynaptic membrane of the motor neuron, thereby directly or indirectly opening ion channels. The ensuing flow of current alters the membrane potential of the motor cell, a change called the synaptic potential.
Like the receptor potential, the synaptic potential is graded; its amplitude depends on how much transmitter is released. In the same cell the synaptic potential can be either depolarizing or hyperpolarizing depending on the type of receptor molecule that is activated. Synaptic potentials, like receptor potentials, spread passively and thus are local changes in potential unless the signal reaches beyond the axon's initial segment and thus can give rise to an action potential. The features of receptor and synaptic potentials are summarized in Table 2–1.
Table 2–1Comparison of Local (Passive) and Propagated Signals ||Download (.pdf) Table 2–1 Comparison of Local (Passive) and Propagated Signals
|Signal type ||Amplitude (mV) ||Duration ||Summation ||Effect of signal ||Type of propagation |
|Local (passive) signals |
|Receptor potentials || |
|Graded ||Hyperpolarizing or depolarizing ||Passive |
|Synaptic potentials || |
Brief to long
(5 ms–20 min)
|Graded ||Hyperpolarizing or depolarizing ||Passive |
|Propagated (active) signals |
|Action potentials || |
|All-or-none ||Depolarizing ||Active |
The Trigger Zone Makes the Decision to Generate an Action Potential
Sherrington first pointed out that the function of the nervous system is to weigh the consequences of different types of information and then decide on appropriate responses. This integrative function of the nervous system is clearly seen in the actions of the trigger zone of the neuron, the initial segment of the axon.
Action potentials are generated by a sudden influx of Na+ through channels in the cell membrane that open and close in response to changes in membrane potential. When an input signal (a receptor potential or synaptic potential) depolarizes an area of membrane, the local change in membrane potential opens local Na+ channels that allow Na+ to flow down its concentration gradient, from outside the cell where the Na+ concentration is high to inside where it is low.
Because the initial segment of the axon has the highest density of voltage-sensitive Na+ channels and therefore the lowest threshold for generating an action potential, an input signal spreading passively along the cell membrane is more likely to give rise to an action potential at the initial segment than at other sites in the cell. This part of the axon is therefore known as the trigger zone. It is here that the activity of all receptor (or synaptic) potentials is summed and where, if the sum of the input signals reaches threshold, the neuron generates an action potential.
The Conductive Component Propagates an All-or-None Action Potential
The action potential is all-or-none: Stimuli below the threshold do not produce a signal, but stimuli above the threshold all produce the signals of the same amplitude. However much the stimuli vary in intensity or duration, the amplitude and duration of each action potential are pretty much the same. In addition, unlike receptor and synaptic potentials, which spread passively and decrease in amplitude, the action potential does not decay as it travels along the axon to its target —a distance that can be as great as 2 m —because it is periodically regenerated. This conducting signal can travel at rates as fast as 100 m/s.
The remarkable feature of action potentials is that they are highly stereotyped, varying only subtly (but in some cases importantly) from one nerve cell to another. This feature was demonstrated in the 1920s by Edgar Adrian, one of the first to study the nervous system at the cellular level. Adrian found that all action potentials have a similar shape or wave-form (see Figure 2–2). Indeed, the action potentials carried into the nervous system by a sensory axon often are indistinguishable from those carried out of the nervous system to the muscles by a motor axon.
Only two features of the conducting signal convey information: the number of action potentials and the time intervals between them (Figure 2–10C). As Adrian put it in 1928, summarizing his work on sensory fibers: "all impulses are very much alike, whether the message is destined to arouse the sensation of light, of touch, or of pain; if they are crowded together the sensation is intense, if they are separated by long intervals the sensation is correspondingly feeble." Thus, what determines the intensity of sensation or speed of movement is the frequency of the action potentials. Likewise, the duration of a sensation or movement is determined by the period over which action potentials are generated.
In addition to the frequency of the action potentials, the pattern of action potentials also conveys important information. For example, some neurons are not silent in the absence of stimulation but are spontaneously active. Some spontaneously active nerve cells (beating neurons) fire action potentials regularly; other neurons (bursting neurons) fire in brief bursts of action potentials. These diverse cells respond differently to the same excitatory synaptic input. An excitatory synaptic potential may initiate one or more action potentials in a cell that does not have a spontaneous activity, but in spontaneously active cells that same input will modulate the rhythm by increasing the rate of firing of action potentials.
An even more dramatic difference is seen when the input signal is inhibitory. Inhibitory inputs have little information value in a silent cell. By contrast, in spontaneously active cells inhibition can have a powerful sculpting role. By establishing periods of silence in otherwise ongoing activity, inhibition can produce a complex pattern of alternating firing and silence where none existed. These subtle differences in firing patterns may have important functional consequences for the information transfer between neurons. This has led mathematical modelers of neuronal networks to attempt to delineate neural codes in which information is also carried by the fine-grained pattern of firing —the exact timing of action potentials (Figure 2–11).
Neurons in the mammalian brain exhibit widely varying electrophysiological properties.
(Reproduced, with permission, from McCormick, 2004.)
A. Intracellular injection of a depolarizing current pulse in a cortical pyramidal cell results in a train of action potentials that decline in frequency. This pattern of activity is known as regular firing. Some cortical cells generated bursts of three or more action potentials, even when depolarized only for a short period.
B. Cerebellar Purkinje cells generate high-frequency trains of action potentials in their cell bodies that are disrupted by the generation of Ca2+ action potentials in their dendrites. These cells can also generate plateau potentials from the persistent activation of Na+ conductances.
C. Thalamic relay cells may generate action potentials either as bursts or tonic trains of action potentials owing to the presence of a large low-threshold Ca2+ current.
D. Medial habenular cells generate action potentials at a steady and slow rate, in a pacemaker fashion.
If signals are stereotyped and reflect only the most elementary properties of the stimulus, how can they carry the rich variety of information needed for complex behavior? How is a message that carries visual information about a bee distinguished from one that carries pain information about the bee's sting, and how are these sensory signals distinguished from motor signals for voluntary movement? The answer is simple and yet is one of the most important organizational principles of the nervous system: Pathways of connected neurons, not individual neurons, convey information. Interconnected neurons form anatomically and functionally distinct pathways. The neural pathways activated by receptor cells in the retina that respond to light are completely distinct from the pathways activated by sensory cells in the skin that respond to touch.
The Output Component Releases Neurotransmitter
When an action potential reaches a neuron's terminal it stimulates the release of chemical substances from the cell. These substances, called neurotransmitters, can be small organic molecules, such as l-glutamate and acetylcholine, or peptides like substance P or LHRH (luteinizing hormone releasing hormone).
Neurotransmitter molecules are held in subcellular organelles called synaptic vesicles, which accumulate at specialized release sites in the terminals of the axon called active zones. To eject their transmitter substance into the synaptic cleft, the vesicles move up to and fuse with the neuron's plasma membrane, then burst open, a process known as exocytosis. The molecular machinery of neurotransmitter release is described in Chapters 11 and 12.
Once released, the neurotransmitter is the neuron's output signal. Like the input signal, it is graded. The amount of transmitter released is determined by the number and frequency of the action potentials that reach the presynaptic terminals (Figure 2–10C,D). After release the transmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic neuron. This binding causes the postsynaptic cell to generate a synaptic potential. Whether the synaptic potential has an excitatory or inhibitory effect depends on the type of receptor in the postsynaptic cell, not on the particular chemical neurotransmitter. The same transmitter substance can have different effects at different receptors.
The Transformation of the Neural Signal from Sensory to Motor Is Illustrated by the Stretch-Reflex Pathway
We have seen that the properties of a signal are transformed as the signal moves from one component of a neuron to another or between neurons. This transformative chain of events can be seen in the relay of signals for the stretch reflex.
When a muscle is stretched, the amplitude and duration of the stimulus are reflected in the amplitude and duration of the receptor potential generated in the sensory neuron (Figure 2–12A). If the receptor potential exceeds the threshold for an action potential in that cell, the graded signal is transformed at the trigger zone into an action potential, an all-or-none signal. The more the receptor potential exceeds threshold, the greater the depolarization and consequently the greater the frequency of action potentials in the axon. The duration of the input signal also determines the duration of the train of action potentials.
The sequence of signals that produces a reflex action.
A. The stretching of a muscle produces a receptor potential in the specialized receptor (the muscle spindle). The amplitude of the receptor potential is proportional to the intensity of the stretch. This potential spreads passively to the integrative or trigger zone at the first node of Ranvier. If the receptor potential is sufficiently large, it triggers an action potential that then propagates actively and without change along the axon to the axon terminal. At specialized sites in the terminal the action potential leads to an output signal, the release of a chemical neurotransmitter. The transmitter diffuses across the synaptic cleft between the axon terminal and a target motor neuron that innervates the stretched muscle; it then binds to receptor molecules on the external membrane of the motor neuron.
B. This interaction initiates a synaptic potential that spreads passively to the trigger zone of the motor neuron's axon, where it initiates an action potential that propagates actively to the terminal of the motor neuron's axon. The action potential releases a neuro transmitter where the axon terminal meets a muscle fiber.
C. The neurotransmitter binds receptors on the muscle fiber, triggering a synaptic potential in the muscle. If sufficiently large, or if combined with signals from other motor neurons, the synaptic potential will generate an action potential in the muscle, causing contraction of the muscle fiber.
The information encoded by the frequency and duration of firing is faithfully conveyed along the axon to its terminals, where the firing of action potentials determines the amount of transmitter released. These stages of signaling have their counterparts in the motor neuron (Figure 2–12B) and in the muscle (Figure 2–12C).