Neurophysiology

Cell body

The cell body, or soma, surrounds the nucleus of the neuron and contains the endoplasmic reticulum and Golgi apparatus. It is responsible for the neuron’s synthesis and processing of proteins.

Dendrites

Dendrites are tapering processes that arise from the cell body. They receive information and thus contain receptors for neurotransmitters that are released from adjacent neurons.

Axon

The axon is a projection arising from a specialized region of the cell body called the axon hillock, which adjoins the spike initiation zone (or initial segment) where action potentials are generated to send information. Whereas dendrites are numerous and short, each neuron has a single axon, which can be quite long (up to 1 meter in length).

The cytoplasm of the axon contains dense, parallel arrays of microtubules and microfilament that rapidly move organelles and vesicles (containing proteins and neurotransmitters synthesized in the cell body) from the cell body to the axon terminus. This process is called fast axoplasmic transport and involves moving mitochondria and vesicles along the microtubules via an ATP-dependent motor protein called kinesin. Cytoskeletal elements and various soluble proteins also move from the cell body down the axon by slow axoplasmic transport. One direction of both fast and slow axoplasmic transport is from cell body to axon terminus, and thus both are termed anterograde. There are also transport processes in the other direction, called fast retrograde transport, which move growth factors and membrane fragments from the axon terminus to the cell body.

Axons carry action potentials between the neuron cell body and the targets of that neuron, either other neurons or muscle. Axons may be insulated with myelin (see Chapter 1 ), which increases conduction velocity; breaks in the myelin sheath occur at the nodes of Ranvier.

Multipolar neurons

The most common type of neuron in the mammalian nervous system is multipolar, having a single axon and many dendrites originating from the cell body. Multipolar neurons vary in shape, in the length of their axons, and in the complexity of their dendritic tree. The extent of dendritic branching correlates with the number of synaptic contacts from other neurons. For example, the dendritic tree of a cerebellar Purkinje cell can have up to one million contacts!

Presynaptic terminals

The axon terminates on its target cells (e.g., other neurons) in multiple endings, called presynaptic terminals. When the action potential transmitted down the axon reaches the presynaptic terminal, neurotransmitter is released into the synapse. The transmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic membrane (e.g., of dendrites of other neurons). In this way, information is transmitted rapidly from neuron to neuron (or, in the case of the neuromuscular junction, from neuron to skeletal muscle).

Types of receptors

Receptors are classified by the type of stimulus that activates them. The five types of receptors are mechanoreceptors, photoreceptors, chemoreceptors, thermoreceptors, and nociceptors. Table 3.2 summarizes the receptors and gives examples and locations of each type.

Mechanoreceptors are activated by pressure or changes in pressure. Mechanoreceptors include, but are not limited to, the pacinian corpuscles in subcutaneous tissue, Meissner corpuscles in nonhairy skin (touch), baroreceptors in the carotid sinus (blood pressure), and hair cells on the organ of Corti (audition) and in the semicircular canals (vestibular system). Photoreceptors are activated by light and are involved in vision. Chemoreceptors are activated by chemicals and are involved in olfaction, taste, and detection of oxygen and carbon dioxide in the control of breathing. Thermoreceptors are activated by temperature or changes in temperature. Nociceptors are activated by extremes of pressure, temperature, or noxious chemicals.

Sensory transduction and receptor potentials

Sensory transduction is the process by which an environmental stimulus (e.g., pressure, light, chemicals) activates a receptor and is converted into electrical energy. The conversion typically involves opening or closing of ion channels in the receptor membrane, which leads to a flow of ions (current flow) across the membrane. Current flow then leads to a change in membrane potential, called a receptor potential, which increases or decreases the likelihood that action potentials will occur. The following series of steps occurs when a stimulus activates a sensory receptor:

• 1.

  The environmental stimulus interacts with the sensory receptor and causes a change in its properties. A mechanical stimulus causes movement of the mechano receptor (e.g., sound waves move the hair cells in the organ of Corti). Photons of light are absorbed by pigments in photo receptors on the retina, causing photoisomerization of retinal (a chemical in the photoreceptor membrane). Chemical stimulants react with chemo receptors, which activate G _s proteins and adenylyl cyclase. In each case, a change occurs in the sensory receptor.

• 2.

  These changes cause ion channels in the sensory receptor membrane to open or close, which results in a change in current flow. If net ionic current flow is inward (i.e., positive charges move into the receptor cell), then depolarization occurs. If net current flow is outward (i.e., positive charges move out of the cell), then hyperpolarization occurs. The resulting change in membrane potential, either depolarization or hyperpolarization, is called the receptor potential or generator potential. The receptor potential is not an action potential. Rather, the receptor potential increases or decreases the likelihood that an action potential will occur, depending on whether it is depolarizing or hyperpolarizing (i.e., whether it brings the membrane potential toward or away from threshold). Receptor potentials are graded electronic potentials, whose amplitude correlates with the size of the stimulus.

• 3.

  If the receptor potential is depolarizing, it moves the membrane potential toward the threshold potential and increases the likelihood that an action potential will occur ( Fig. 3.5 ). Because receptor potentials are graded in amplitude, a small depolarizing receptor potential still may be subthreshold and therefore insufficient to produce an action potential. However, a larger stimulus will produce a larger depolarizing receptor potential, and if it reaches or exceeds threshold, action potentials will occur. If the receptor potential is hyperpolarizing (not illustrated), it moves the membrane potential away from the threshold potential, always decreasing the likelihood that action potentials will occur.

  

Receptive fields

A receptive field defines an area of the body that, when stimulated, results in a change in firing rate of a sensory neuron. The change in firing rate can be an increase or a decrease; therefore receptive fields are described as excitatory (producing an increase in the firing rate of a sensory neuron) or inhibitory (producing a decrease in the firing rate of a sensory neuron).

There are receptive fields for first-, second-, third-, and fourth-order sensory neurons. For example, the receptive field of a second-order neuron is the area of receptors in the periphery that causes a change in the firing rate of that second-order neuron.

Receptive fields vary in size ( Fig. 3.6 ). The smaller the receptive field, the more precisely the sensation can be localized or identified. Typically, the higher the order of the CNS neuron, the more complex the receptive field, since more neurons converge in relay nuclei at each level. Thus first-order sensory neurons have the simplest receptive fields, and fourth-order sensory neurons have the most complex receptive fields.

As noted, receptive fields can be excitatory or inhibitory, with the pattern of excitatory or inhibitory receptive fields conveying additional information to the CNS. Figure 3.7 illustrates one such pattern for a second-order neuron. The receptive field on the skin for this particular neuron has a central region of excitation, bounded on either side by regions of inhibition. All of the incoming information is processed in relay nuclei of the spinal cord or brain stem. The areas of inhibition contribute to a phenomenon called lateral inhibition and aid in the precise localization of the stimulus by defining its boundaries and providing a contrasting border.

Sensory coding

Sensory neurons are responsible for encoding stimuli in the environment. Coding begins when the stimulus is transduced by sensory receptors and continues as the information is transmitted to progressively higher levels of the CNS. One or more aspects of the stimulus are encoded and interpreted. For example, in seeing a red ball, its size, location, color, and depth all are encoded. The features that can be encoded include sensory modality, spatial location, frequency, intensity, threshold, and duration of stimulus.

• ♦

  Stimulus modality is often encoded by labeled lines, which consist of pathways of sensory neurons dedicated to that modality . Thus the pathway of neurons dedicated to vision begins with photoreceptors in the retina. This pathway is not activated by somatosensory, auditory, or olfactory stimuli. Those modalities have their own labeled lines.

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  Stimulus location is encoded by the receptive field of sensory neurons and may be enhanced by lateral inhibition as previously described.

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  Threshold is the minimum stimulus that can be detected. Threshold is best appreciated in the context of the receptor potential. If a stimulus is large enough to produce a depolarizing receptor potential that reaches threshold, it will be detected. Smaller, subthreshold stimuli will not be detected.

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  Stimulus intensity is encoded in three ways. (1) Intensity can be encoded by the number of receptors that are activated. Thus large stimuli will activate more receptors and produce larger responses than will small stimuli. (2) Intensity can be encoded by differences in firing rates of sensory neurons in the pathway. (3) Intensity even may be encoded by activating different types of receptors. Thus a light touch of the skin may activate only mechanoreceptors, whereas an intense damaging stimulus to the skin may activate mechanoreceptors and nociceptors. The intense stimulus would be detected not only as stronger but also as a different modality.

• ♦

  Stimulus information also is encoded in neural maps formed by arrays of neurons receiving information from different locations on the body (i.e., somatotopic maps), from different locations on the retina (i.e., retinotopic maps), or from different sound frequencies (i.e., tonotopic maps).

• ♦

  Other stimulus information is encoded in the pattern of nerve impulses. Some of these codes are based on mean discharge frequency, others are based on the duration of firing, while others are based on a temporal firing pattern. The frequency of the stimulus may be encoded directly in the intervals between discharges of sensory neurons (called interspike intervals).

• ♦

  Stimulus duration is encoded by the duration of firing of sensory neurons. However, during a prolonged stimulus, receptors “adapt” to the stimulus and change their firing rates. Sensory neurons may be rapidly adapting or slowly adapting.

Adaptation of sensory receptors

Sensory receptors “adapt” to stimuli. Adaptation is observed when a constant stimulus is applied for a period of time. Initially, the frequency of action potentials is high, but as time passes, this frequency declines even though the stimulus continues ( Fig. 3.8 ). The pattern of adaptation differs among different types of receptors. Some receptors are phasic, meaning they adapt rapidly to the stimulus (e.g., pacinian corpuscles), and others are tonic, meaning they adapt slowly to the stimulus (e.g., Merkel cells).

The physiologic basis for adaptation also is illustrated in Figure 3.8 . Two types of receptors are shown: a phasic receptor and a tonic receptor. A stimulus (e.g., pressure) is applied (on), and then the stimulus is removed (off). While the stimulus is on, the receptor potential and the frequency of action potentials are measured. (In the figure, action potentials appear as “spikes.”)

• ♦

  Phasic receptors are illustrated by the pacinian corpuscles, which detect rapid changes in the stimulus or vibrations. These receptors adapt rapidly to a constant stimulus and primarily detect onset and offset of a stimulus and a changing stimulus. The phasic receptor responds promptly at the onset of the stimulus with a depolarizing receptor potential that brings the membrane potential above threshold. A short burst of action potential follows. After this burst, the receptor potential decreases below the threshold level, and although the stimulus continues, there are no action potentials (i.e., there is silence). When the stimulus is turned off, the receptor is once again activated, as the receptor potential depolarizes to threshold, causing a second short burst of action potentials.

• ♦

  Tonic receptors are illustrated by mechanoreceptors (e.g., Merkel receptors) in the skin, which detect steady pressure. When compared with the pacinian corpuscles (which detect vibration with their fast on-off response), tonic mechanoreceptors are designed to encode duration and intensity of stimulus. The tonic receptor responds to the onset of the stimulus with a depolarizing receptor potential that brings the membrane to threshold, resulting in a long series of action potentials. Unlike the pacinian corpuscle, whose receptor potential returns quickly to baseline, here the receptor potential remains depolarized for a longer portion of the stimulus period, and the action potentials continue. Once the receptor potential begins to repolarize, the rate of action potentials declines and eventually there is silence. Tonic receptors encode stimulus intensity: The greater the intensity, the larger the depolarizing receptor potential, and the more likely action potentials are to occur. Thus tonic receptors also encode stimulus duration: The longer the stimulus, the longer the period in which the receptor potential exceeds threshold.

Mechanoreceptors

Mechanoreceptors are subdivided into different types of receptors, depending on which kind of pressure or proprioceptive quality they encode. Some types of mechanoreceptors are found in nonhairy skin and other types in hairy skin. Mechanoreceptors are described in Table 3.3 according to their location in the skin or muscle, the type of adaptation they exhibit, and the sensation they encode, and they are illustrated in Figure 3.9 .

An important characteristic of each receptor is the type of adaptation that it exhibits. Among the various mechanoreceptors, adaptation varies from “very rapidly adapting” (e.g., pacinian corpuscle), to “rapidly adapting” (e.g., Meissner corpuscle and hair follicles), to “slowly adapting” (e.g., Ruffini corpuscle, Merkel receptors, and tactile discs). Very rapidly and rapidly adapting receptors detect changes in the stimulus and therefore detect changes in velocity. Slowly adapting receptors respond to intensity and duration of the stimulus.

• ♦

  Pacinian corpuscle. Pacinian corpuscles are encapsulated receptors found deep in the dermis, in the subcutaneous layers of nonhairy and hairy skin, and in muscle. They are the most rapidly adapting of all mechanoreceptors. Because of their very rapid on-off response, they can detect changes in stimulus velocity and encode the sensation of vibration.

• ♦

  Meissner corpuscle. Meissner corpuscles are also encapsulated receptors found in the dermis of nonhairy skin, most prominently on the fingertips, lips, and other locations where tactile discrimination is especially good. They have small receptive fields and can be used for two-point discrimination. Meissner corpuscles are rapidly adapting receptors that encode point discrimination, precise location, tapping, and flutter.

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  Hair follicle. Hair-follicle receptors are arrays of nerve fibers surrounding hair follicles in hairy skin. When the hair is displaced, it excites the hair-follicle receptors. These receptors are also rapidly adapting and detect velocity and direction of movement across the skin.

• ♦

  Ruffini corpuscle. Ruffini corpuscles are located in the dermis of nonhairy and hairy skin and in joint capsules. These receptors have large receptive fields and are stimulated when the skin is stretched. The stimulus may be located some distance from the receptors it activates. Ruffini corpuscles are slowly adapting receptors. When the skin is stretched, the receptors fire rapidly, then slowly adapt to a new level of firing that corresponds to stimulus intensity. Ruffini corpuscles detect stretch and joint rotation.

• ♦

  Merkel receptors and tactile discs. Merkel receptors are slowly adapting receptors found in nonhairy skin and have very small receptive fields. These receptors detect vertical indentations of the skin, and their response is proportional to stimulus intensity. Tactile discs are similar to Merkel receptors but are found in hairy, rather than nonhairy, skin.

Thermoreceptors

Thermoreceptors are slowly adapting receptors that detect changes in skin temperature. The two classes of thermoreceptors are cold receptors and warm receptors ( Fig. 3.10 ). Each type of receptor functions over a broad range of temperatures, with some overlap in the moderate temperature range (e.g., at 36° C, both receptors are active). When the skin is warmed above 36° C, the cold receptors become quiescent, and when the skin is cooled below 36° C, the warm receptors become quiescent.

If skin temperature rises to damaging levels (above 45° C), warm receptors become inactive; thus warm receptors do not signal pain from extreme heat. At temperatures above 45° C, polymodal nociceptors will be activated. Likewise, extremely cold (freezing) temperatures also activate nociceptors.

Transduction of warm temperatures involves transient receptor potential (TRP) channels in the family of vanilloid receptors (i.e., TRPV). These channels are activated by compounds in the vanilloid class, which includes capsaicin, an ingredient in spicy foods. (This phenomenon explains why people describe the taste of chili peppers as “hot.”)

Transduction of cold temperatures involves a different TRP channel, TRPM8, which is also opened by compounds like menthol (which gives a cold sensation).

Nociceptors

Nociceptors respond to noxious stimuli that can produce tissue damage. There are two major classes of nociceptors: thermal or mechanical nociceptors and polymodal nociceptors. Thermal or mechanical nociceptors (TRPV or TRPM8 channels) are supplied by finely myelinated A-delta afferent nerve fibers and respond to mechanical stimuli such as sharp, pricking pain. Polymodal nociceptors are supplied by unmyelinated C fibers and respond to high-intensity mechanical or chemical stimuli and hot and cold stimuli.

Damaged skin releases a variety of chemicals including bradykinin, prostaglandins, substance P, K ⁺ , and H ⁺ , which initiate the inflammatory response. The blood vessels become permeable, and, as a result, there is local edema and redness of the skin. Mast cells near the site of injury release histamine, which directly activates nociceptors. In addition, axons of the nociceptors release substances that sensitize the nociceptors to stimuli that were not previously noxious or painful. This sensitization process, called hyperalgesia, is the basis for various phenomena including reduced threshold for pain.

Dorsal column system

The dorsal column system is used for transmitting somatosensory information about discriminative touch, pressure, vibration, two-point discrimination, and proprioception. The dorsal column system consists mainly of group I and II nerve fibers. The first-order neurons have their cell bodies in the dorsal root ganglion cells or in cranial nerve ganglion cells and ascend ipsilaterally to the nucleus gracilis (lower body) or nucleus cuneatus (upper body) in the medulla of the brain stem. In the medulla, first-order neurons synapse on second-order neurons, which cross the midline. The second-order neurons ascend to the contralateral thalamus, where they synapse on third-order neurons, which ascend to the somatosensory cortex and synapse on fourth-order neurons.

Anterolateral system

The anterolateral (spinothalamic) system transmits somatosensory information about pain, temperature, and light touch. The anterolateral system consists mainly of group III and group IV fibers. (Recall that group IV fibers have the slowest conduction velocities of all the sensory nerves.) In the anterolateral system, first-order neurons have their cell bodies in the dorsal horn and synapse on thermoreceptors and nociceptors in the skin. The first-order neurons synapse on second-order neurons in the spinal cord. In the spinal cord, the second-order neurons cross the midline and ascend to the contralateral thalamus. In the thalamus, second-order neurons synapse on third-order neurons, which ascend to the somatosensory cortex and synapse on fourth-order neurons.

Fast pain (e.g., pin prick) is carried on A-delta, group II, and group III fibers; has a rapid onset and offset; and is precisely localized. Slow pain (e.g., burn) is carried on C fibers and is characterized as aching, burning, or throbbing pain that is poorly localized.

Referred pain is of visceral origin that is misperceived as pain arising from a somatic location. The pain is “referred” according to the dermatomal rule, which states that sites on the skin are innervated by nerves arising from the same spinal cord segments as those innervating the visceral organs. Thus according to the dermatomal rule, ischemic heart pain (angina) is referred to the chest and shoulder, gallbladder pain is referred to the abdomen, kidney pain is referred to the lower back, and so forth.