How does metabolism of food produce acid and alkali, and what effect does the composition of the diet have on systemic acid-base balance What are the mechanisms for H+ transport in the various segments of the nephron, and how are these mechanisms regulated How is ammonium produced by the kidneys, and how does its excretion contribute to renal acid excretion What are the major mechanisms by which the body defends itself against changes in acid-base balance What are the differences between simple metabolic and respiratory acid-base disorders, and how are they differentiated by arterial blood gas measurements Also, cellular metabolism produces a number of substances that have an impact on the pH of body fluids. Without appropriate mechanisms to deal with this daily acid and alkali load and thereby maintain acid-base balance, many processes necessary for life could not occur. Although the emphasis is on the role of the kidneys in this process, the roles of the lungs and liver are also considered. In addition the impact of diet and cellular metabolism on acid-base balance is presented. Finally, disorders of acid-base balance are considered, primarily to illustrate the physiological processes involved. Throughout this chapter, acid is defined as any substance that adds H+ to body fluids, whereas alkali is defined as a substance that removes H+ from body fluids. This normally slow reaction is greatly accelerated in the presence of carbonic anhydrase. Slow Fast The concentration of H+ in body fluids is low compared with that of other ions. For example, Na+ is present at a concentration some three million times greater than that of H+ ([Na+] = 140 mEq/L; [H+] = 40 nEq/L). Because of the low [H+] of the body fluids, it is commonly expressed as the negative logarithm, or pH. As described later, although diet dependent, the net effect of these processes is the addition of acid to body fluids. For acid-base balance to be maintained, acid must be excreted from the body at a rate equivalent to its addition. The cellular metabolism of other dietary constituents also has an impact on acid-base balance. For example, cysteine and methionine, sulfur-containing amino acids, yield sulfuric acid when metabolized, whereas hydrochloric acid results from metabolism of lysine, arginine, and histidine. Also, pK is the negative logarithm of the overall dissociation constant for the reaction in Eq. On average the metabolism of dietary amino acids yields net nonvolatile acid production. In addition to the metabolically derived acids and alkalis, the foods ingested contain acid and alkali. Thus in a single day the nephrons must secrete approximately 4390 mEq of H+ into the tubular fluid. Therefore to excrete sufficient acid, the kidneys excrete H+ with urinary buffers such as phosphate (Pi). This term is derived from the method by which these buffers are quantitated in the laboratory. The amount of alkali added is equal to the H+ titrated by these urine buffers and is termed titratable acid. The mechanisms involved in this process are discussed in more detail later in this chapter. From a physiological perspective the primary factor that regulates H+ secretion by the nephron is a change in systemic acid-base balance. The response of the kidneys to changes in acid-base balance includes both immediate changes in the activity and/or number of transporters in the membrane and longerterm changes in the synthesis of transporters. For example, with metabolic acidosis, H+ secretion is stimulated by multiple mechanisms, depending on the particular nephron segment. First, the decrease in intracellular pH that occurs with acidosis will create a more favorable cell-to­tubular fluid H+ gradient and thereby make secretion of H+ across the apical membrane more energetically favorable. Second, the decrease in pH may lead to allosteric changes in transport proteins, thereby altering their kinetics. The precise function of this cell type in acid-base transport is not fully understood. There is now good evidence that NaCl reabsorption is also carried out by intercalated cells (B type). Although some of the effects just described may be attributable directly to acidosis, many of these changes in cellular H+ transport are mediated by hormones or other factors. Acidosis also stimulates secretion of the glucocorticoid hormone cortisol by the adrenal cortex. In so doing, more Pi is delivered to the distal nephron, where it serves as a urinary buffer and thus increases the capacity of the kidneys to excrete titratable acid. Other factors not necessarily related to maintaining acidbase balance can influence secretion of H+ by the cells of the nephron. Because a significant H+ transporter in the nephron is the Na+/H+ antiporter, factors that alter Na+ reabsorption can secondarily affect H+ secretion. For example, with volume contraction (negative Na+ balance), Na+ reabsorption by the nephron is increased (see Chapter 35), including reabsorption of Na+ via the Na+/H+ antiporter. One mechanism involves the renin-angiotensinaldosterone system, which is activated by volume contraction. By stimulating Na+ reabsorption by principal cells, aldosterone hyperpolarizes the transepithelial voltage. This change in transepithelial voltage then facilitates secretion of H+ by intercalated cells. It is thought that K+-induced changes in intracellular pH are responsible at least in part for this effect, with hypokalemia acidifying and hyperkalemia alkalinizing the cells. Importantly, this process is regulated in response to the acid-base requirements of the body. During systemic acidosis, the enzymes in the proximal tubule cell responsible for metabolism of glutamine are stimulated. This involves synthesis of new enzyme and requires several days for complete adaptation. These defense mechanisms do not correct the acid-base disturbance but merely minimize the change in pH imposed by the disturbance. Restoration of the blood pH to its normal value requires correction of the underlying process or processes that produced the acid-base disorder. Extracellular and Intracellular Buffers the first line of defense against acid-base disorders is extracellular and intracellular buffering. The response of the extracellular buffers is virtually instantaneous, whereas the response to intracellular buffering is slower and can take several minutes. Metabolic disorders that result from addition of nonvolatile acid or alkali to body fluids are buffered in both For simplicity of presentation in this chapter, the value of 7. Intracellular buffering involves movement of H+ into cells (during buffering of nonvolatile acid) or movement of H+ out of cells (during buffering of nonvolatile alkali). Virtually all buffering in respiratory acid-base disorders occurs intracellularly. The respiratory response to metabolic acid-base disturbances may be initiated within minutes but may require several hours to complete. Renal Compensation the third and final line of defense against acid-base disorders involves the kidneys. Respiratory Compensation the lungs are the second line of defense against acid-base disorders. Thus when metabolic acidosis occurs, a rise in the [H+] (decrease in pH) stimulates the ventilatory rate. Conversely, during metabolic alkalosis, a decreased [H+] (increase in pH) reduces the ventilatory rate. When the pH falls, the respiratory centers are stimulated and the ventilatory rate is increased (respiratory compensation). It results from decreased gas exchange across the alveoli as a result of either inadequate ventilation. Consequently, respiratory acid-base disorders are commonly divided into acute and chronic phases. It results from increased gas exchange in the lungs, usually caused by increased ventilation from stimulation of the respiratory centers. As with respiratory acidosis, respiratory alkalosis has both acute and chronic phases reflecting the time required for renal compensation to occur. The acute phase of respiratory alkalosis reflects intracellular buffering, whereas the chronic phase reflects renal compensation. Analysis of Acid-Base Disorders Analysis of an acid-base disorder is directed at identifying the underlying cause so appropriate therapy can be initiated. When pH is considered first, the underlying disorder can be classified as either an acidosis or an alkalosis. The defense mechanisms of the body cannot correct an acid-base disorder by themselves. Thus even if the defense mechanisms are completely operative, the change in pH indicates the acid-base disorder. Therefore the acid-base disorder is a simple metabolic acidosis with appropriate respiratory compensation. A mixed acid-base disorder reflects the presence of two or more underlying causes for the acid-base disturbance. Mixed acid-base disorders can occur, for example, in an individual who has a history of a chronic pulmonary disease such as emphysema. Such a condition can develop in a patient who has ingested a large quantity of aspirin. Salicylic acid (active ingredient in aspirin) produces metabolic acidosis and at the same time stimulates the respiratory centers, causing hyperventilation and respiratory alkalosis. The pulmonary response to metabolic acid-base disorders occurs in a matter of minutes. The kidneys respond to respiratory acid-base disorders over several hours to days. Map out and differentiate a simple endocrine negative feedback loop and one involving the hypothalamus, anterior pituitary and peripheral endocrine gland, and list the major endocrine glands under each type of feedback loop. Explain the chemical nature and the characteristics of protein/peptide hormones, catecholamine hormones, steroid hormones, and iodothyronines (thyroid hormones). Include such characteristics as site of regulation (synthesis or secretion), circulating form of hormone, subcellular localization of hormone receptor, and metabolic clearance. Integrate the concept of peripheral conversion with the function/action of a secreted hormone. Integrate the intracellular steps associated with a hormone response in a target cell. The ability of cells to communicate with each other is an underpinning of human biology. As discussed in Chapter 3, cell-to-cell communication exists at various levels of complexity and distance. Endocrine signaling involves (1) the regulated secretion of an extracellular signaling molecule, called a hormone, into the extracellular fluid; (2) diffusion of the hormone into the vasculature and its circulation throughout the body; and (3) diffusion of the hormone out of the vascular compartment into the extracellular space and binding to a specific receptor within cells of a target organ. Because of the spread of hormones throughout the body, one hormone often regulates the activity of several target organs. The endocrine system is a collection of glands whose function is to regulate multiple organs within the body to (1) meet the growth and reproductive needs of the organism and (2) respond to fluctuations within the internal environment, including various types of stress. In addition to dedicated endocrine glands, there are endocrine cells within organs whose primary function is not endocrine (see Table 38. There also exist collections of cell bodies (called nuclei) within the hypothalamus that secrete peptides, called neurohormones, into capillaries associated with the pituitary gland. A third subset of the endocrine system is represented by numerous cell types that express intracellular enzymes, ectoenzymes, or secreted enzymes that modify inactive precursors or less active hormones into highly active hormones (see Table 38. Another example is activation of vitamin D by two subsequent hydroxylation reactions in the liver and kidneys to produce the highly bioactive hormone 1,25-dihydroxyvitamin D (vitamin D). Configuration of Feedback Loops Within the Endocrine System the predominant mode of a closed feedback loop among endocrine glands is negative feedback. In a negative feedback loop, a hormone acts on one or more target organs to induce a change (either a decrease or increase) in circulating levels of a specific component, and the change in this component then inhibits secretion of the hormone. A closed positive feedback loop, in which a hormone increases levels of a specific component and this component stimulates secretion of the hormone, confers instability. Under the control of positive feedback loops, something has got to give; for example, positive feedback loops control processes that lead to rupture of a follicle through the ovarian wall or expulsion of a fetus from the uterus. There are two basic configurations of negative feedback loops within the endocrine system: a physiological response­driven feedback loop (referred to simply as a response-driven feedback loop) and an endocrine axis­driven feedback loop. The response-driven feedback loop is observed in endocrine glands that control blood glucose levels (pancreatic islet cells), blood Ca++ and Pi levels (parathyroid glands, kidneys), blood osmolarity and volume (hypothalamus/posterior pituitary gland), and blood Na+, K+, and H+ levels (zona glomerulosa of the adrenal cortex and atrial cells). In the response-driven configuration, secretion of a hormone is stimulated or inhibited by a change in the level of a specific extracellular parameter. Alterations in hormone levels lead to changes in the physiological characteristics of target organs. The change in the parameter (decreased blood glucose level) then inhibits further secretion of the hormone. Much of the endocrine system is organized into endocrine axes; each axis consists of the hypothalamus, the pituitary gland, and the peripheral endocrine glands. Thus the endocrine axis­driven feedback loop involves a three-tiered configuration. The first tier is represented by hypothalamic neuroendocrine neurons that secrete releasing hormones. Releasing hormones stimulate (or, in a few cases, inhibit) the production and secretion of tropic hormones from the pituitary gland (second tier).

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• Pioglitazone hydrochloride
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Piezo2 has been found in the main proprioceptors (muscle spindles and Golgi tendon organs [see Chapter 9]) and appears to be the main mechanotransducer protein there as well. Thermal Transduction the receptor that binds capsaicin (the molecule in chili peppers responsible for their spiciness) has been identified, and either it or one of a family of related proteins has been found to be expressed in populations of dorsal root ganglion cells. Nevertheless, touch and pain sensitivity is altered in such knockdown mutants, so they may still play a modulatory role in the transduction process. Currently, Piezo2 is thought to be channel protein underlying the transduction for cutaneous mechanical rapidly adapting responses, because it forms a nonselective cation pore that opens in response to mechanical stimuli. Moreover, the activation and inactivation kinetics of this channel are consistent with its causing the rapidly adapting mechanoactivated current, and it is blocked by agents Temperature (°C) ·. Note how the response ranges of the afferents largely match up with those of individual heat-sensitive channels. These substances and others released from the damaged cells cause neurogenic inflammation (edema and redness of the surrounding skin). In addition to causing a local reaction, these substances may serve to activate the insensitive or silent nociceptors mentioned earlier, such that they can henceforth respond to any subsequent damaging stimuli. Sensitization of silent nociceptors has been suggested to underlie allodynia (elicitation of painful sensations by stimuli that were innocuous before an injury) and hyperalgesia (increase in the level of pain felt to already painful stimuli). The Piezo2 current is increased by substances known to cause mechanical hyperalgesia and allodynia, suggesting changes in this current underlie these phenomena. Centrifugal Control of Somatosensation Sensory experience is not just the passive detection of environmental events. Thus sensory information is often received as a result of activity in the motor system. Furthermore, transmission in pathways to the sensory centers of the brain is regulated by descending control systems. These systems allow the brain to control its input by filtering the incoming sensory messages. Important information can be attended to and unimportant information can be ignored. The tactile and proprioceptive somatosensory pathways are regulated by descending pathways that originate in the S-I and motor regions of the cerebral cortex. For example, cortical projections to the dorsal column nuclei help control the sensory input that is transmitted by the dorsal column­ medial lemniscus pathway. Of particular interest is the descending control system that regulates transmission of nociceptive information. For example, it is well known that soldiers on the battlefield, accident victims, and athletes in competition often feel little or no pain at the time a wound occurs or a bone is broken. Although the descending regulatory system that controls pain is part of a more general centrifugal control system that modulates all forms of sensation, the pain control system is so important medically that it is distinguished as a special system called the endogenous analgesia system. Several centers in the brainstem and pathways descending from these centers contribute to the endogenous analgesia system. Each of the proteins listed is expressed in at least some dorsal root ganglion cells, but they are also expressed inothercelltypes. In this model, gating of transmission of pain information would be due to a balance of the excitatory and inhibitory activity in the descending pathways. Other inhibitory pathways originate in the sensorimotor cortex, hypothalamus, and reticular formation. The endogenous analgesia system can be subdivided into two components: one component uses endogenous opioid peptides as neurotransmitters and the other does not. Endogenous opioids are neuropeptides that activate one of several types of opiate receptors. Opiate analgesia can generally be prevented or reversed by the narcotic antagonist naloxone. Therefore naloxone is frequently used to determine whether analgesia is mediated by an opioid mechanism. The opioid-mediated endogenous analgesia system can be activated by exogenous administration of morphine or other opiate drugs. Thus one of the oldest medical treatments of pain depends on the triggering of a sensory control system. One hypothesis is that the descending analgesia system is under tonic inhibitory control by inhibitory interneurons in both the midbrain and medulla. The action of opiates would inhibit the inhibitory interneurons and thereby disinhibit the descending analgesia pathways. Some endogenous analgesia pathways operate by neurotransmitters other than opioids and thus are unaffected by naloxone. One way of engaging a nonopioid analgesia pathway is through certain forms of stress. Serotonin can inhibit nociceptive neurons and presumably plays an important role in the endogenous analgesia system. Other brainstem neurons release catecholamines, such as norepinephrine and epinephrine, in the spinal cord. These catecholamines also inhibit nociceptive neurons; therefore catecholaminergic neurons may contribute to the endogenous analgesia system. In addition, there is evidence for the existence of endogenous opiate antagonists that can prevent opiate analgesia. Sensory neurons have cell bodies in sensory nerve ganglia: (1) dorsal root ganglia for neurons innervating the body and (2) cranial nerve ganglia for neurons innervating the face, oral and nasal cavities, and dura, except for proprioceptive neurons, which are in the trigeminal mesencephalic nucleus. They connect peripherally to a sensory receptor and centrally to second-order neurons in the spinal cord or brainstem. A and C nociceptors detect noxious mechanical, thermal, and chemical stimuli and may be sensitized by release of chemical substances from damaged cells. Peripheral release of substances, such as peptides, from nociceptors themselves may contribute to inflammation. Large primary afferent fibers enter the dorsal funiculus through the medial part of the dorsal root; collaterals synapse in the deep dorsal horn, intermediate zone, and ventral horn. Small primary afferent fibers enter the spinal cord through the lateral part of the dorsal root; collaterals synapse in the dorsal horn. Ascending branches of large primary afferent fibers synapse on second-order neurons in the dorsal column nuclei. The dorsal column spinal cord pathways signal the sensations of flutter-vibration, touch-pressure, and 6. Parallel nociceptive pathways in the ventrolateral funiculus are the spinoreticular and spinomesencephalic tracts; these tracts and the spinothalamic projection to the medial thalamus contribute to the motivational-affective aspects of pain. Referred pain is explained by convergent input to spinothalamic tract cells from the body wall and from viscera. These nuclei contain multiple somatotopic maps, one for each somatosensory submodality. The S-I cortex contains columns of neurons with similar receptive fields and response properties. Transmission in somatosensory pathways is regulated by descending control systems. The endogenous analgesia system regulates nociceptive transmission, and it uses transmitters such as endogenous opioid peptides, norepinephrine, and serotonin. What are the synaptic pathways for the central and surround portions of the receptive field of an on-center bipolar cell What are the receptive field properties of simple and complex cells in the visual cortex What are the stimuli that are normally transduced by the hair cells in the semicircular canals and otolith organs What are the functional consequences of the differing numbers of different receptor molecules between olfactory and gustatory receptor cells The evolution of vertebrates shows a trend called cephalization in which special sensory organs develop in the heads of animals, along with the corresponding development of the brain. These special sensory systems, which include the visual, auditory, vestibular, olfactory, and gustatory systems, detect and analyze light, sound, and chemical signals in the environment, as well as signal the position and movement of the head. The stimuli transduced by these systems are most familiar to humans when they provide conscious awareness of the environment, but they are equally important as the sensory basis for reflexive and subconscious behavior. Cones, in contrast, are not as sensitive to light as rods are and thus operate best under daylight conditions (photopic vision). Thus information processing within the retina is performed by retinal neurons, and the output signals are carried to the brain by the axons of retinal ganglion cells in the optic nerves. There is a partial crossing of these axons in the optic chiasm that causes all input from one side of the visual space to pass to the opposite side of the brain. Posterior to the optic chiasm, the axons of retinal ganglion cells form the optic tracts and synapse in nuclei of the brain. Other visual pathways project to the superior colliculus, pretectum, and hypothalamus, structures that participate in orientation of the eyes, control of pupil size, and circadian rhythms, respectively. The outer layer, or the fibrous coat, includes the transparent cornea, with its epithelium, and the opaque sclera. The iris contains both radially and circularly oriented smooth muscle fibers, which make up the pupillary dilator and constricter muscles, respectively. The choroid is rich in blood vessels that support the outer layers of the retina, and it also contains pigment. The functional part of the retina covers the entire posterior aspect of the eye except for the optic nerve head, or optic disc, which is where the optic nerve axons leave the retina. Because there are no receptors at this location, it is often referred to as the anatomical "blind spot". Externally attached extraocular muscles aim the eyes toward an appropriate visual target (see Chapter 9). These muscles are innervated by the oculomotor nerve 127 the Visual System Vision is one of the most important special senses in humans and, along with audition, is the basis for most human communication. The visual system detects electromagnetic waves between 400 and 750 nm long as visible light, which enters the eye and impinges on photoreceptors in a specialized sensory epithelium, the retina. The photoreceptors, rods and cones, can distinguish two aspects of light: its brightness (or luminance) and its wavelength (or color). The muscles in the ciliary body control lens shape and thereby the focus of images on the retina. The pupillary dilator and sphincter muscles in the iris control the amount of light entering the eye, in a way similar to that of the diaphragm of a camera. The dilator is activated by the sympathetic nervous system, whereas the sphincter and ciliary muscles are controlled by the parasympathetic nervous system (through the oculomotor nerve; see Chapter 11). Light enters the eye through the cornea and passes through a series of transparent fluids and structures that are collectively called the dioptric media. These fluids and structures consist of the cornea, aqueous humor, lens, and vitreous humor. The aqueous humor (located in the anterior and posterior chambers) and the vitreous humor (located in the space behind the lens) help maintain the shape of the eye. Although the geometrical optic axis of the human eye passes through the nodal point of the lens and reaches the retina at a point between the fovea and the optic disc. Light from the fixation point passes through the nodal point of the lens and is focused on the fovea. Light from the remainder of the visual target falls on the retina surrounding the fovea. Normally, light from a visual target is focused sharply on the retina by the cornea and lens, which bend or refract the light. The cornea is the major refractive element of the eye, with a refractive power of 43 dioptersa (D). However, unlike the cornea, the lens can change shape and vary its refractive power between 13 and 26 D. Suspensory ligaments (or zonule fibers) attach to the wall of the eye at the ciliary body. When the muscles in the ciliary body are relaxed, the tension exerted by the suspensory ligaments flattens the lens. When the ciliary muscles contract, the tension on the suspensory ligaments is reduced; this process allows the somewhat elastic lens to assume a more spherical shape. The ciliary muscles are activated by the parasympathetic nervous system via the oculomotor nerve. In this way, the lens allows the eye to focus on, or accommodate to , either near or distant objects. For instance, when light from a distant visual target enters a normal eye (one with a relaxed ciliary muscle), the target image is in focus on the retina. However, if the eye is directed at a nearby visual target, the light is initially focused behind the retina. Thus it is a unit of reciprocal length, and a 2-D lens would bring parallel rays of light into focus at a distance of 0. Proper imaging of light on the retina depends not only on the lens and cornea but also on the iris, which adjusts the amount of light that can enter the eye through the pupil. In this regard, the pupil is analogous to the aperture in a camera, which also controls the depth of field of the image and the amount of spherical aberration produced by the lens. When the pupil is constricted, the depth of field is increased, and the light is directed through the central part of the lens, where spherical aberration is minimal. Pupillary constriction occurs reflexively when the eye accommodates for near vision or adapts to bright light, or both. Thus when a person reads or does other fine visual work, the quality of the image is improved by adequate light. The outermost portion is the pigmented epithelium (layer 1), which is just inside the choroid. The pigment cells have Retinal layers 10 Inner limiting membrane 9 Nerve fiber layer Components 8 Ganglion cell layer Axons at surface of retina passing via optic nerve, chiasm and tract to lateral geniculate body Ganglion cell 7 Inner plexiform layer 6 Inner nuclear layer Müller cell (supporting glial cell) Bipolar cell Amacrine cell 5 Outer plexiform layer Horizontal cell Rod Cone 4 Outer nuclear layer 3 Outer limiting membrane 2 Photoreceptor layer 1 Pigment epithelium Inner segment Outer segment Pigment cells Choroid ·. In addition, they serve a mechanical function in maintaining contact between layers 1 and 2 so that the pigmented epithelium can (1) provide nutrients and remove waste from the photoreceptors; (2) phagocytose the ends of the outer segments of the rods, which are continuously shed; and (3) reconvert metabolized visual pigment into a form that can be reused after it is transported back to the photoreceptors. Retinal glial cells, known as Müller cells, play an important role in maintaining the internal geometry of the retina. Müller cells are oriented radially, parallel to the light path through the retina. The outer ends of Müller cells form tight junctions with the inner segments of the photoreceptors, and these numerous connections have the appearance of a continuous layer, the outer limiting membrane (layer 3 of the retina). The innermost layer of the retina is the inner limiting membrane (layer 10) formed by the end-feet of Müller cells. Structure of Photoreceptors: Rods and Cones Each rod or cone photoreceptor cell is composed of a cell body (in layer 4), an inner and an outer segment that extend into layer 2, and a set of synaptic terminals that synapse in layer 5 onto other retinal cells.

Bifidobacterium (Bifidobacteria). Zerit.

• Are there safety concerns?
• Common cold and flu (influenza); diarrhea caused by antibiotics; liver problems; high cholesterol; lactose intolerance; mastitis; mumps; cancer; stomach problems; replacing bacteria removed by diarrhea; chemotherapy; Lyme disease; preventing infections after exposure to radiation, aging, antibiotics, and other causes; and other conditions.
• Prevention of diarrhea in infants, when used with another bacterium called Streptococcus thermophilus.
• Reducing side effects of treatment for the ulcer-causing bacterium Helicobacter pylori.
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• Prevention of a type of colitis caused by bacteria (necrotizing enterocolitis).
• Treating a skin condition in infants called atopic eczema. Inflammation of the intestines in infants.
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Thus transection of a single dorsal root causes little sensory loss in the corresponding dermatome. Anesthesia of any given dermatome requires interruption of several adjacent dorsal roots. Rather the large myelinated primary afferent fibers assume a medial position in the dorsal root, whereas the small myelinated and unmyelinated fibers are more lateral. The large medially placed afferent fibers enter the dorsal column, where they bifurcate into rostrally and caudally directed branches. These branches give off collaterals that terminate in several neighboring segments. The rostral branch also ascends to the medulla as part of the dorsal column­medial lemniscus pathway. The axonal branches that terminate locally in the spinal cord gray matter transmit sensory information to neurons in the dorsal horn and also provide the afferent limb of reflex pathways (see Chapter 9). The dorsal root of a given spinal segment is composed entirely of the central processes of its associated dorsal root ganglion cells. The ventral root consists chiefly of motor axons, including and motor neuron axons (see Chapter 9), and at certain segmental levels, autonomic preganglionic axons (see Chapter 11). Innervation of the Face the arrangement of primary afferent fibers that supply the face is comparable to that of fibers that supply the body and is provided for primarily by fibers of the trigeminal nerve. Peripheral processes of neurons in the trigeminal ganglion (also called the gasserian or semilunar ganglion) pass through the ophthalmic, maxillary, and mandibular divisions of the trigeminal nerve to innervate dermatome-like regions of the face. The central processes of these neurons terminate in the motor trigeminal nucleus (to subserve segmental reflexes equivalent to the segmental spinal cord reflexes [see Chapter 9]), the reticular formation, and the chief sensory trigeminal nucleus. For example, from the body, fine discriminatory touch information is conveyed by the dorsal column­medial lemniscus pathway, whereas pain, temperature, and crude touch information is conveyed by the anterolateral system. Proprioceptive information is transmitted by yet another route that partially overlaps with the dorsal column­medial lemniscal pathway. Note, however, that this functional segregation is not absolute, so, for example, there can be some recovery of discriminative touch ability after a lesion of the dorsal columns. The anterolateral system will be discussed in the section on pain because it is the critical pathway for that information. Here, the central pathways also innervates the teeth, the oral and nasal cavities, and the cranial dura mater. The central processes of trigeminal ganglion cells enter the brainstem at the midpontine level, which also corresponds to the level of the chief sensory trigeminal nucleus (nucleus of cranial nerve V). Some axons terminate in this nucleus (primarily large-caliber axons carrying the information needed for fine discriminative touch), whereas others (intermediate- and small-caliber axons that carry information about touch as well as pain and temperature) form the descending trigeminal tract, which descends through the medulla just lateral to the descending trigeminal nucleus. The dorsal columns are formed by ascending branches of the large myelinated axons of dorsal root ganglion cells (the first-order neurons). These axons enter at each spinal segmental level and travel rostrally up to the caudal medulla to synapse in one of the dorsal column nuclei: the nucleus gracilis, which receives information from the lower part of the body and leg, and the nucleus cuneatus, which receives information from the upper part of the body and arm. Note that across the dorsal columns and across the dorsal column nuclei there is a somatotopic representation of the body, with the legs represented most medially, followed by the trunk and then the upper limb. This somatotopy is a consequence of newly entering afferents being added to the lateral border of the dorsal funiculus as the spinal cord is ascended. Such somatotopic maps are present at all levels in the somatosensory system, at least through the primary sensory cortices. The dorsal column nuclei are located in the medulla and contain the second-order neurons of the pathway for discriminatory touch sensation. These cells respond similarly to the primary afferent fibers that synapse on them (see the earlier description of afferent types). The main differences between the responses of dorsal column neurons and primary afferent neurons are as follows: (1) dorsal column neurons have larger receptive fields because multiple primary afferent fibers synapse on a given dorsal column neuron, (2) dorsal column neurons sometimes respond to more than one class of sensory receptor because of the convergence of several different types of primary afferent fibers on the second-order neurons, and (3) dorsal column neurons often have inhibitory receptive fields that are mediated through local interneurons. The axons of dorsal column nuclear projection neurons exit the nuclei and are referred to as the internal arcuate fibers as they sweep ventrally and then medially to cross the midline at the same medullary level as the nuclei. Immediately after crossing the midline, these fibers form the medial lemniscus (see Chapter 4. Knowledge of the level of this decussation is clinically important because damage to the dorsal column­medial lemniscal pathway below this level, which includes all of the spinal cord, will produce loss of fine somatosensory discriminatory abilities on the same, or ipsilateral, side of the lesion, whereas lesions above this level will produce contralateral deficits. Moreover, because there is a clear somatotopic arrangement of fibers in the medial lemniscus, localized lesions cause selective loss of fine-touch sensations limited to specific body regions. The dorsal column­medial lemniscus pathway conveys information about fine-touch and vibratory sensations. This information is critical for many of the discriminatory tactile abilities we have. For example, spatial acuity is lowered by damage to this pathway, and the ability to identify objects by their shape and texture can be lost by damage to this pathway. Clinically, one may test for impaired graphesthesia, or the ability to recognize letters or numbers traced on the skin, or for loss of the ability to tell the direction of a line drawn across the skin. Importantly, some tactile function remains even after complete loss of the dorsal columns, and awareness and localization of nonnoxious tactile stimuli can still occur. Thus at least some of the information carried by the dorsal column pathway is also conveyed by additional ascending pathways. In contrast to the severe deficits in discriminatory touch sensation, cutaneous pain and temperature sensations are unaffected by lesions of the dorsal columns. However, visceral pain is substantially diminished by damage to the dorsal columns. Trigeminal Pathway for Fine-Touch Sensation From the Face Primary afferent fibers that supply the face, teeth, oral and nasal cavities, and cranial meninges synapse in several brainstem nuclei, including the main sensory nucleus and the descending nucleus of the trigeminal nerve. Spinocerebellar and Proprioceptive Pathways Proprioceptors provide information about the positions and movement of parts of the body. In addition to being used for local reflexes (see Chapter 9), this information has two main targets, the cerebellum and the cerebral cortex. The information sent to the cerebral cortex is the basis for conscious awareness of our body parts. The major pathways by which somatosensory information is brought to the cerebellum are shown in. These pathways carry both cutaneous and proprioceptive information to the cerebellum. The ventral spinocerebellar tract also provides somatosensory input from the lower limb to the cerebellum. Note the double decussation of the ventral spinocerebellar pathway (one decussation at the spinal cord levels and a second one in the cerebellar white matter). This double crossing highlights the general rule that each half of the cerebellum is functionally related to the ipsilateral side of the body. To provide proprioceptive information from the lower limb to the cerebral cortex, the main axons of the dorsal spinocerebellar tract give off a branch in the medulla that terminates in nucleus z, which is just rostral to the nucleus gracilis. The ascending somatosensory pathways to the cerebellum for the upper limb are simpler than those from the lower limb. The route to the cerebellum starts with dorsal root ganglion fibers from the cervical spinal levels that ascend in the cuneate fasciculus to the external cuneate nucleus. The axons of the external cuneate nucleus then form the cuneocerebellar tract, which enters the cerebellum via its inferior peduncle. For the head, proprioceptive input is carried by cells of the mesencephalic nucleus of the trigeminal nerve. Recall that the neurons in this nucleus are actually the cell bodies of the primary afferents that innervate stretch receptors in the muscles of mastication (muscles that move the jaw) and in other muscles of the head. The central processes of these neurons project to the trigeminal motor nucleus for local reflexes or to the nearby reticular formation. There are also trigeminocerebellar pathways for conveying somatosensory (tactile and proprioceptive) information from the head to the cerebellum. Thalamic and Cortical Somatosensory Areas Thalamus the ventroposterior nuclear complex of the thalamus represents the main termination site for ascending somatosensory information in the diencephalon. These nuclei also receive input conveying pain and temperature information from the spinothalamic or equivalent trigeminothalamic tracts, respectively. In addition, the spinothalamic tract terminates in parts of the posterior nuclear complex and several other thalamic nuclei. Single-unit recordings from the ventroposterior complex of nuclei have shown that the responses of many of the neurons in these nuclei to stimuli resemble those of first- and second-order neurons in the ascending tracts. The receptive fields of thalamic cells are small but somewhat larger than those of primary afferent fibers. Moreover, the responses may be dominated by a particular type of sensory receptor. The inhibition may actually take place in the dorsal column nuclei or in the dorsal horn of the spinal cord. During a state of drowsiness or during barbiturate anesthesia, thalamic neurons tend to undergo an alternating sequence of excitatory and inhibitory postsynaptic potentials. The alternating bursts of discharges in turn intermittently excite neurons in the cerebral cortex. Such patterns of excitation and inhibition result in an rhythm or in spindling on the electroencephalogram. It may also reflect inhibition of the thalamic neurons by recurrent pathways through the reticular nucleus. Thalamic neuron receptive fields are on the side of the body contralateral to the neuron, and the receptive field locations vary systematically across the ventroposterior nuclear complex. Moreover, the fact that thalamic neurons often receive input from only one class of receptor suggests that there are multiple somatotopic maps laid out across the ventroposterior nuclear complex. This parallel flow of information into thalamus and then onto the cortex is diagramed in. The spinothalamic tract also projects to other thalamic regions, including the posterior nucleus and the central lateral nucleus of the intralaminar complex of the thalamus. The intralaminar nuclei of the thalamus are not somatotopically organized, and they project diffusely to the cerebral cortex as well as to the basal ganglia (see Chapter 9). The projection of the central lateral nucleus to the S-I cortex may be involved in arousal of this part of the cortex and in selective attention. Somatosensory Cortex Third-order sensory neurons in the thalamus project to the somatosensory cortex. As previously discussed, the S-I cortex, like the somatosensory thalamus, has a somatotopic organization. In the S-I cortex the face is represented in the lateral part of the postcentral gyrus, above the lateral fissure. The hand and the rest of the upper extremity are represented in the dorsolateral part of the postcentral gyrus, and the lower extremity on the medial surface of the hemisphere. A map of the surface of the body and face of a human on the postcentral gyrus is called a sensory homunculus. The map is distorted because the volume of neural tissue devoted to a body region is proportional to the density of its innervation. Thus in humans, the perioral area, the thumb, and other digits take up a disproportionately large expanse of cortex relative to their size. The sensory homunculus is an expression of place coding of somatosensory information. A locus in the S-I cortex encodes the location of a somatosensory stimulus on the surface of the body or face. For example, the brain knows that a certain part of the body has been stimulated because certain neurons in the postcentral gyrus are activated. The S-I cortex has several morphological and functional subdivisions, and each subdivision has a somatotopic map. These subdivisions were originally described by Brodmann, and they were based on the arrangements of neurons in the various layers of the cortex, as seen in Nissl-stained preparations. The subdivisions are therefore known as Brodmann areas 3a, 3b, 1, and 2 (see Chapter 10). Cutaneous input dominates in areas 3b and 1, whereas muscle and joint input (proprioceptive) dominates in areas 3a and 2. Thus separate cortical zones are specialized for processing tactile and proprioceptive information. Within any particular area of the S-I cortex, all the neurons along a line perpendicular to the cortical surface have similar response properties and receptive fields. A comparable columnar organization has also been demonstrated for other primary sensory receiving areas, including the primary visual and auditory cortices (see Chapter 8). Nearby cortical columns in the S-I cortex may process information for different sensory modalities. Besides being responsible for the initial processing of somatosensory information, the S-I cortex also begins higher-order processing such as feature extraction. For example, certain neurons in area 1 respond preferentially to a stimulus that moves in one direction across the receptive field but not in the opposite direction. Effects of Lesions of the Somatosensory Cortex A lesion of the S-I cortex in humans produces sensory changes similar to those produced by a lesion of the somatosensory thalamus. However, usually only a part of the cortex is involved, and thus the sensory loss may be confined, for example, to the face or to the leg, depending on the location of the lesion with respect to the sensory homunculus. Pain and thermal sensation may be relatively unaffected, although loss of pain sensation may follow cortical lesions. Conversely, cortical lesions can result in a central pain state that resembles thalamic pain (see "Effects of Interruption of the Spinothalamic Tract and Lesions of the Thalamus on Somatosensory Sensation"). Nociceptors and Primary Afferents the axons that carry painful and thermal sensations are members of the relatively slowly conducting A and C classes. However, not all A and C axons carry pain and temperature information; some respond to light touch in a manner similar to what was described for low-threshold mechanoreceptors. Unlike the case for low-threshold mechanoreceptors in which morphologically distinct receptors correspond to response properties, the A and C axons conveying pain and temperature information appear to originate mostly as "free nerve endings. This ability to sense tissue-damaging stimuli (mechanical, thermal, or chemical) is mediated by what are called nociceptors. Indeed, there appear to be a significant number of C fibers that are silent or unresponsive to any stimuli until first sensitized.

Usage: p.r.n.

If the axons that provide the sole or predominant synaptic input to a neuron or to an effector cell are interrupted, the postsynaptic cell may undergo transneuronal degeneration Chromatolysis Neuron Axon Axon severed Severed axon sprouting Sprouts degenerating Axon regenerating Chromatolysis no longer present Schwann cell Muscle Effector denervated Target reinnervated A ·. The best known example of this is atrophy of skeletal muscle fibers after their innervation by motor neurons has been interrupted. However, if only one or a few of the innervating axons are removed, the other surviving axons may sprout additional terminals, thereby taking up the synaptic space of the damaged axons and increasing their influence on the postsynaptic cell. The Schwann cells in the distal stump of the nerve not only survive the wallerian degeneration but also proliferate and form rows along the course previously taken by the axons. Growth cones of the sprouting axons find their way along these rows of Schwann cells, and they may eventually reinnervate the original peripheral target structures. The rate of regeneration is limited by the rate of slow axonal transport to about 1 mm/day. However, proper guidance for the sprouts is lacking, in part because the oligodendroglia do not form a path along which the sprouts can grow. This limitation may be a consequence of the fact that a single oligodendroglial cell myelinates many central axons, whereas a single Schwann cell provides myelin for only a single axon in the periphery. In addition, different chemical signals may affect peripheral and central attempts at regeneration differently. The functions of the nervous system include excitability, sensory detection, information processing, and behavior. The brain includes the medulla, pons, cerebellum, midbrain, thalamus, hypothalamus, basal ganglia, and cerebral cortex. The first two receive and integrate signals, and the axon conveys the output signals of the neuron to other cells. Information is conveyed through neural circuits by action potentials in the axons of neurons and by synaptic transmission between axons and the dendrites and somas of other neurons or between axons and effector cells. Different types of neurons are specialized as a consequence of their individual morphology and the ion channel distribution in the cell membrane of their soma, dendrites, and axons. Stimuli are environmental events that excite sensory receptors, responses are the effects of stimuli, and sensory transduction is the process by 8. Sensory receptors can be classified in terms of the type of energy they transduce or by the source of the input. Central pathways are usually named by their origin and termination or for the type of information conveyed. Chemical substances are distributed along the axons by fast or slow axonal transport. Damage to the axon of a neuron causes an axonal reaction (chromatolysis) in the cell body and wallerian degeneration of the axon distal to the injury. How does the presence of the Na+ channel inactivation gate cause the responses to differ How do the gating properties of Na+ and K+ channels relate to the absolute and relative refractory periods of the action potential What are the structural properties of myelin that underlie its ability to increase conduction velocity Given the all-or-none nature of action potentials, how are the characteristics of different stimuli distinguished by the central nervous system More detailed information about these sensory mechanisms and systems is provided in other chapters. Membrane Potentials Observations on Membrane Potentials When a microelectrode (tip diameter <0. The internal electrode is approximately 70 mV negative with regard to the external electrode, and this difference is referred to as the resting membrane potential or, simply, the resting potential (see Chapter 1 for details on the basis of the resting potential). One of the signature features of neurons is their ability to change their membrane potential rapidly from rest in response to an appropriate stimulus. Two such classes of responses are action potentials and synaptic potentials, which are described in this chapter and the next, respectively. Current knowledge about the ionic mechanisms of action potentials comes from experiments with many species. This chapter describes how action potentials are generated by voltage-dependent ion channels in the plasma membrane and propagated with the same shape and size along the length of an axon. The influences of axon geometry, ion channel distribution, and myelin are discussed and explained. The ways in which information is encoded by the frequency and pattern of action potentials in individual cells and in groups of nerve cells are also described. Finally, because the nervous system provides important information about the external world A the Passive Response To understand how an action potential is generated and why it is needed, it is necessary to understand the passive electrical properties of the nerve cell membrane. The term passive properties refers to the fact that components of the cell membrane behave very similarly to some of the passive elements of electric circuits, including batteries, resistors, and capacitors. Over time, however, the current flow through the capacitor decreases, whereas that through the resistor increases. As this happens, the rate of voltage change across the capacitor (and resistor) slows, and the voltage approaches a steady-state value. This change in voltage has an exponential time course whose specific characteristics depend on the resistance (R) and capacitance (C) of the resistor and capacitor. Moreover, a time constant, for this circuit can be defined by the equation = R * C, and it equals the time it takes for the voltage to rise (or fall) exponentially by approximately 63% of the difference between its initial and final values. The changes in transmembrane potential are mirror images of the small amplitude pulses. Current pulseamplitude is plotted on the x-axis,and voltageresponse(measuredatdottedline)isplottedonthey-axis. The injection of positive charge is depolarizing because it makes the cell less negative. Conversely, the injection of negative charge makes the membrane potential more negative, and this change in potential is called hyperpolarization. The larger the current that is injected, the greater the change in the membrane potential will be. In contrast, the shapes of the responses to the larger depolarizing stimulus pulses differ from those to hyperpolarizing and small-amplitude depolarizing current pulses because the larger stimuli activate nonpassive elements in the membrane. For the responses to hyperpolarizing current pulses, once a long enough time has elapsed from the start of the current pulse to allow the membrane voltage to plateau (essentially several times), virtually all of the injected current is flowing through the membrane resistance. If the difference between the initial and steady-state voltages is plotted against the amplitude of the current pulse. The slope of this line (V/I) is referred to as the input resistance of the cell (Rin) and is determined experimentally, exactly as just described. Rin is related to the membrane resistance (rm) of the cell, but the exact relationship depends on the geometry of the cell and is complex in most cases. Next, note that although the current is injected as rectangular pulses, with vertical rising and falling edges, the shape of the membrane voltage responses just after the starts and ends of the pulses have slower rises and falls. Moreover, with regard to only the responses to hyperpolarizing and small-amplitude depolarizing current pulses. However, this model circuit, with only a single resistor and capacitor, takes no account of the fact that axons are spatially extended structures and that because of this, the resistance of the intracellular space is a significant factor in how electrical events in one region affect other regions. That is, if axons had no intracellular resistance, their intracellular space would be isoelectric, and voltage changes, like those just described, across one part of the axonal membrane would occur across all regions instantaneously. In actuality, axons (and neurons in general) are spatially extended structures with significant resistance to current flow between different regions (this is one reason the relationship of Rin and rm is complicated). Therefore, it is important to understand how current injected at one point along the axon affects the membrane potential at other points because this both helps explain why action potentials are needed and helps explain some of their characteristics. When current pulses that elicit only passive responses are passed across the plasma membrane, the size of the change in potential recorded depends on the distance of the recording electrode from the point of passage of the current. The closer the recording electrode is to the site of current passage, the larger and steeper the change in potential is. The magnitude of the change in potential decreases exponentially with distance from the Current 4. As the recording electrode is moved farther from the point of stimulation, the response of the membrane potential is slower and smaller. Such passively conducted changes in potential do not spread very far along the membrane before they become insignificant. The distance over which the change in potential decreases to 1/e (37%) of its maximal value is called the length constant or space constant (where e is the base of natural logarithms and is equal to 2. A length constant of 1 to 3 mm is typical for mammalian axons, which can be more than a meter long, which makes obvious the need for a mechanism to propagate information about electrical events generated at the soma to the far end of the axon. The length constant can be related to the electrical properties of the axon according to cable theory because nerve fibers have many of the properties of an electrical cable. In a perfect cable, the insulation surrounding the core conductor prevents all loss of current to the surrounding medium, so that a signal is transmitted along the cable with undiminished strength. If an unmyelinated nerve fiber (discussed later) is compared to an electrical cable, the plasma membrane equates to the insulation and the cytoplasm as the core conductor, but the plasma membrane is not a perfect insulator. Thus the spread of signals depends on the ratio of the membrane resistance to the axial resistance of the axonal cytoplasm (ra). When the ratio of rm to ra is high, less current is lost across the plasma membrane per unit of axonal length, the axon can function better as a cable, and the distance that a signal can be conveyed electrotonically without significant decrement is longer. The more holes there are in the hose, the more water leaks out along its length (analogous to more loss of current when rm is low) and the less water is delivered to its nozzle. According to cable theory, the length constant can be related to axonal resistance and is equal to rm /ra. This relationship can be used to determine how changes in axonal diameter affect the length constant and, hence, how the decay of electrotonic potentials varies. However, rm is inversely proportional to diameter (because it is related to the circumference of the axon), whereas ra varies inversely to the diameter squared (because it is related to the crosssectional area of the axon). Thus ra decreases more rapidly than rm does as axonal diameter increases, and the length constant therefore increases. Nevertheless, the local response is not self-regenerating but, again, decreases in amplitude with distance. The change in membrane properties is insufficient for what is needed to generate an action potential. This is most easily observed with pulses that elicit depolarizations either just below or to the threshold membrane potential for an action potential but fail to evoke an action potential (tracings 0. In these cases, the voltage response shape is altered from that of the passive responses because the stimulus has changed the membrane potential sufficiently to cause the opening of significant numbers of voltage-sensitive Na+ channels (described later). Also, note the upward deviation from linearity for the corresponding points in the I-V curve. This entry of positive charge (Na+ current) enhances the depolarization by adding to the current pulse delivered by the electrode. The local response Suprathreshold Response: the Action Potential Local responses will increase in size as the amplitude of the depolarizing current pulse is increased, until the threshold membrane potential is reached, at which point a different sort of response, the action potential (or spike), can occur. Normally, when the membrane potential exceeds this value, an action potential is always triggered. The membrane potential then returns toward the resting membrane potential (repolarizes) almost as rapidly as it was depolarized, and in general, it hyperpolarizes beyond its resting potential (the afterhyperpolarization). The action potential differs from the subthreshold and passive responses in three important ways: (1) It is a response of much larger amplitude, in which the polarity of the membrane potential actually overshoots 0 mV (the cell interior becomes positive in relation to the exterior). This all-or-none nature is in contrast both to the graded nature of the passive and local responses described previously and to synaptic responses (see Chapter 6). If, however, the relative conductances to these ions were to change, this would cause a corresponding change in the membrane potential. An axonic action potential is, in fact, the result of a rapid sequence of transient changes in gNa or gK, or both. In all axons there is a brief rise in gNa, followed by a decline back to baseline levels. In some axons, this change in gNa occurs against a fixed resting gK (because of leak channels, which are not voltage-gated; discussed later). Thus as with the resting membrane potential, the action potential depends on the opposing tendencies of (1) the Na+ gradient to bring the resting membrane potential toward the Nernst potential for Na+ and (2) the K+ gradient to bring the resting membrane potential toward the Nernst potential for K+; but in contrast to when the neuron is at rest, the gK/gNa ratio is not constant but is changing continuously. One additional difference is that because the membrane potential is changing, a capacitative current also exists, and this must also be taken into account to describe the membrane potential quantitatively during an action potential (as a corollary, note that the chord conductance equation is valid only when the membrane potential is constant because then there is no capacitative current). These changes cause the membrane potential to move toward the equilibrium potential for Na+. Because of the nature of the underlying Na+ channels (described later), the rise in gNa with depolarization is transient. In cases in which the repolarization involves a rise in gK, the membrane potential hyperpolarizes temporarily beyond its normal rest value (if gK does not change, the drop in gNa causes the membrane simply to return to its resting potential). This afterhyperpolarization occurs because gK remains elevated for a period of time after the action potential. As gK returns to its baseline level, the membrane potential returns to its rest value. These changes in conductance can be explained by the properties of Na+ and K+ ion channels, which are described next. Ion Channels and Gates Early studies of the mechanism underlying action potentials indicated that ion currents pass through separate Na+ and K+ channels, each with distinct characteristics, in the cell membrane. The amino acid sequences of the channel proteins and many of the functional and structural characteristics of the channels are now known in detail. The subunit has four repeated motifs each of six transmembrane helices that surround a central ion pore. Most voltage-gated K+ channels are composed of four separate subunits, each consisting of a polypeptide with six membrane-spanning segments, similar to the motifs that make up the subunit of the Na+ channel. An important characteristic of some channels, such as those that underlie the action potential, is that they are gated by the membrane voltage. These voltage-gated channels sense the potential across the membrane and then act to either open or close the pore according to the membrane potential. The gates are formed by groups of charged amino acid residues, and the voltage dependence of the Na+ and K+ channel gates can account for the complex changes in gNa and gK that occur during an action potential. B, 1 and 2 subunits flanking an subunit are shown with their transmembrane helices.