Medical Physiology, 3rd Edition

Active Regulation of Body Temperature by the Central Nervous System

Dedicated neural circuits in the CNS actively regulate body temperature. The central thermoregulatory network includes the following:

1. Afferent neurons that are the skin and visceral thermoreceptors

2. Thermal afferent pathways within the CNS

3. The thermoregulatory integration center in the preoptic anterior hypothalamus imageN59-4

4. Efferent pathways providing autonomic and somatomotor inputs to effectors

5. Thermal effectors that control heat transfer between the body and environment, and that control heat production by the body

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Preoptic Area and Anterior Hypothalamus

Contributed by Shaun Morrison, edited by Alisha Bouzaher

Inconsistent findings have led to debate among anatomists regarding the exact anatomical location of the preoptic area. Overall, the literature tends to suggest that the preoptic area is located in the anterior hypothalamus rather than anterior to the hypothalamus. A neutral view would be that the preoptic area lies immediately anterior to the optic chiasm.

This central thermoregulatory network is an active system that is superimposed on, and regulates, the passive poikilothermic system described on pages 1194–1198, in which the circulatory system and the laws of physics determine heat transfer between the body core and the environment.

Thermoreceptors in the skin and temperature-sensitive neurons in the hypothalamus respond to changes in their local temperature

Skin-temperature receptors, although ideal for sensing changes in environmental temperature, do not serve well during exercise because internal temperatures would rise to intolerably high levels before the skin temperature rose to allow them to detect this excess heat. Temperature-sensitive neurons in the brain, in contrast, although ideal for detecting changes in Tcore, are inadequate for sensing changes in the environmental temperature. Because of the thermal inertia of the body's mass, the lag time in using sensors of Tcore to detect externally induced changes in temperature would be too great to achieve effective regulation. Not surprisingly, then, the body is endowed with temperature sensing neurons in both the periphery and in the CNS. The integration of their signals within the CNS central thermoregulatory network permits a rapid and effective balance of heat loss and heat production that normally maintains Tcore within relatively narrow limits.

Skin Thermoreceptors

The body has specialized sensory neurons (thermoreceptors) that provide the CNS with information about the thermal condition of the skin. The thermosensitive elements of thermoreceptors are free nerve endings that are distributed over the entire skin surface and contain cation channels that alter their conductance as the environmental temperature rises (TRPV1 to TRPV4 channels; see p. 386) or falls (TRPM8 channels; see p. 386). Peripheral thermoreceptors fall into two categories—warmth receptors and cold receptors (Fig. 59-3). Each type is anatomically distinct and each innervates definable warmth- or cold-sensitive spots on the skin surface (see p. 386). Thermal discrimination varies over the surface of the body; it is coarsest on the body trunk and limbs, and finest on the face, lips, and fingers. Warmth receptors increase their steady firing rate as local skin temperature increases from ~32°C up to ~45°C (see Fig. 59-3). Cold receptors, which are the predominant type of skin thermoreceptor, characteristically increase their steady firing rate as local temperature decreases from ~40°C down to 26°C. Both receptors respond to step changes in temperature with an initial, temporary change (i.e., phasic or dynamic response), followed by a stable change in the sensor's firing rate (i.e., tonic or static response; see Fig. 15-28).

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FIGURE 59-3 Response of warmth and cold receptors to temperature change.

Because of their location, skin thermoreceptors primarily provide the hypothalamic thermoregulatory center with information about ambient temperature (Fig. 59-4), although their discharge rate also depends on the temperature of the blood perfusing the skin. As discussed on page 1200, skin thermoreceptors provide an anticipatory (feed-forward) signal, relaying information on changes in ambient temperature to the central thermoregulatory network, which drives reflex thermoregulation and thereby minimizes changes in Tcore. Information from skin thermoreceptors also travels through thalamic pathways to the cerebral cortex, thus providing the basis for conscious perception of the thermal environment. Therefore, we can localize thermal stimuli on the skin surface and have an appreciation of thermal comfort. This thalamocortical pathway may be responsible for triggering behavioral thermoregulation; for example, moving from the sun to the shade when we feel too hot (see p. 1224).

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FIGURE 59-4 Overall model of temperature regulation. C, cold receptor; W, warmth receptor.

Hypothalamic Temperature-Sensitive Neurons

The principal mechanism through which the central thermoregulatory network senses changes in Tcore is via temperature-sensitive neurons in the preoptic area of the anterior hypothalamus (see Fig. 47-3), imageN59-4 where ~10% of neurons are warmth sensitive (i.e., their discharge rate increases as local temperature rises). As in skin thermoreceptors, TRPV channels endow preoptic temperature-sensitive neurons with the ability to change their discharge rate as the temperature of their local environment changes. The temperature-sensitive neurons in the preoptic area play the major role in detecting changes in deep body temperature (see Fig. 59-4). Sensing of Tcore by preoptic temperature-sensitive neurons is especially important during exercise, intake of hot fluids, or the resolution of a fever. In these conditions, heat storage increases more rapidly than heat dissipation, a situation calling for a prompt increase in heat loss to avoid a significant increase in Tcore.

The CNS thermoregulatory network integrates thermal information and directs changes in efferent activity to modify rates of heat transfer and production

Warming or cooling of the skin—via skin thermoreceptors—alters both the tonic and the phasic components of afferent neuronal activity (see Fig. 59-4). The cell bodies of the warmth receptors and cold receptors are in the dorsal root ganglia and their axons synapse in the dorsal horn on second-order thermal sensory neurons, which project rostrally to two integration sites: (1) In the thalamus, they synapse on third-order neurons that provide somatosensory information to the cerebral cortex for conscious perception of skin-temperature changes and their localization to particular areas of the skin. (2) In the parabrachial nucleus of the pons, they synapse on third-order neurons that provide autonomic sensory information to the preoptic hypothalamus. Here, fourth-order neurons integrate cutaneous-temperature information with Tcoreinformation encoded in the discharge rates of the preoptic warmth-sensitive neurons.

Cutaneous warmth thermoreceptors—upon exposure to a warm environment—increase the activity of warmth sensory neurons in the thermal afferent pathway and thereby stimulate the discharge of the preoptic warmth-sensitive neurons. Conversely, cutaneous cold sensory signals inhibit the discharge of the preoptic warmth-sensitive neurons. Thus, the input from the warmth and cold sensory neurons, which report Tskin, shifts the discharge rate of the preoptic warmth-sensitive neurons away from the level otherwise determined by Tcore. imageN59-7

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Effect of Skin Temperature on the Response to Hypothalamic Drive

Contributed by John Stitt

In the experiments on rabbits (see eFigure 59-4), the investigators implanted water-perfused thermodes to control the temperature of the preoptic area/anterior hypothalamus (POAH), shown on the x-axis. Metabolic rate, shown on the y-axis, was calculated from image, and the animals were placed in a temperature-controlled chamber. Mean skin temperature (three different symbols) was also measured. eFigure 59-4 demonstrates how changes in ambient (skin) temperatures (Tskin) affects the POAH gain (the slope of a fitted line). This gain was determined by plotting the metabolic responses to brief step changes in the POAH temperature away from its normal level of 39.2°C (vertical dashed line in the figure). The POAH gain is flattest at the warmest skin temperature (Tskin = 34.3°C) and it is steepest at the coldest skin temperature (Tskin = 30.5°C). It can also be seen that when hypothalamic temperature is left undisturbed at its normal level of 39.2°C, the metabolic rate is at resting level (3.0 watt/kg) when Tskin is 34.3°C (i.e., with the subject in a relatively warm room). On the other hand, when Tskin is 30.5°C (i.e., with the subject in a cooler room), the metabolic rate rises to >6.0 watt/kg, due to the shivering thermogenesis induced by the low skin temperatures.

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EFIGURE 59-4 Thermoeffector responses. These results are from experiments in rabbits imageN59-7 in which the investigators implanted water-perfused thermodes to control the temperature of the preoptic/anterior hypothalamic area imageN59-4 (x-axis) at three different skin temperatures (Tskin).

The preoptic warmth-sensitive neurons provide a variable level of inhibition to descending efferent pathways that otherwise would excite two types of spinal neurons: (1) sympathetic preganglionic neurons that promote cutaneous vasoconstriction (limiting heat transfer within and from the body) and brown adipose tissue thermogenesis, and (2) α motor neurons that cause shivering in skeletal muscle (generating heat). For example, a fall in Tskin would disinhibit the activity of the efferent pathways to the cold-defense effectors and thereby tend to increase Tcore.

The efferent pathways from the preoptic area are different for each of the thermal effectors, consistent with the variety of thermal effectors and their interchangeable roles in other functions (e.g., muscles that shiver also produce net movement). Moreover, nonthermal inputs have unique effects on different efferent pathways. For instance, dehydration increases plasma osmolality, which stimulates CNS osmoreceptors (see Fig. 40-8) that can strongly inhibit the efferent pathway for sweating, so that the body conserves free water at the expense of cooling. Similarly, hypoxia (e.g., ascent to high altitude, late stages of emphysema) stimulates the arterial chemoreceptor reflex, which strongly inhibits the efferent pathways for thermogenesis in brown adipose tissue and skeletal muscle, tissues with high rates of O2consumption.

The skin receptors provide information mainly about environmental temperature, which affects the body's heat-loss rate and could ultimately cause Tcore to change if the body did not initiate the appropriate thermoregulatory responses to skin cooling or warming. Thus, reflex responses driven by changes in the average skin temperature may be thought of as anticipatory or feed-forward, inasmuch as these responses do not bring skin temperature to a regulated level because of the skin's exposure to the ambient environment. However, these anticipatory reflexes are essential elements for an effective thermoregulatory system because the body's thermal inertia is too great to rely on central receptors alone. For example, low skin temperature, which is lowered still further by cutaneous vasoconstriction in the cold, ensures a rapid and continuous cold signal that maintains a drive for cutaneous vasoconstriction, brown adipose thermogenesis, and shivering. Conversely, thermoregulatory responses to changes in core (i.e., hypothalamic) temperature exhibit negative feedback.imageN1-1 For example, during exercise, the increase in Tcore directly increases the discharge of the preoptic warmth-sensitive neurons; this increased discharge causes them to decrease the intensity of heat retention and heat generation, and thereby promotes a return of Tcore to the regulated level.

In conclusion, Tcore depends upon the balance between the active thermoregulatory system (i.e., the network from sensors to effectors) and the passive thermal elements (i.e., the overall metabolic heat load and the physical exchange of heat between the body and the environment). Presumably, human evolution of warmth-sensitive preoptic neurons has conferred the particular membrane properties and sensitivities to peripheral inputs that produce a Tcore of ~37°C, which is optimal for cellular chemical machinery.

Thermal effectors include behavior, cutaneous circulation, sweat glands, and skeletal muscles responsible for shivering

Humans have become quite adept at devising behavioral adaptations that permit survival in a wide range of environmental temperatures. As a thermal effector, behavior (from simply moving out of the hot sun, to building a fire, to designing a suit for space walks) is usually the central thermoregulatory system's first response to a change in environmental temperature, as sensed by skin thermoreceptors (see p. 1224). Behavior is also an essential anticipatory mechanism (e.g., putting on heavy clothing before going outside in a snowstorm) that is so habitual we do not even recognize it as part of our thermoregulatory repertoire.

The thermal effectors that modulate heat transfer are under the control of the sympathetic nervous system. Adjusting the smooth-muscle tone of cutaneous arterioles and of arteriovenous anastomoses (shunts) controls cutaneous blood flow (see pp. 570–571)—and therefore heat flow—from the core to the skin surface, the primary site of heat dissipation to the environment. Over most of the skin, the sympathetic nervous system controls blood flow. When it is necessary to increase heat dissipation, active vasodilation can increase cutaneous blood flow up to 10-fold above the resting level. Conversely, when it is necessary to conserve heat in a cold environment, cutaneous blood flow falls, partly by inhibition of active vasodilation and also by increased sympathetically mediated cutaneous vasoconstriction. As vasoconstriction increases, the reduced flow of warm blood through the cutaneous circulation causes skin temperature to fall even closer to ambient temperature, which results in further activation of the skin cold thermoreceptors. Even with maximal vasoconstriction in effect, heat losses to a very cold environment do not fall to zero because of a small thermal conductance of the body's tissues to the skin surface and a temperature difference between the skin and the environment.

Piloerection reduces the rate of heat loss by retaining a layer of warm air next to the skin and occurs by activation of the sympathetic input to smooth muscles in the hair follicles. Although the thermoregulatory benefit of piloerection waned as humans lost their thick fur, the central thermoregulatory circuits and sympathetic innervation of hair follicles maintain this vestigial reflex response to cold.

With a moderate heat load, the autonomic response primarily increases heat transfer from core to skin by elevating cutaneous blood flow. However, when the heat load is sufficiently great, the preoptic warmth-sensitive neurons also drive activation of the eccrine sweat glands (see pp. 1215–1216), which secrete sweat onto the skin surface. Sweating elevates the partial pressure of water vapor at the skin surface and promotes increased evaporation, which takes heat from the skin. The innervation of the secretory segment of the sweat gland is sympathetic, but it is unusual in that acetylcholine is the neurotransmitter (see p. 342). Because sweating can lead to the loss of large amounts of water (>1 L/hr) and electrolytes, adequate hydration in hot environments is essential to prevent circulatory collapse and fatal hyperthermia (see Box 59-1).

As cold stress increases, cutaneous vasoconstriction is supplemented with heat production—thermogenesis—initially in brown adipose tissue and subsequently through shivering. The sympathetic nervous system heavily innervates brown adipocytes (see pp. 1164–1166), releasing norepinephrine onto β3-adrenergic receptors. The subsequent oxidation of fatty acids leads to the production not of ATP but of heat by virtue of the uncoupling protein UCP1 (see pp. 1013 and 1166) and the abundant mitochondria. This thermogenesis depends on the size of the brown adipose tissue depots and the sympathetic input. Substantial brown adipose tissue depots have long been recognized in small rodents, hibernating animals, and human infants. However, the demonstration of brown adipose tissue in adult humans—and, in particular, its relative absence in the obese—has stimulated research into its potential role in metabolic homeostasis.

Shivering begins with an often-unrecognized increase in basal skeletal muscle tone, followed by the familiar involuntary, clonic, rhythmic contractions and relaxations of skeletal muscles. Shivering can triple or quadruple the metabolic rate for brief intervals and double the metabolic rate for extended periods (hours) before fatigue occurs. The same α motor neurons that innervate skeletal muscle for normal body movement and posture also drive shivering, but the mechanism underlying the rhythmic activations of α motor neurons during shivering is unknown.