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Thermoregulation

The hypothalamus is the primary locus for coordinating thermoregulatory information and integrating thermoregulatory responses. It continually monitors local brain temperature through temperature sensitive neurons and by utilizing thermoreceptors in the skin and spinal cord, and then orchestrates a series of responses to maintain normal, core body temperature by utilizing the autonomic nervous system, altering behavior, and through neuroendocrine responses. Thyroid hormone is a necessary component for heat regulation since in its absence (myxedema), hypothermia commonly develops.

Although thermosensitive neurons can be found throughout the hypothalamus (283) the most important locus is the preoptic region including neurons in medial and lateral portions of the preoptic nucleus, anterior hypothalamus including the perifornical region, and nearby regions of the septum (Fig. 35). Preoptic cooling increases heat production by inducing shivering, or by nonshivering thermogenesis mediated by sympathetic activation uncoupling proteins-1 (UCP-1) in brown adipose tissue and by increasing intermediary metabolism in muscle and other parenchymal organs. In addition, cooling induces heat retention responses by cutaneous vasoconstriction and redirecting blood flow from cutaneous to deep vascular beds, results in to behavioral responses (seek warmer environment, put on more cloths, increase food intake), and in some animal species can increase thyroid thermogenesis by activating the hypothalamic-pituitary-thyroid axis (284). Conversely, preoptic warming reduces heat production and increases heat loss responses through vasoconstriction, sweating, increased respiration (panting), inhibition of UCP-1 in brown adipose tissue, and specific behavioral responses (283).

Two types of thermosensitive neurons can be found in the preoptic region, warm sensitive neurons that increase their firing rate when preoptic temperature rises and cold sensitive neurons that increase their firing when preoptic temperature falls (283). However, the warm sensitive neurons predominate both in cell number and in importance of the regulatory responses for both heat loss and heat production mechanisms. Thus, lesions involving the preoptic region per se are commonly characterized by abnormalities in heat dissipation and lead to hyperthermia and elevated temperature in brown adipose tissue (285). Surprisingly, the neurotransmitter/peptide mediators and pathways mediating thermoregulatory responses are not precisely known. When injected directly into the preoptic area, however, a number of different substances can induce hypothermic or hyperthermic responses (Table 9). Since thermoregulation involves the coordination of multiple responses that can differ between animal species (i.e. panting in the dog, increased salivation in the rat which can be applied to the fur to enhance evaporative heat loss, sweating in man), it is logical that several different pathways are employed at the same time (Fig. 36). Evidence suggests that efferent pathways governing shivering involve ipsilateral and crossed fibers (286) that traverse the median forebrain bundle to terminate in the posterior hypothalamus, using GABA as a neurotranasmitter (287). The pathway continues caudally through the midbrain, dorsolateral to the red nucleus, and interacts with reticulospinal neurons. It then proceeds through the reticulospinal tract, to innervate a-motor neurons in the ventral horn of the spinal cord. Regulation of heat production in brown adipose tissuse also proceeds from preoptic neurons through the medial forebrain bundle to hypothalamic nuclear groups involved in autonomic regulation, particularly the PVN, but also the DMN and VMN (287). The PVN has direct efferent projections to preganglionic neurons in the intermediolateral column of the spinal cord which give rise to the sympathetic innervation of brown adipose tissue (288). Regulation of cutaneous blood flow also proceeds from thermosensitive neurons in the preoptic region through axons descending in the medial forebrain bundle, but likely relayed to neurons in ventrolateral portions of the midbrain periaqueductal gray (PAG) before proceeding to sympathetic preganglionic neurons in the spinal cord. PAG neurons show strong c-fos induction following unilateral preoptic region heating (289) and induce cutaneous vasodilatation when stimulated (290). Preoptic warming also inhibits vasoconstrictor neurons in the medullary raphe (raphe magnus and pallidus) (291) that have projections directly to preganglionic sympathetic neurons in the intermediolateral column of the spinal cord (292). Pathways mediating behavioral changes associated with thermoregulation are unknown.

Under normal circumstances, there is a diurnal variation of body temperature, highest in late afternoon and early evening and lowest in morning upon arising. The hypothalamic suprachiasmatic nucleus controls this rhythm, and would appear to do so through direct projections to the dorsal portion of the subparaventricular zone, a region just ventral to the PVN. Thus, bilateral focal lesions in the dorsal subparaventricular zone disrupts the circadian variation of body temperature, whereas bilateral lesions of the PVN, itself, is without effect (293). Since the subparaventricular zone has prominent projections to the preoptic area (294), it is presumed that the suprachiasmatic nucleus relays information to thermosensitive neurons in the preoptic region by a multisynaptic pathway involving the subparaventricular zone (293). However, the precise targets in the preoptic region from subparaventricular zone neurons have not yet been identified.

The set point for temperature regulation is also sensitive to circulating levels of sex steroids, with core body temperature falling just prior to the midcycle surge in women and rising during the luteal phase (295,296). Estrogen, itself, would appear to be responsible for the fall in temperature in the late follicular phase by increasing the firing rate of preoptic warm sensitive neurons (297), whereas progesterone increases temperature in the luteal phase by decreasing the firing rate of preoptic warm sensitive neurons and, perhaps, increasing the firing rate of cold sensitive neurons (298). Both steroids readily pass the blood-brain barrier and thereby are presumed to act directly on thermosensitive neurons in the preoptic nucleus (299). Not unexpectedly, therefore, the lack of estrogen in the postmenopausal period gives rise to altered thermoregulatory responses (hot flashes) that occurs in over 80% of this group, and can be readily reversed by the administration of estrogen. It has been proposed that in the absence of estrogen, the sensitivity of warm sensitive neurons to even small increases in body temperatur is increased (300). Along these lines, it is of interest that in one study, the frequency of hot flashes was greatest during the afternoon and evening when body temperature normally rises under the influence of the suprachiasmatic nucleus circadian pacemaker (301). The therapeutic response of some women with postmenopausal hot flashes to clonidine (302), an a2-adrenergic agonist, would indicate that catecholamines also participate in the heat loss responses.

Under certain circumstances, there is an adaptive advantage to elevate body temperature beyond the normal physiologic range that is highly conserved among animal species. Such is the situation during infection, when fever is a necessary response to facilitate recovery by improving the efficiency of immune cells and impairing replication of microorganisms (302,304). This homeostatic response is achieved by altering the thermoregulatory set point in medial preoptic neurons, but through a different mechanism than described above. Under these circumstances, it is proposed that circulating endotoxin and proinflammatory cytokines interact with specific receptors on vascular endothelial cells and/or subendothelial microglia in the OVLT, resulting in activation of cyclooxygenase and production of PGE2 (305,306). PGE2 released into the surrounding tissue, activates neighboring neurons in the ventromedial preoptic nucleus (VMPO) that inhibit the firing rate of warm-sensitive neurons (306-308), perhaps by projecting to warm sensitive neurons in the hypothalamic anterior periventricular nucleus using GABA as its neurotransmitter (309). Signals are then relayed to autonomic regulatory neurons in the parvocellular subdivision of the paraventricular nucleus which through projections to the brainstem or directly to the spinal cord (310), contribute to autonomic mechanisms involved in the generation of fever.

Blatteis et al (311) suggest an alternative mechanism for fever induction in which PGE2 release into the preoptic region is mediated by norepinephrine, arising in noradrenergic (A2 cell group) neurons in the ventrolateral medulla. This is based on the observation that in guinea pigs, the intra-preoptic microdialysis of a2-receptor antagonists potentiate the febrile response to LPS (312). The mechanism proposed involves activation of hepatic branches of the vagus nerve by mediators (possibly PGE2) produced by liver Kupffer cells following the systemic administration of LPS. Vagal afferent signals are then carried to the nucleus tractus solitarius in the brainstem, and after projecting to noradrenergic neurons in the ventrolateral medulla (A2), ascend in the ventral noradrenergic pathway and medial forebrain bundle to terminate in the preoptic region. Ek et al (313) have also demonstrated in the rat that the intravenous administration of interleukin-1 is capable of activating vagal sensory neurons in the nodose ganglion and can be attenuated by inhibitors of prostaglandin synthesis.

In addition to inducing fever, endotoxin simultaneously activates an endogenous, counterregulatory, antipyretic response, to prevent body temperature from rising too severely. This is largely achieved by stimulating the hypothalamic-pituitary-adrenal axis (see above) that exerts a dampening effect on the cytokine response, but more specifically by the direct antipyretic actions of a-MSH within the CNS (314). The latter situation occurs only in association with cytokine activation, as a-MSH has no effect on temperature regulation in the absence of fever (314,315). Alpha-MSH arises from the neuronal population in the hypothalamic arcuate nucleus (200), and while it is unknown precisely where a-MSH exerts its actions, the preoptic region including the VMPO is heavily innervated by axon terminals containing a-MSH, suggesting a direct effect on thermosensitive neurons (316). Alpha-MSH is also contained in axons that heavily innervate autonomic regulatory neurons in the parvocellular PVN and the hypothalamic DMN, providing an alternative route for regulatory control over vasomotor responses and heat generation.

Circadian Rhythmicity

Circadian rhythms are genetically detemined, cyclic modifications of specific physiological functions and behaviors, generated through endogenous mechanisms in nearly all living organisms (317,318). The basic organization of the circadian timing system includes an endogenous rhythm generator or pacemaker (also called endogenous clock or zeitgeber), a light-dark receptive system to entrain the endogenous clock to the time of day mediated by retinal photoreceptors (mainly cones) and visual pathways (retinohypothalamic pathway), and an efferent neural system coupling the pacemaker activity with effector systems in the brain that give rise to specific physiological functions and behaviors (317,318). The master clock in mammals is the hypothalamic suprachiasmatic nucleus (SCN), a small, paired nucleus embedded in the dorsal surface of the optic chiasm. Contained within this nucleus are multiple, small neurons that produce autonomous, self-sustaining oscillations synchronously firing to generate a common rhythmic output, perhaps mediated by the local releasse of GABA (319,320). If the SCN is lesioned bilaterally, "free-running circadian rythmicity" is produced, characterized by disruption of the sleep-wake cycle and loss of predictable daily oscillations in feeding, drinking, melatonin secretion and the secretion of some anterior pituitary hormones (321,322). Normal rhythmicity can be restored if the SCN is transplanted back into the lesioned animals (323). Molecular mechanisms for the endogenous pacemaker activity of SCN neurons has been attributed to clock genes that currently include period (per), Clock, Cryptochrome (Cry), and Bmal (317,318).

Two different subdivisions of the SCN have been described, a ventrolateral and dorsomedial subdivision (317). The ventrolateral subdivision or "core", receives the major input to the SCN, including a massive projection of pituitary adenylyl cyclase-activating peptide (PACAP)- and nitric oxide (NO)-containing axons from the retinohypothalamic pathway, GABA- and NPY-containing axonal projections from the intergeniculate leaflet of the thalamus, and serotonin neurons from the midbrain raphe (317,318,324). These inputs have an important role in modulating the endogenous rhythms of the individual SCN pacemaker cells during the day or night. The dorsomedial subdivision or "shell", primarily serves as the field for afferent information coming from the limbic system (hippocampus, bed nucleus of the stria temrinalis, septum) and the hypothalamus, itself (324). Both subdivisions are composed of a heterogeneous populaltion of immunocytochemically distinct neurons. The ventrolateral SCN contains neurons that express vasoactive intestinal polypeptide, gastric-releasing peptide and GABA (317). Dorsomedial neurons express argenine vasopressin, angiotensin II, somatostatin and GABA (317). However, while ventrolateral susbdivision neurons receive light information, most of these neurons do not produce rhythmic patterns (325). In contrast, the dorsomedial subdivision does contain rhythmic neurons, particularly apparent for argenine vasopressin-producing neurons in which the peptide peaks during the day and is lowest at night (326). This rhythmic pattern is partly secondary to the presence of binding sites for clock genes in the argenine vasospressin promoter region (327), but also dependent upon synaptic transmission from other SCN neurons (328), perhaps those in the ventrolateral subdivision through intra-SCN connections (329).

The SCN has massive projections to three major regions of the neuraxis. The most important is to the subparaventricular zone of the hypothalamic PVN and the anterior periventricular hypothalamus. These projections are believed to be involved in the regulation of the sleep-wake cycle, thermoregulation and in the the secretion of melatonin from the pineal gland (330), the latter by way of a multisynaptic pathway involving autonomic centers in the hypothalamic PVN, preganglionic sympathetic neurons in the intermediolateral cell column of the spinal cord, and postganglionic neurons in the superior cervical ganglion (331,332). Melatonin is of importance as a humoral signal that feeds back on the SCN through melatonin receptors expressed in this nucleus, modulating activity of the circadian clock by communicating information concerning the length of the dark cycle (317,318). This signal may also contribute to the regulation of sleep and immune function, and is of particular importance for reproductive function in animals with seasonal breeding patterns (333,334). The second major projection is to the medial and lateral tuberal hypothalamus, including the dorsomedial nucleus, ventromedial nucleus, arcuate nucleus and lateral hypothalamic area. This projection may be involved in the regulation of neuroendocrine tuberoinfundibular and neurohypophysial secretion through secondary projections to the medial preoptic area, arcuate nucleus, PVN and supraoptic nucleus (324). The final pathway is to nuclei of the reticular formation, both in the midline thalamus and midbrain central gray (324), and may contribute to the effects of the SCN on the sleep-wake cycle. Figure 37 schematically deptics an integrated view of the mammalian circadian timing system and the main physiological functions and behaviors it controls.