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Functional Anatomy of Hypothalamic Homeostatic Systems Regulation of Hypophysiotropic Neurons The secretion of hypothalamic releasing and inhibitory hormones from
axon terminals of tuberoinfundibular neurons into the portal capillary
system is dependent upon several layers of control that can be exerted
directly on the perikarya and/or processes of these neurons. For one,
neurons of the tuberoinfundibular system can be modulated by substances
circulating in the bloodstream that either pass the blood-brain barrier
because they are fat soluble steroids or small molecules, or access
tuberoinfundibular neurons via the cerebrospinal fluid due to the
periventricular location of many tuberoinfundibular neurons and poor
development of tight junctions between ependymal cells in these regions
(43). Feedback effects of thyroid hormone, for example, occur directly
on TRH-producing neurons within the paraventricular nucleus as
demonstrated by the ability of a microcrystalline implant of T3 adjacent
to the paraventricular nucleus to prevent the hypothyroid-induced
increase in TRH biosynthesis on that side but not the opposite side
(159,160). In addition, tuberoinfundibular neurons receive numerous
axosomatic and/or axodendritic contacts from local interneurons and/or
other regions in the brain that contain a variety of chemical messengers
that contribute to intercommunication between specific neuronal groups
or are important in establishing the set point at which the
hypophysiotropic substances are secreted in response to hormonal
feedback signals. To demonstrate how the CNS can exert regulatory
control over hypophysiotropic neurons, examples of modulation of GH
secretion and regulation of the hypothalamic-pituitary-adrenal (HPA) and
hypothalamic-pituitary-thyroid (HPT) axis will be given below. A well-studied example of local afferent influences on the activity of tuberoinfundibular neurons is demonstrated by the hypothalamic regulatory system involved in the control of GH secretion. The pattern of GH secretion is episodic, showing a regular periodicity of one pulse every 2 to 4 hours and low or undetectable trough values (161). This rhythm is the result of the control by two separate components of the tuberoinfundibular system, including GHRH-producing neurons (stimulatory) in the basolateral portion of the arcuate nucleus and somatostatin-producing neurons (inhibitory) in the periventricular nucleus, each secreting into the portal capillary plexus. To coordinate this rhythmic secretion, reciprocal axonal connections between these two populations of neurons may be necessary (Fig. 28). In this manner, somatostatin neurons receive direct, stimulatory inputs from GHRH neurons while GHRH neurons receive direct, inhibitory inputs from somatostatin-containing neurons, which in addition to hormonal feedback signals from the periphery (GH and IGF-1), contribute to a finely tuned regulatory system (162). GH secretion can also be modulated by a number of neurotransmitters, peptides and circulating hormones as a result of their action on somatostatin and/or GHRH producing tuberoinfundibular neurons (163). The rise of GH during sleep, for example, is probably mediated by cholinergic pathways suppressing somatostatin secretion (164). Stress and sepsis can also be associated with a rise in GH levels mediated by catecholamines by increasing GHRH (163). The precise origin of the neurons giving rise to these neuromodulators, however, is not known.
A new and potentially exciting chapter in the understanding of the
physiology of GH secretion has been the discovery of ghrelin, the most
potent (on a molar basis) GH secretagogue known in man (165). Ghrelin
circulates in the bloodstream, secreted primarily from the stomach, but
is also produced by neurons in the hypothalamic arcuate nucleus (166).
Although the anterior pituitary somatotrophs contain receptors for
ghrelin, suggesting a direct action, it is more likely that ghrelin
exerts its main effects in the hypothalamus by triggering GHRH secretion
(167). Ghrelin levels fall in response to rising levels of GH, providing
evidence for a gastro-hypophysial feedback loop (168). Afferent input to tuberoinfundibular neurons from distant loci in the brain is yet another important regulatory mechanism over hypophysiotrophic function and is one way that tuberoinfundibular neurons are integrated with other functions of the brain. The parvocellular subdivision of the paraventricular nucleus receives direct, dense, afferent input from autonomic centers in the lower brain stem including the nucleus of the tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMNv) and several catecholamine groups in the dorsal and ventral lateral medulla, carrying visceral sensory information primarily from the abdomen and thorax through the vagus and glossopharyngeal nerves (169). At least part of this projection is noradrenergic but other substances such as neuropeptide Y (170), activin (171), and GLP-1 (172) are also carried in these fibers, some coexisting in catecholaminergic neurons. After traversing through the medial forebrain bundle in the lateral hypothalamus, axons containing catecholamines have been observed to make numerous synaptic contacts with CRH-producing neurons in the paraventricular nucleus (173,174) and to induce the secretion of CRH primarily via a1 adrenergic receptors (175). In this manner, sensory information from the periphery (e.g. heart rate, blood pressure as during hemorrhagic shock) has the potential to alter the set point for the secretion of hypophysiotropic CRH using norepinephrine as the central mediator, and thereby increase circulating levels of glucocorticoids. In a similar fashion, increased secretion of glucocorticoids in response to infection or inflammation is due to the activation of catecholaminergic neurons of the NTS (A2 noradrenergiac, C2 adrenergic) and rostral ventrolateral medulla but initiated by endotoxin and proinflamnmatory cytokines such as interleukin-1 (IL-1) (176). Under these circumstances, the set point for feedback inhibition of hypophysiotropic CRH secretion is altered to allow the powerful immunosuppressant action of glucocorticoids to limit the severity of the inflammatory response (177). If the ascending catecholamine pathway to the PVN is transected, the ability of IL-1 to increase CRH mRNA in PVN neurons is reduced (178). It is proposed that IL-1 exerts its effect on endothelial cells and/or perivascular microglia at the blood-brain interface, resulting in activation of cyclooxygenase-2 (the rate limiting enzyme for the formation of prostaglandins), the release of of prostaglandin E2 (PGE2) into the surrounding tissue, and ultimately activation of catecholaminergic neurons through prostaglandin receptors (179). This hypothesis is supported by the demonstration that focal injection of PGE2 into the medulla reproduces the activating effects of IL-1 on CRH neurons in the PVN (180). Alternatively, cytokines may exert their effects on vascular cells at the blood-brain-barrier directly within the PVN, itself, or after penetrating the blood-brain barrier at circumventricular organs such as the OVLT and then transmitting the information through neural pathways that interconnect these structures with the PVN (179, see Thermoregulation below). Neurogenic stress also leads to resetting of the HPA axis and similarly characterized by elevated circulating glucocorticoid levels and increased CRH gene expression in hypophysiotropic neurons (176). However, the mechanism would appear to be vastly different than that described above as indicated by persistent HPA activation under these conditions despite disruption of the ascending catecholaminergic pathways to the PVN (181). CRH neurons receive inputs from other portions of the brain such as the forebrain limbic system, and surgical ablation of hippocampal efferents to the hypothalamus (182) or lesions in the bed nucleus of the stria terminalis (183) increase the concentration of CRH mRNA in the paraventricular nucleus. Thus, while the end result to increase circulating levels of glucocorticoids is similar in all stress paradigms, depending upon the type of stress, different regions of the brain are recruited to allow resetting of the HPA axis. The circuitry described above that allows resetting of the HPA axis is illustrated in Fig. 29.
Elucidation of the mechanisms by which the hypothalamic-pituitary-thyroid (HPT) axis responds to fasting provides another excellent example of how afferent input from neurons arising outside of the PVN can influence the secretion of hypophysiotropic neurons. Similar to the feedback mechanisms controlling the adrenal axis, maintenance of normal thyroid function is dependent upon a negative feedback control system in which circulating levels of thyroid hormone (T4 and T3) influence the biosynthesis and secretion of TRH in hypophysiotropic neurons in the PVN (Fig. 30A,B) and TSH in the anterior pituitary (160). In response to fasting or infection, however, this normal homeostatic system is altered in a way that is presumably beneficial for survival. Under these circumstances, there is a fall in circulating thyroid hormone levels but a seemingly paradoxical reduction in TRH gene expression in the PVN (Fig. 30C,D), reduced secretion of TRH into the portal blood and low or inappropriately normal plasma TSH (184-187), rather than the anticipated increase in all of these parameters as seen in primary hypothyroidism. Thus, during fasting, the normal feedback mechanism described above is overridden, and a state of central hypothyroidism is transiently induced. Presumably, by reducing thyroid thermogenesis and preserving nitrogen stores, this mechanism is an important adaptive response to reduce energy expenditure until the adverse stimulus is removed (188).
The HPT axis is primarily modulated by afferent input derived from the hypothalamus, itself. At least two anatomically distinct populations of neurons in the arcuate nucleus with opposing functions, proopiomelanocortin (POMC)-producing neurons that also co-express cocaine and amphetamine-regulated transcript (CART), and NPY-producing neurons that co-express agouti related peptide (AGRP), appear to be responsible (122,189-191). Both neuronal populations express receptors for the white adipose tissue-derived circulating hormone, leptin, and project to hypophysiotropic TRH neurons in the PVN through a monosynaptic, arcuate-PVN pathway (192-194). Alpha-MSH, a translation product of POMC, and CART (originally described as a mRNA induced in the striatum following psychostimulant drug administration) both induce transcription of the TRH gene in hypophysiotropic neurons (114,189), whereas NPY and AGRP are inhibitory (190,191), NPY via direct effects on Y1 and Y5 receptors on TRH neurons (195), and AGRP by antagonizing a-MSH at melanocortin receptors (196). Thus, during fasting, when circulating levels of leptin decline, expression of the genes encoding POMC and CART are reduced simultaneously with a marked increase in the genes encoding NPY and AGRP (197,198), effectively lowering the threshold of feedback inhibition of hypophysiotropic TRH by circulating levels of thyroid hormone. This important homeostatic system, which is present in all animal species studied including man, is illustrated in Fig. 31.
Circulating thyroid hormone levels also fall in association with severe illnesses and infection (199), but use a different set of regulatory controls. This is based on the observation that both POMC and CART gene expression are increased in the arcuate nucleus (200) and circulating levels of leptin are elevated under these conditions (201). In addition, norepinephrine secretion is increased in the PVN, and ordinarily would be expected to stimulate the secretion of TRH (202). The precise anatomical pathways and mediators that override the activating effects of catecholamines, leptin and a-MSH on TRH neurons are not yet known. Modulation of Vasopressin Secretion and Osmoregulation Maintenance of the appropriate solute concentration in plasma (osmotic homeostasis) and plasma volume (volume homeostasis) is dependent upon two major factors, the perception of thirst and the ability to synthesize and secrete the antidiuretic hormone, arginine vasopressin from magnocellular neurons in the hypothalamic PVN (203). These two factors are closely interrelated such that amount of vasopressin circulating in the periphery is proportional to the plasma osmolality (204). Vasospressin induces cAMP and the translocation of specific aquaporin-2 water channels to the apical plasma membrane of tubular epithelial cells in the kidney, allowing water resorption (205). In addition, the rise in osmolality has independent behavioral effects. Thus, when plasma osmolality rises above basal levels, there is inducement to drink, shortly following the rise in vasopressin (203). While vasopressin neurons in the PVN are intrinsically osmosensitive (206), the major mechanism of osmoregulation is via afferent pathways originating from osmoreceptor cells in other neuronal populations. These include inputs from the OVLT and the median preoptic nucleus, which if damaged, simultaneously abolish vasopressin secretion and thirst responses to hyperosmolality in both experimental animals and man (96,207). The SFO is also activated by a rise in osmolality and may contribute to vasopressin release through direct afferent projections to the PVN and/or to the OVLT using angiotensin II as a mediator (94-96,208). Whereas forebrain pathways communicate information about osmolality to the PVN, brainstem projections tend to carry nonosmotic, baroregulatory information, and important for vasopressin secretion, particularly in association with hypovolemia and hypotension (96,204). This information is carried through the vagus and glossopharyngeal nerves to the NTS and ventral lateral medulla, and then to the PVN through the ascending catecholaminergic pathways (Fig. 32). Magnocellular neurons in the PVN appear to be primarily innervated by the A1 catecholamine-producing cells in the ventral lateral medulla (169).
As described for hypothalamic tuberoinfundibular neurons, the
threshold for vasopressin secretion by neurons of the magnocellular
neurosecretory system can also be modified by their afferent signals as
well as circulating factors. For example, the osmotic threshold for
vasopressin release can be altered by glucocorticoids. Dexamethasone
attenuates the vasopressin response to salt loading (209) and
hypoadrenalism is commonly associated with the syndrome of inappropriate
secretion of antidiuretic hormone (SIADH) that can be corrected by
glucocorticoid administration (210). These effects are exerted directly
on vasopressin neurons given the presence of glucocorticoid receptors in
these cells (211). Other causes for SIADH, however, such as pulmonary
disease and central nervous system disorders may be mediated through
afferent pathways to the PVN. Hormone mediators of these projections
include vasoactive intestinal polypeptide (VIP), acetylcholine,
angiotensin II, neuropeptide Y and noradrenaline, among numerous others
(212,213). The demonstration that discrete regions of the hypothalamus control food intake were based on the early studies of Hetherington and Ranson (214) in 1940 showing that localized lesions of the hypothalamus result in obesity. These observations were seemingly confirmed in man when Reeves and Plum (215) reported that a discrete lesion (hypothalamic hamartoma) involving the hypothalamic ventromedial nucleus in a 28 year old woman was associated with increased food consumption and profound obesity. In contrast, bilateral lesions of the lateral hypothalamus in animals result in anorexia and weight loss (214). Thus, the concept of a hypothalamic ventromedial nucleus satiety center and lateral hypothalamic orexigenic center that can be influenced by peripheral signals was developed, and dominated thinking about the hypothalamic control of feeding for several decades. It was not until 1994, however, when the discovery of leptin revolutionized thinking on the mechanisms governing appetite and satiety (216). Leptin serves as an important humeral signal that reflects body fat stores, and by acting on discrete regions in the hypothalamus, orchestrates the behavioral, metabolic, and neuroendocrine adaptations to nutrient availability (196-198,217-219). Thus, during nutrient abundance, leptin secretion is increased, leading to decreased appetite and increased caloric disposal, whereas nutrient insufficiency leads to decreased leptin secretion, resulting in increased appetite, energy conservation, and a shift to a neuroendocrine profile that facilitates metabolic adaptation. The site of leptin's action is the mediobasal hypothalamus (Fig. 33), but primarily the hypothalamic arcuate nucleus via specific receptors (Ob-Rb) that influence the activities of two separate groups of neurons with opposing functions. These include a-MSH-producing neurons that co-express CART, and AGRP neurons that co-express NPY (197). These neurons send monosynaptic projections to identical target regions within discrete regions of the hypothalamus where the signals are integrated and then relayed by independent pathways to regions of the brain governing feeding behavior, energy expenditure, and hypophysiotropic function (197,198, 217-219). When circulating leptin levels are suppressed, such as during fasting, expression of genes encoding proteins that promote weight loss, and energy expenditure, a-MSH and CART, are reduced simultaneously with a marked increase in the genes encoding proteins that promote weight gain and reduce energy expenditure, AGRP and NPY. Cooperation between the opposing components of the regulatory system governing appetite and satiety is underscored by the biological action of AGRP as both a competitive antagonist and inverse agonist at melanocortin receptors (MC3r and MC4r) (196,220). Thus, during fasting, the rise in AGRP cooperates in downregulation of melanocortin signalling by antagonizing the action of a-MSH concurrently with inhibition of the POMC gene. Reciprocal connections between the arcuate nucleus NPY/AGRP neurons and a-MSH/CART neurons also are present (221), suggesting an even greater complexity to this regulatory system.
It is becoming increasingly recognized that the melanocortin signaling system may be the predominant regulatory system governing appetite and satiety. Whereas animals with targeted deficiency of NPY have an essentially normal phenotype and intact responses to fasting (222), animal models with targeted deletion of the type 4 melanocortin receptor (MC4r) and in humans bearing mutations that interfere with the function of the MC4r, the POMC gene, or the processing enzymes necessary to generate a fully mature a-MSH, develop a severe obesity syndrome (223-226). Loss of tone in the melanocortin signaling system as a result of senescence of the arcuate nucleus POMC neurons may also explain the tendency for weight gain with aging (227,228). Conversely, recent studies by Wisse et al (229) and Marks et al (230) have demonstrated that cancer cachexia can be prevented in experimental animals by the administration of melanocortin receptor antagonists. Maintaining adequate tone in the melanocortin signaling system, therefore, would appear to have an especially important role in the maintenance of normal body weight. The arcuate nucleus is the main sensor of circulating levels of leptin, and by projecting to several different regions in the brain, provide the mechanism whereby leptin is capable of integrating a host of responses involved in energy homeostasis. The arcuate-PVN projection pathway has an important role in regulation of the thyroid axis (see above). Thus, hypophysiotropic TRH neurons in the medial parvocellular PVN receive direct projections from NPY/AGRP- and a-MSH/CART-producing neurons in the arcuate nucleus, altering the setpoint at which circulating thyroid hormone inhibits TRH (122,189-191). The end result during fasting is suppression of the HPT axis as a way to reduce energy expenditure. Other targets include neurons in the anterior and ventral parvocellular subdivisions of the PVN on the basis that these neurons show phosphorylation of CREB following the central administration of a-MSH (231). Both subdivisions receive a high density of axons containing a-MSH and AGRP derived from the arcuate nucleus (232,233). Thus, these regions may be involved in some of the other actions of leptin including the regulation of feeding and energy disposal. This concept is supported by the observation that focal injections of a-MSH or a-MSH agonists directly into the PVN reduces feeding and can fully replicate the reduced feeding responses following icv administration (234). Conversely, a-MSH antagonists injected into the PVN have a potent effect to increase feeding (235). Since anterior parvocellular PVN neurons project to the limbic system (lateral septum and amygala) (236,237), it is possible that this part of the PVN is involved in the behavioral manifestations of feeding. The ventral parvocellular subdivision is involved in the regulation of the autonomic nervous system through descending projections to brainstem and spinal cord targets (115, 237,238). This region, therefore, may be involved in the regulation of energy disposal by controlling heat loss from brown adipose tissue through effects on uncoupling protein-1 (UCP-1) (239) and by affecting lipolysis and proteolysis in white fat and muscle, respectively (240). In addition to the PVN, leptin-responsive neurons in the arcuate nucleus synapse on two separate populations of neurons in the lateral hypothalamus that produce melanin-concentrating hormone (MCH) and orexin (241). These neurons project to multiple regions of the brain including the cerebral cortex, midbrain and pons (242). MCH acts as an endogenous stimulator of food intake and its mRNA is increased during fasting (243,244) whereas orexin promots arousal responses (245) that would have an essential role in permitting food seeking behavior during periods of nutrient deficiency. Leptin-responsive, CART-producing neurons in the arcuate nucleus also project directly to the intermediolateral cell column of the spinal cord (246), indicating their importance in autonomic control. Leptin receptors are also expressed by other hypothalamic nuclear groups including the caudal part of the hypothalamic dorsomedial nucleus (DMN) and the dorsomedial division of the ventromedial nucleus (VMN) (247). The DMN has extensive projections to the PVN, particularly portions involved in autonomic control, as well as direct brainstem projections to the dorsomotor complex of the vagus (248). In addition, the DMN receives extensive projections from the arcuate nucleus, including projections from NPY/AGRP- and a-MSH/CART-leptin-responsive neurons (193,194). As lesions of the DMN produce hypophagia and reduce linear growth, this nucleus has an important role in the homeostatic control of feeding behavior (249). The DMN may also mediate the anorexic effect of cholecystokinin-8 (CCK-8) (250), through projections from CCK-8-producing neurons in the superior lateral subdivision of the parabrachial nucleus in the pons (251). The VMN has been long implicated in the regulation of feeding behavior as lesions of the VMN produce hyperphagia (252). However, these observations were likely due to transection of surrounding fiber pathways. Because the dorsomedial portion of the VMN projects to the subparaventriculr zone, it has been proposed that leptin-sensitive VMN neurons may have a role in circadian rhythms (197). The brainstem may also contribute to leptin-regulated neuroendocrine responses involved in feeding, particularly the nucleus tractus solitarius (NTS) (253). The NTS is an important relay center in the brainstem for visceral sensory information carried by the vagus nerve from the liver GI tract, but also receives descending information from the forebrain including the PVN (238). Galanin-like peptide (GLP-1)-producing neurons in the NTS have been shown to be leptin responsive (254), and this peptide has potent anorexic effects (255). NPY-producing neurons in the hypothalamic arcuate nucleus have been proposed as the primary target for GLP-1 due to the high concentration of GLP-1 receptors in this region and because GLP-1 can inhibit NPY-induced feeding (256,257). However, the arcuate nucleus contains relatively few GLP-1-containing nerve terminals as compared to the PVN and DMN (258), and discrete injections of GLP-1 into the PVN are capable of suppressing feeding (259). In addition to leptin, other peptides that are secreted in the bloodstream may contribute to the central regulation of appetite and satiety. Among these are insulin, CCK, peptide YY, and ghrelin. Like leptin, levels of insulin vary with adiposity (260) and are suppressed by fasting and increased by eating. In addition, the intracerebroventricular administration of insulin reduces food intake and body weight (261) and prevents fasting-induced increases of NPY and AGRP mRNA in arcuate nucleus neurons (262). Both CCK and pYY are secreted by the gut in response to feeding and may have a role in the termination of eating, CCK through effects on visceral sensory axons that travel in the vagus nerve (263) and pYY through blood-borne inhibitory signals exerted on NPY/AGRP neurons in the hypothalamic arcuate nucleus (264). Ghrelin is also secreted directly into the bloodstream originating primarily from the stomach, but as opposed to leptin, insulin and pYY, ghrelin stimulates food intake and is highest just prior to a meal and falls after eating (265). Thus, ghrelin may have a primary role in meal initiation. Its target is also NPY/AGRP neurons in the hypothalamic arcuate nucleus, increasing the expression of their mRNAs (266). Hypersecretion of ghrelin has recently been proposed as the mechanism for the morbid obesity associatied with the Prader Willi syndrome (267). A summary diagram of the complex mechanisms involved in the
regulation of appetite and satiety is shown in Fig. 33. Suckling is a well recognized physiological stimulus for increased prolactin secretion from the anterior pituitary gland (268). This stimulus is relayed to the hypothalamus via the spinal cord and brainstem (269,270), although the pathways have not been precisely elucidated. Using c-fos as a marker for neuronal activation, several potential relay centers in the brainstem have been identified including the ventrolateral medulla (A1 catechalomine cell group), locus coeruleus, lateral parabrachial nucleus, caudal portion of the paralemniscal nucleus, and lateral and ventrolateral portions of the caudal part of the periaqueductal gray (271). By inhibiting tuberoinfundibular dopamine neurons in the arcuate nucleus and increasing prolactin releasing factors in tuberoinfundibular neurons in the hypothalamic PVN and posterior pituitary (272), these signals permit high circulating levels of prolactin. Prolactin is not only important for the synthesis and maintenance of milk secretion, but contributes to the physiologic responses that complement lactation including the development of material behavior and inhibition of reproductive function (268). These effects are facilitated by upregulation of prolactin receptors in the choroid plexus during lactation (273), allowing increased entry of prolactin from the circulation into the brain, as well as in several hypothalamic nuclear groups including the medial preoptic nucleus, PVN, supraoptic nucleus and arcuate nucleus (274). In particular, binding of prolactin to its receptor in the medial preoptic nucleus may be important for maternal behavior, as antagonizing prolactin receptors with a specific prolactin receptor antagonist injected directly into the preoptic area delays the onset of material behavior (275). In addition, inhibition of pulsatile gonadotropin secretion associated with lactation may be at least partly mediated by the effects of prolactin on GnRH neurons in this region (268). Suckling also results in a marked increase in NPY gene expression in arcuate nucleus neurons (276,277), mediated both by neuronal afferents relayed from the brainstem and by the fall in circulating levels of leptin brought about by negative energy balance resulting from milk production (278). As described above (see Appetite and Satiety), NPY is a powerful orexigenic substance. Its increase during suckling, therefore, has been proposed to explain the hyperphagia associated with lactation (278), although other changes are also observed in arcuate nucleus neurons that may contribute to hyperphagic responses including an increase in AGRP gene expression and decrease in POMC and CART mRNAs (279,280), similar to that described above for fasting. NPY-containing axon terminals of arcuate nucleus origin also richly innervate the medial preoptic region and can be found in close proximity to GnRH neurons (281). The suckling-induced rise in NPY, therefore, may also contribute to inhibition of reproductive function (280) through direct actions on GnRH neurons by binding to NPY Y5 receptors (282). The circuitry involved in the coordinated responses to suckling is
illustrated in Fig. 34.
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.
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