**2. Hypothalamic control of thermoregulation**

Homeothermia is present in mammals and birds and enables them to maintain their deepbody temperature (Tcore) at stable levels. Tcore can physiologically deviate from its normal value (the value at rest in thermoneutral environment) under the influence of the day-night cycle, the menstrual cycle, or seasonal cycles, such as hibernation. Pathophysiological changes in Tcore include fever (a hyperthermic response to infections), dehydration hyperthermia, and starvation-induced hypothermia. The key role played by the preoptic area/anterior hypothalamus (PO/AH) in the regulation of Tcore was recognized more than a 100 years ago, based on experiments using experimental brain lesions, and selective hypothalamic cooling and heating with chronically implanted thermodes (reviewed in [1]). Sustained or alternating PO/AH cooling and heating induce thermoregulatory activities (physiological or behavioral), causing Tcore to change in the direction opposite to that of the

© 2013 Tabarean, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

hypothalamic temperature (Thy). Hammel and collegues proposed that a particular net thermoregulatory response was proportional to (Thy –Tset), where Tset was conceived as a hypothetical set reference, a complex parameter representing the state of activity of thermosensitive neuronal populations [2].

Histaminergic Modulation of Body Temperature and Energy Expenditure 195

labeling and immunocytochemistry revealed that EP3 prostanoid receptor-positive GABAergic PO/AH neurons project to the sympathetic premotor neurons in the rostral raphe pallidus (rRPA). The projections are either direct or via the dorsomedial hypothalamus (DMH) [16,17]. Bilateral microinjections of GABA-A receptor agonists or antagonists into the rRPa or DMH, blocked the fever induced by intra-PO/AH PGE2 applications. The central role of EP3-receptors in PO/AH neurons in the fever response was demonstrated also by local knockdown of its expression [18]. The role of the DMH in the control of BAT thermogenesis was proven also by direct chemical or electrical stimulation [19]. These studies clearly revealed a tonic GABAergic inhibition of the DMH and rRPA by

Recent studies have established also the existence of direct glutamatergic projections from the PO/AH [20,21] as well as from the lateral hypothalamus [22] to the rRPA that control thermoregulation. Some glutamatergic PO/AH neurons projecting to rRPa are also

Injections of excitatory amino acids as well as PO/AH warming inhibited cold-induced shivering suggesting that this mechanism, similar to BAT thermogenesis, is controlled by PO/AH warm-sensitive neurons [15]. In contrast, cooling of the PO/AH had little effect on cold-induced shivering. The efferent signals mediating shivering descend in the medial

Evaporative heat loss is also controlled by a network originating in the PO/AH since it is the only brain region that induces salivary secretion when warmed [23]. Preoptic warming, glutamate injections as well as electrical stimulation facilitate salivary secretion [5,13,15] as

Warming the PO/AH elicits skin vasodilation [25], by activation of warm-sensitive neurons [15]. The efferent pathway descends through the medial forebrain bundle [23]. It is believed that warm-sensitive neurons in PO/AH send excitatory signals to vasodilator neurons and inhibitory signals to vasoconstrictor neurons. PO/AH neurons controlling cutaneous blood flow project to the rostral medullary raphe region directly [26], suggesting that distinct populations of PO/AH neurons control thermogenesis and cutaneous vasomotion. This concept is supported by the observation that the two thermoregulatory mechanisms are

Little is known about the local networks comprising warm-sensitive and temperatureinsensitive neurons. One study found little thermosensitivity in the frequency of spontaneous IPSPs and EPSPs recorded in either warm-sensitive or temperature-insensitive PO/AH neurons, suggesting that the former do not send local projections [28]. This study also compared the morphologies of w-s and t-i PO/AH neurons filled with Lucifer yellow or biocytin. The dendritic arbors were characterized, however the axonal projections could not be described. This finding may reflect technical limitations or the fact that PO/AH neurons

The neuronal network controlling cutaneous blood flow also originates in the PO/AH.

well as body extension [24], another aspect of evaporative heat loss.

activated at different threshold temperatures [27].

Shivering, a different mechanism of thermogenesis, is also controlled by the PO/AH.

the PO/AH as crucial for basal thermoregulation and hyperthermic responses.

peptidergic [20].

forebrain bundle [23].

Since the first extracellular single-unit study [3], which found that some PO/AH neurons, termed "warm-sensitive", increase their firing rates when Thy increases, it has been considered that they represent the central thermoreceptors. The other PO/AH neurons, which display little temperature-dependent changes in firing rate, are considered temperature-insensitive. PO/AH thermosensitive neurons respond not only to changes in local and peripheral temperature, but also to hormones, osmolarity and glucose concentration (reviewed in [1]). These findings suggest that these neurons, or a subgroup of them, also play a role in the integration of thermoregulation with other homeostatic processes such as control of metabolic rate (glucose sensing). The thermosensitivity of PO/AH neurons is a plastic property both *in vivo* and *in vitro*. It has been found that the thermosensitivity can change rapidly in the presence of the pyrogens PGE2 [4] or IL-1 [5,6]. Slower changes are observed in some warm-sensitive PO/AH neurons which decrease their thermosensitivity during NREM sleep [7].

The mechanism of intrinsic thermosensitivity of PO/AH neurons is controversial. Boulant and colleagues consider that the increased firing rate is solely due to an increased rate of rise of the prepotential which precedes an action potential (reviewed in [8]. Other studies describe strong depolarizations (10 mV or larger) in response to heating which cause the increased firing rate in warm-sensitive neurons ([9]). In cultured PO/AH neurons both phenomena are present, however they occur also in temperature-insensitive neurons [10]. Finally, the warming-activated inward current was found to be tetrodotoxin (TTX) insensitive in some studies [9,10,11] and TTX-sensitive (i.e. mediated by voltage-gated Na channels) in others [12]. The question remains open as to whether all warm-sensitive PO/AH neurons have some intrinsic thermosensitivity or if they can also display thermosensitive firing that is synaptically-driven [10]. We have shown that prostaglandin E2 (PGE2), a well established endogenous pyrogen, increases the thermosensitivity and firing rates of PO/AH neurons by decreasing the frequency of IPSPs [4]. In contrast, IL-1β hyperpolarizes a different set of PO/AH neurons and reduces their thermosensitivity by increasing the frequency of IPSPs and of miniature IPSPs [5,13].
