Central circuitries for body temperature regulation and fever

Abstract

Nakamura K. Central circuitries for body temperature regulation and fever. Am J Physiol Regul Integr Comp Physiol 301: R1207-R1228, 2011. First published September 7, 2011 doi:10.1152/ajpregu.00109.2011.-Body temperature regulation is a fundamental homeostatic function that is governed by the central nervous system in homeothermic animals, including humans. The central thermoregulatory system also functions for host defense from invading pathogens by elevating body core temperature, a response known as fever. Thermoregulation and fever involve a variety of involuntary effector responses, and this review summarizes the current understandings of the central circuitry mechanisms that underlie nonshivering thermogenesis in brown adipose tissue, shivering thermogenesis in skeletal muscles, thermoregulatory cardiac regulation, heat-loss regulation through cutaneous vasomotion, and ACTH release. To defend thermal homeostasis from environmental thermal challenges, feedforward thermosensory information on environmental temperature sensed by skin thermoreceptors ascends through the spinal cord and lateral parabrachial nucleus to the preoptic area (POA). The POA also receives feedback signals from local thermosensitive neurons, as well as pyrogenic signals of prostaglandin E 2 produced in response to infection. These afferent signals are integrated and affect the activity of GABAergic inhibitory projection neurons descending from the POA to the dorsomedial hypothalamus (DMH) or to the rostral medullary raphe region (rMR). Attenuation of the descending inhibition by cooling or pyrogenic signals leads to disinhibition of thermogenic neurons in the DMH and sympathetic and somatic premotor neurons in the rMR, which then drive spinal motor output mechanisms to elicit thermogenesis, tachycardia, and cutaneous vasoconstriction. Warming signals enhance the descending inhibition from the POA to inhibit the motor outputs, resulting in cutaneous vasodilation and inhibited thermogenesis. This central thermoregulatory mechanism also functions for metabolic regulation and stress-induced hyperthermia.

Behavioral fever in ectothermic vertebrates

“…Moreover, experiments in rats with important electrolytic lesions performed in the POA demonstrate that destruction of this brain region does not impact their ability to express thermoregulatory behaviors but impair their capacity for autonomic thermoregulation . In conclusion, the neural pathways controlling these behaviors are different from those controlling autonomic thermogenesis (Nakamura, 2011;Saper et al, 2012). Further investigations are required to unravel the induction pathways of behavioral thermoregulation in endotherms.…”

“…Four subtypes of PGE 2 receptors have been described, namely EP1-EP4 (Oka, 2004), among which EP3 was shown to be critical in the induction of fever (Lazarus et al, 2007;Saper et al, 2012;Ushikubi et al, 1998). These EP3 receptor-bearing neurons are GABAergic neurons (Nakamura et al, 2002), which through neuronal projections inhibit the activity of neurons in dorsomedial nucleus of the hypothalamus (DMH) and rostral medullary raphe (rMR) (Nakamura, 2011). The binding of PGE 2 to the EP3 receptor-bearing neurons reduces their activity and so disinhibits the downstream neurons in the DMH and rMR.…”

“…The binding of PGE 2 to the EP3 receptor-bearing neurons reduces their activity and so disinhibits the downstream neurons in the DMH and rMR. The disinhibition of neurons in the DMH induces excitatory outputs on sympathetic premotor neurons in the rMR, which in turn activate the sympathetic preganglionic neurons (Nakamura, 2011). This triggers the release of norepinephrine (NE) which elicits intrinsic thermogenesis in brown adipose tissue (non-shivering thermogenesis) and heat conservation by peripheral vasoconstriction.…”

“…Moreover, the disinhibition of rMR neurons excites the somatomotor neurons which release acetylcholine (ACh) and activate skeletal muscles for shivering. The increased thermogenesis by shivering and non-shivering dependent processes and the reduction of heat loss by peripheral vasoconstriction lead to the elevation of core temperature (Nakamura, 2011;Saper et al, 2012) (Fig. 1a).…”

Role of serotonergic system in thermoregulation in rats

“…In thermoregulation, the raphe pallidus is especially involved in forming a connection by receiving afferent and efferent information. Two reviews 21,22) have discussed the role of the medullary raphe nuclei in the regulation of Tb.…”