@„@ƒgƒbƒvƒy[ƒW@|@1. Sˆφ«”­”M

3. Neurocircuitry mediating stress-induced hyperthermia@ƒ“ϊ–{Œκ„

@The mechanism by which activation of brain circuitry underlying psychological stress results in increases in core body temperature (Tc) is poorly understood. Therefore, we have been investigating the neurocircuitry that mediates stress-induced hyperthermia (SIH) in rats.

Neurocircuitry that mediates infection/inflammation-induced fever

@Infection- or systemic inflammation-induced fever is initiated by the release of brain-permeable prostaglandin E2 (PGE2) from macrophages. When PGE2 binds to the EP3 receptor present in neurons within the preoptic area of the hypothalamus (POA), a fever center, Tc increases. EP3 receptor-expressing POA neurons directly project to the dorsomedial hypothalamus (DMH) and the rostral medullary raphe region, including the raphe pallidus nucleus and the raphe magnus, which receives monosynaptic excitatory inputs from the DMH. Stimulation of premotor neurons in the rostral medullary raphe region activates sympathetic preganglionic neurons in the spinal cord, resulting in activation of b3-adrenoceptor-mediated non-shivering thermogenesis in brown adipose tissue (BAT), a-adrenoceptor mediated cutaneous vasoconstriction, and activation of shivering thermogenesis in skeletal muscles (Fig. 1).


iFig.1jMechanisms of infection/inflammation-induced fever.

Hypothesis and aim

@We hypothesized that stress-induced hyperthermia is mediated by the activation of the premotor neurons in the rostral medullary raphe region in a similar manner as it is in infection/inflammation-induced fever. To test this hypothesis, we used the defeat stress model which is characterized by psychological stress that intruder rats feel when they are placed into the home cages of dominant resident rats. Using this model, we studied whether socially-induced hyperthermia was associated with the activation of premotor neurons within the rostral medullary raphe region.

Methods and results

(1) Intruder rats that were defeated by a dominant resident conspecific exhibited a rapid increase in abdominal temperature by up to 2.0Ž.
(2) This hyperthermia was not attenuated by intraperitoneal (i.p.) injection of indomethacin, an antipyretic drug and a cyclooxygenase inhibitor, but was attenuated by diazepam (i.p.), an anxiolytic agent, or by SR59230A (i.p.), a b3 adrenoceptor antagonist (Fig. 2).


(Fig. 2) Stress-induced hyperthermia was not attenuated by indomethacin, but was attenuated by SR59230A.

(3) Expression of Fos, a marker of neuronal activation, was increased in the rostral medullary raphe region centered in the rostral raphe pallidus and adjacent raphe magnus nuclei. In this region, Fos expression was observed in a large population of neurons expressing vesicular glutamate transporter 3 (VGLUT3), which are known as sympathetic premotor neurons controlling non-shivering thermogenesis in BAT and thermoregulatory constriction of skin blood vessels. Diazepam reduced Fos expression in this region as well.
@These results suggest that psychological stress signals activate VGLUT3-expressing medullary raphe sympathetic premotor neurons, which then drive hyperthermic effector responses including BAT thermogenesis through b3-adrenoreceptors.

@At the present time, we do not know if the POA or the DMH are involved in the psychological stress-induced hyperthermic response. However, these study findings suggest that psychological stress and infection/systemic inflammation activate common efferent pathways to increase Tc, i.e. the rostral medullary raphe region - sympathetic nervous system - b3 adrenoceptor in the BAT (Fig. 3).i2012, July 28thj

(Fig. 3) Infection/inflammation and psychological stress activate common pathways to increase Tc.

@This study was conducted by Battuvshin Lkhagvasuren, a graduate student from Mongolia and was supported by Grants-in-Aid for Scientific Research (22590671 and 23390189) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The study results have been published (1). Additionally, I have also authored a review article on the mechanisms of psychogenic fever (2), which includes the latest findings.

1) Lkhagvasuren, B et al.: Social defeat stress induces hyperthermia through activation of thermoregulatory sympathetic premotor neurons in the medullary raphe region. Eur J Neurosci 34,1442-52,2011.
2) Oka T et al.: Mechanisms of psychogenic fever. Adv Neuroimmune Biol 3,3-17,2012.

inserted by FC2 system