Identification of Sympathetic Premotor Neurons in Medullary Raphe Regions Mediating Fever and Other Thermoregulatory Functions

Abstract

Sympathetic premotor neurons directly control sympathetic preganglionic neurons (SPNs) in the intermediolateral cell column (IML) of the thoracic spinal cord, and many of these premotor neurons are localized in the medulla oblongata. The rostral ventrolateral medulla contains premotor neurons controlling the cardiovascular conditions, whereas rostral medullary raphe regions are a candidate source of sympathetic premotor neurons for thermoregulatory functions. Here, we show that these medullary raphe regions contain putative glutamatergic neurons and that these neurons directly control thermoregulatory SPNs. Neurons expressing vesicular glutamate transporter 3 (VGLUT3) were distributed in the rat medullary raphe regions, including the raphe magnus and rostral raphe pallidus nuclei, and mostly lacked serotonin immunoreactivity. These VGLUT3-positive neurons expressed Fos in response to cold exposure or to central administration of prostaglandin E 2 , a pyrogenic mediator. Transneuronal retrograde labeling after inoculation of pseudorabies virus into the interscapular brown adipose tissue (BAT) or the tail indicated that those VGLUT3-expressing medullary raphe neurons innervated these thermoregulatory effector organs multisynaptically through SPNs of specific thoracic segments, and microinjection of glutamate into the IML of the BAT-controlling segments produced BAT thermogenesis. An anterograde tracing study further showed a direct projection of those VGLUT3-expressing medullary raphe neurons to the dendrites of SPNs. Furthermore, intra-IML application of glutamate receptor antagonists blocked BAT thermogenesis triggered by disinhibition of the medullary raphe regions. The present results suggest that VGLUT3-expressing neurons in the medullary raphe regions constitute excitatory neurons that could be categorized as a novel group of sympathetic premotor neurons for thermoregulatory functions, including fever.

A thermosensory pathway mediating heat-defense responses

“…Recent findings on the efferent control of sympathetic CVC tone indicate that the effector signaling from the POA leading to temperature-dependent CVC control is mediated by the rostral medullary raphe including the rostral raphe pallidus (30), a site of sympathetic premotor neurons controlling skin blood vessels (31,32). The absence of evidence for brain sites intermediate between the POA and the rostral medullary raphe that are required for the POA efferent signaling for temperature-dependent CVC control supports the significance of the direct projection from POA neurons to the rostral medullary raphe as the efferent pathway for febrile and thermoregulatory control of cutaneous vasoconstriction (30,33,34).…”

Central neural distribution of immunoreactive Fos and CRH in relation to plasma ACTH and corticosterone during sepsis in the rat

“…These neurons respond to preoptic cooling or intracerebroventricular administration of PGE 2 and fire at rates in direct proportion to the temperature of brown fat (Nason and Mason, 2006). However, both hyperthermia (Gourine et al, 1998) and hypothermia (Clemmer et al, 1992) can occur during the septic course, and glutaminergic cells in this same medullary area may also contribute to the control of core temperature (Nakamura et al, 2004).…”

A thermosensory pathway that controls body temperature

“…The sections were observed under a confocal laser-scanning microscope (LSM510; Zeiss). Double immunoperoxidase staining for CTb and Fos and PHA-L and Fluoro-Gold followed our previous method 22, 46 .…”