A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons

Abstract

Systemic administration of the cytokine interleukin-1 (IL-1) results in increased secretion of ACTH and corticosterone in rats. The available evidence suggests that the acute effects of IL-1 are exerted ultimately at the level of the hypothalamus to increase corticotropin-releasing factor (CRF) secretion into the hypophyseal portal circulation, and hence the central drive on the pituitary-adrenal system. However, the route(s) and mechanism(s) by which circulating IL-1 gains access to central mechanisms governing pituitary-adrenal output remain poorly understood. In this study, we show that intravenous injection of IL-1 beta provokes time- and dose-dependent increases in the expression of the immediate-early gene c-fos, in identified CRF and oxytocin-producing cells of the paraventricular nucleus of the hypothalamus (PVH). Several cell groups known to be involved in central visceromotor regulation also displayed comparable time- and dose-related activation to systemic IL-1, including the bed nucleus of the stria terminalis, the central nucleus of the amygdala, the lateral parabrachial nucleus, and cell groups of the dorsomedial and ventrolateral medulla. Activation of circumventricular organs, which have been hypothesized to serve as central monitors of circulating IL-1, required doses roughly an order of magnitude above those required to activate CRF neurons in the PVH. Combined immunohistochemical and retrograde tracing experiments revealed many IL-1-responsive cells in the nucleus of the solitary tract and the ventrolateral medulla to be catecholaminergic and to project to the region of the PVH. Discrete and unilateral interruption of ascending catecholaminergic projections from the medulla attenuated IL-1-stimulated increases in Fos immunoreactivity and CRF mRNA in the PVH on the ipsilateral side. Disruption of descending projections from circumventricular structures associated with the lamina terminalis did not affect IL-1-mediated Fos induction in the PVH. We conclude that medullary catecholaminergic projections to the PVH play either a mediating or a permissive role in the IL-1-induced activation of the central limb of the hypothalamo-pituitary-adrenal axis.

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

“…Vagal sensory input from the abdomen implicated in the central neural (Wan, et al, 1994), hyperthermic , and hormonal (Fleshner, et al, 1995;Gaykema, et al, 1995;Kapcala, et al, 1996) responses to inflammatory stimuli may have contributed to this response as may the action of circulating mediators on the area postrema (Cunningham et al, 1994). However, Fos appeared in this circumventricular organ only in the rats with the most intense dorsomedullary responses as reported previously during acute inflammation Ericsson, et al, 1994).…”

“…For example long-term suckling fails to induce Fos in oxytocin-containing neurons (Fenelon et al, 1993). Furthermore, intravenous doses of endotoxin Zhang, et al, 2003) or interleukin-1 (Ericsson, et al, 1994) increase central Fos for about 6 h with a peak at 2 to 3 h. Improved detection of Fos through the use of optimized fixation and antibodies as in the present study may reveal responses of longer duration, but their intensity frequently declines from the initial peak. Sustained expression of Fos in the NTS and ventrolateral medulla does occur in some experimental models of chronic hypertension (Lohmeier et al, 2002;Lohmeier et al, 2003); and, in contrast to the present findings, CRH neurons in the PVH show a sustained increase in Fos mRNA during chronic insulin-induced hypoglycemia (Brown and Sawchenko, 1997).…”

“…The responsive subnuclei of the parabrachial nucleus receive converging input from the NTS ) and somatosensory structures (Cechetto et al, 1985) and were shown previously to respond to acute administration of endotoxin and interleukin-1 (Ericsson, et al, 1994). Many Fos-positive cells in this region were found among CRH-containing processes, and occasional small cells in the dorso-and central lateral subnuclei were double-stained for Fos and CRH after CLP.…”

“…The central neural responses to acute doses of endotoxin Wan, et al, 1994) or inflammatory cytokines (Chan et al, 1993;Crane et al, 2003;Ericsson et al, 1994;Xu et al, 1999) have been well described and are likely to be present in sepsis but may comprise only a subset of the complete response to prolonged systemic infection. The central modulation of the immune system and of metabolism is likely to affect the clinical course of sepsis significantly.…”

Effects of cytokines and infections on brain neurochemistry

“…Mascarucci et al [53] showed that ip hIL-1β (4 μg/rat ip) increased apparent glutamate release from the nucleus tractus solitarius (NTS), although heat-treated IL-1 also elicited a partial response. [54][55][56]. The structure most markedly affected is the hypothalamic PVN, which contains the cell bodies of the neurons that synthesize CRF involved in the activation of the HPA axis.…”