A FUNCTIONAL ANATOMICAL ANALYSIS OF CENTRAL PATHWAYS SUBSERVING THE EFFECTS OF INTERLEUKIN-1 ON STRESS-RELATED NEUROENDOCRINE NEURONS

Systemic administration of the cytokine interleukin-1 (IL-1) results i n increased secretion of ACTH and corticosterone in rats. The availabl e evidence suggests that the acute effects of IL-1 are exerted ultimat ely at the level of the hypothalamus to increase corticotropin-releasi ng 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 c entral mechanisms governing pituitary-adrenal output remain poorly und erstood. In this study, we show that intravenous injection of IL-1 bet a 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). Severa l cell groups known to be involved in central visceromotor regulation also displayed comparable time- and dose-related activation to systemi c IL-1, including the bed nucleus of the stria terminalis, the central nucleus of the amygdala, the lateral parabrachial nucleus, and cell g roups of the dorsomedial and ventrolateral medulla. Activation of circ umventricular organs, which have been hypothesized to serve as central monitors of circulating IL-1, required doses roughly an order of magn itude above those required to activate CRF neurons in the PVH. Combine d immunohistochemical and retrograde tracing experiments revealed many IL-1-responsive cells in the nucleus of the solitary tract and the ve ntrolateral medulla to be catecholaminergic and to project to the regi on of the PVH. Discrete and unilateral interruption of ascending catec holaminergic projections from the medulla attenuated IL-1-stimulated i ncreases in Fos immunoreactivity and CRF mRNA in the PVH on the ipsila teral side. Disruption of descending projections from circumventricula r structures associated with the lamina terminalis did not affeet IL-1 -mediated Fos induction in the PVH. We conclude that medullary catecho laminergic projections to the PVH play either a mediating or a permiss ive role in the IL-1-induced activation of the central limb of the hyp othalamo-pituitary-adrenal axis.