Hypothalamic Effector Mechanisms: Stress and Fever

Indiana Univ-Purdue Univ At Indianapolis, Indianapolis IN

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The cardiac stimulation associated with stress in mammals and the activation of the hypothalamic-pituitary-adrenal (HPA) axis that accompanies it are both associated with adverse health consequences in humans, including increased risk for cardiovascular disease and susceptibility to infection. Interestingly, these same changes accompany the febrile response to bacterial infection and exposure to a cold environment where they may also be linked negative outcomes. In spite of their importance, much about the central neural pathways and mechanisms responsible for generating these changes are or had been unknown. Our past findings together with recent reports in the literature suggest that (1) the same projection from neurons in the dorsomedial hypothalamus (DMH) to the brainstem raphe pallidus (RP) plays a key role in the generation of the sympathetically-mediated cardiac stimulation and thermogenesis seen in rats under conditions as different as "emotional" stress, fever, and cold exposure, and (2) the specific neurons that are involved are localized to a sub region of the DMH - the dorsal hypothalamic area (DHA) - that is anatomically distinct from the ventrolateral DMH (VLD) where neurons involved in stress-induced activation of the HPA axis (i.e., those that project to and stimulate the nearby paraventricular nucleus (PVN) to elevate plasma levels of ACTH) are found. The purpose of the following studies is to test this hypothesis and, in so doing, shed light on the hypothalamic pathways and mechanisms responsible for these important physiologic changes. Thus, in chronically-instrumented conscious rats, these studies will (1) employ fos/retrograde tracer double labeling to carefully map the distribution of neurons that both project to the RP (or to the PVN) and are apparently activated in experimental stress, several paradigms for fever, and exposure to cold, (2) examine the response to selective chemical stimulation of the DHA and the VLD on heart rate, body temperature, and plasma levels of ACTH, (3) assess the effect of selective inhibition or destruction of neurons in each [of] these two regions on the changes in these same endpoints evoked by experimental stress, fever, and exposure to cold, and (4) begin experiments designed to characterize these important hypothalamic neurons and their mode of signaling activation of "downstream" neurons.