Characterization of Noradrenergic Thermogenic Input to the Hypothalamus

College Of William And Mary, Williamsburg VA

Investigators

Abstract

DESCRIPTION (provided by applicant): The acute phase response to infection consists of a series of systemic reactions to the presence of an invading pathogen, including a rise in body temperature known as a fever. This hyperthermic shift in the activation of metabolic heat production and retention mechanisms is driven by the interactions of neurons in the preoptic and anterior regions of the hypothalamus (POAH), regions which play an integrative role in thermoregulatory control. The mediators of this response are thought to include endogenous cytokines that trigger the production of prostaglandin E2 within the POAH, leading to thermally dependent changes in neuronal activity. While this pathway of activation is well established and a major focus of ongoing research, it is clear that fever can begin before these cytokines are present in the circulation, and that it can be preceded by either a decrease in body temperature or a small initial rise. Recent investigations suggest that noradrenergic (NA) afferents to the POAH, responding to immunological activation of hepatic vagal pathways, can stimulate these initial changes in temperature and contribute to the long term development of a fever. Using an isolated tissue slice preparation, the electrophysiologic activity and local network properties of POAH neurons will be characterized in response to NA receptor activation. Initial studies will record the extracellular single-unit activity of POAH neurons to pharmacologically characterize the specific 1-1 and 1-2 receptor subtypes involved. This will be followed by intracellular recordings to determine the specific ionic conductances responsible for NA receptor dependent changes in neuronal activity. In some experiments, neurons in the POAH which have axonal projections to the dorsomedial hypothalamus or raphe pallidus, two important regions in the efferent control of thermoregulatory mechanisms, will be identified by retrograde labeling and selectively targeted for intracellular recording. These investigations will establish the pattern of NA receptor activation and the conductance(s) responsible for changes in the firing rates of thermally classified neurons in the POAH, as well as the role of responsive neurons in efferent thermoregulatory networks. This will provide a better understanding of how fever is initiated as part of the immune system's activation of the acute phase response to infection. PUBLIC HEALTH RELEVANCE: In response to infection, the immune system triggers a series of defensive mechanisms throughout the body, which include an elevation in body temperature known as a fever. Precisely how the nervous system is activated by the immune system to generate this thermoregulatory response, as well as other important neuroimmune responses, is still a major focus of ongoing research. Through the characterization of noradrenergic receptor input to the hypothalamus, an important region in thermoregulatory and autonomic control, these proposed studies will contribute to a better understanding of this important axis of the immunological response.