CNS Stress Pathways and the Development of Acute HAAF

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DESCRIPTION (provided by applicant): A major complication for insulin-requiring diabetic individuals is the development of Hypoglycemia Associated Autonomic Failure, or HAAF. In the acute form of the syndrome the experience of two or more bouts of hypoglycemia within a 24-hour period results in a blunting of the neuroendocnne counterregulatory response which would normally correct plasma glucose levels. This phenomenon can be modeled in non-diabetic humans and experimental animals, and appears to represent a form of 'stress adaptation'. With other stressors, repeated exposure to the same stressor results in a blunting of the neuroendocrine stress response to that stress. We have developed a rat model of HAAF and have found that, concomitant with the blunted neuroendocnne response, patterns of brain activation (reflected in expression of c-fos) are altered when rats are exposed to three (vs. one) bouts of hypoglycemia in a 24-hr period. Specifically c-fos was decreased in the paraventricular (PVN) and dorsomedial (DMH) hypothalamic areas, with no change in activation of the posterior paraventricular nucleus of the thalamus (THPVP), a region which has net inhibitory input to the PVN. We concluded that a combination of decreased stimulatory input (DMH) and unchanged inhibitory input (THPVP) to the PVN may play a significant role in the decreased neural activation of the PVN and thus decreased downstream neuroendocrine activation. In this series of studies we propose to test the roles of these two brain areas, which are important in the mediation of neuroendocnne responses to other types of stressors, in the neuroendocrine response to hypoglycemic stress and in the development of HAAF. We will reversibly inactivate the THPVP and the DMH with lidocaine or the inhibitory GABA analog muscimol and measure neuroendocnne responses to hypoglycemia, with hypothesized outcomes of reversal of HAAF or simulation of HAAF, respectively. Additionally, we will test the hypothesis that a net increase of inhibitory input at the PVN (reflected by GABAergic transmission) causes the expression of HAAF, by blocking GABAergic activity in the PVN in rats that are experiencing a third bout of hypoglycemia. Together these studies will provide new insight into the role of two stress-regulatory brain regions in the normal counterrregulatory response to hypoglycemia, and in the expression of HAAF; and they will further validate the role of the PVN in mediating counterregulation to hypoglycemia.