A continuous supply of glucose is essential for brain function and survival. Increased food intake is one of a highly integrated constellation of responses evoked by reduced brain glucose availability. Other key responses to glucose deficit include: increased food intake, adrenal medullary secretion, corticosterone secretion, glucagon secretion, and suppression of reproductive function. These glucoregulatory responses are adapted to restore, protect and maintain the availability of the brain's essential metabolic fuel. The overall goal of the project is to better understand the mechanisms and neural circuitry through which brain glucose homeostasis is achieved. Our work has demonstrated that the key responses to glucose deficit are initiated by glucoreceptive cells whose general location within the hindbrain is known but whose specific phenotype currently is unknown. We have shown that glucoregulatory responses require hindbrain norepinephrine (NE) or epinephrine (E) neurons. Spinally-projecting NE/E neurons are required for elicitation of the adrenal medullary response to glucoprivation, while hypothalamically-projecting NE/E neurons are required for the feeding, corticosterone and reproductive responses. The specific subgroups of NE/E neurons that mediate each of the glucoregulatory responses remain unclear.
One specific aim of the project is to identify which specific sub-phenotypes of these NE/E neurons mediate each of these glucoregulatory responses. Several experimental approaches, all utilizing targeted neurotoxins, will be employed to lesion specific catecholamine cell populations in order to determine their contribution to each of these glucoregulatory responses. By exploiting the unique properties of different targeted neurotoxins, we will be able to selectively dissect different cell groups. The second specific aim is to characterize the fundamental neural elements and connections required for reflex behavioral and endocrine responses to glucoprivation. Our previous work suggests that both appetitive and reflex consummatory components of glucoprivic feeding are reliant on hindbrain NE or E neurons. Experiments in this aim will utilize immunotoxic lesions and immunohistochemical approaches applied in combination with decerebration to test further the hypothesis that the consummatory feeding response to glucoprivation is mediated by hindbrain collaterals of the same catecholamine neurons that mediate the appetitive response. Results will also clarify which hindbrain neural circuits are activated by [projections of] hindbrain NE/E neurons and which are activated secondarily by descending projections from the forebrain. Finally, the forebrain activational maps generated by these experiments may identify circuitry directly activated by intrinsic forebrain glucoreceptive neurons. Identification of the specific neural circuits controlling glucoregulatory responses may be important for the development of clinical approaches to reduce the occurrence of hypoglycemia associated autonomic failure (HAAF), a potentially lethal side effect of insulin treatment in which central glucoregulatory responses are not elicited by hypoglycemia.
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