Glucose is the obligatory metabolic fuel for the brain. The brain does not store glucose, but is protected from the lethal consequences of glucoprivation by sensitive receptor mechanisms for early detection of glucose deficit. Glucoreceptive mechanisms are coupled to powerful neural, neuroendocrine and behavioral controls for restoration of normoglycemia. Deficits in glucoreception are life-threatening and may be the pathogenic mechanism for hypoglycemia-associated autonomic failure--a compromised responsiveness to hypoglycemia observed in diabetic patients on intensive insulin therapy. Glucoreceptive neurons also drive appetite and may contribute to disorder of body weight regulation. This proposal will focus on the neural circuitry for two essential glucoregulatory controls: increased adrenal medullary secretion, which elevates blood glucose by promoting glycogenolysis, and increased food intake, which elevates glucose by absorption from ingested carbohydrate and replenishes depleted glycogen stores. Compelling new data demonstrate that hindbrain catecholamine neurons are essential mediators of feeding and adrenal medullary responses to glucoprivation, providing the coupling between hindbrain glucoreceptive sites and forebrain and spinal output neurons for these responses.
The specific aims of the grant application are to identify the specific catecholamine neurons involved in glucoprivic feeding and adrenal medullary secretion and to define the functional organization of their respective rostral and spinal projections. Studies will utilize a number of experimental approaches, including measurement of glucoprivic feeding and adrenal medullary secretion, immunotoxin lesions, Fos-immunoreactivity, retrograde tracing and in situ hybridization, to identify precisely the particular catecholamine neurons that are involved in each glucoregulatory response and the distribution of their collateral processes. In addition, the ability of the ascending catecholamine neurons to activate hypothalamic neurons containing the orexigenic peptides NPY, AgRP, ORX and MCH will be studied using in situ hybridization in combination with a selective catecholamine immunotoxin. Spinally projecting catecholamine neurons involved in glucoprivic control of the adrenal medulla will be characterized by identification of co-localized peptides, retrograde tracing and in situ hybridization. The functional relationship of the latter catecholamine neurons with other brain sites providing direct innervation of adrenal medullary preganglionic neurons will be studied.
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