Tuesday, April 23, 2024
4/23/2024
Project Summary Glucose is the required metabolic fuel for the brain. Quantities of stored glucose (glycogen) in the brain are adequate to maintain brain function and survival for only a few minutes. Therefore, glucose must be monitored constantly in order to control diverse behavioral, endocrine and autonomic responses that ensure delivery of glucose from the blood. Mechanisms that detect brain glucose deficit and elicit protective responses, referred to as counter-regulatory responses (CRRs), that mobilize and replenish the brain's glucose supply are of vital importance for survival. These responses include stimulation of appetite, increased glucocorticoid and adrenal medullary secretion and others. Studies employing molecular neurosurgery with targeted immunotoxins, in situ hybridization, gene silencing and CNO/DREAAD technology all support the essential involvement of catecholamine (CA) neuron subpopulations in elicitation of CRRs. However, an obstacle to research in this area has been that CA neurons in the same general areas of the hindbrain that house the glucoregulatory CA neurons are involved in multiple and equally critical homeostatic functions that are not directly glucoregulatory (such as cardiovascular, respiratory, and neuroendocrine controls). However, new data and techniques are available that will allow us to specifically characterize and probe the distinct functions of the glucoregulatory CA subgroups and possibly to identify the underlying causes of their dysregulation in hypoglycemia associated autonomic failure (HAAF), a potentially lethal condition that constantly threatens diabetic patients on insulin therapy. Using a variety of technical approaches, we will attempt to reveal peptides that act as co-transmitters for CA neurons involved in specific CRRs (feeding, glucocorticoid and adrenal medullary secretion), as well as identifying the glucosensing mechanisms they express. We will also evaluate the effect of acute and recurrent glucoprivation on these mechanisms.
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