Neural Pathways for Metabolic Control of Ingestion

描述（由申请人提供）：持续的葡萄糖供应对大脑功能和生存至关重要。食物摄入增加是脑葡萄糖可用性降低引起的高度综合反应之一。葡萄糖缺乏的其他关键反应包括：食物摄入量增加、肾上腺髓质分泌、皮质酮分泌、胰高血糖素分泌和生殖功能抑制。这些血糖调节反应适应于恢复、保护和维持大脑必需代谢燃料的可用性。该项目的总体目标是更好地了解实现脑葡萄糖稳态的机制和神经回路。我们的工作表明，葡萄糖缺乏的关键反应是由葡萄糖接受细胞发起的，其在后脑中的一般位置是已知的，但其具体表型目前尚不清楚。我们已经证明糖调节反应需要后脑去甲肾上腺素（NE）或肾上腺素(E)神经元。脊髓突起的NE/E神经元是激发肾上腺髓质对糖皮质化反应所必需的，而下丘脑突起的NE/E神经元是激发摄食、皮质酮和生殖反应所必需的。介导每种糖调节反应的NE/E神经元的特定亚群尚不清楚。该项目的一个具体目标是确定这些NE/E神经元的哪些特定亚表型介导这些糖调节反应。几种实验方法，所有利用靶向神经毒素，将被用于病变特定的儿茶酚胺细胞群，以确定它们对这些血糖调节反应的贡献。通过利用不同目标神经毒素的独特特性，我们将能够选择性地解剖不同的细胞群。第二个具体目标是表征葡萄糖活化的反射行为和内分泌反应所需的基本神经元素和连接。我们之前的工作表明，葡萄糖摄食的食欲和反射性完成成分都依赖于后脑NE或E神经元。本目的实验将利用免疫毒性病变和免疫组织化学方法结合去脑，进一步验证糖苷化的终性摄食反应是由介导食欲反应的儿茶酚胺神经元的后脑侧枝介导的。结果还将阐明哪些后脑神经回路是由后脑NE/E神经元的[投射]激活的，哪些是由前脑的下行投射次要激活的。最后，这些实验生成的前脑激活图可以识别由内源性前脑糖感受神经元直接激活的电路。识别控制血糖调节反应的特定神经回路可能对临床方法的发展具有重要意义，以减少低血糖相关性自主神经衰竭（HAAF）的发生，这是胰岛素治疗的潜在致命副作用，其中低血糖不能引起中枢血糖调节反应。

DESCRIPTION (provided by applicant): 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.