Neural Pathways for Metabolic Control of Ingestion

描述（由申请人提供）：持续供应葡萄糖对大脑功能和生存至关重要。食物摄入量增加是由大脑葡萄糖可用性降低引起的高度集成的反应星座之一。对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。这些葡萄糖调节反应适于恢复、保护和维持大脑基本代谢燃料的可用性。该项目的总体目标是更好地了解大脑葡萄糖稳态实现的机制和神经回路。我们的工作已经证明，葡萄糖缺乏的关键反应是由葡萄糖受体细胞，其一般位置在后脑内是已知的，但其具体的表型目前是未知的。我们已经表明，葡萄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。脊髓投射NE/E神经元是激发肾上腺髓质对葡萄糖缺乏反应所必需的，而下丘脑投射NE/E神经元是摄食、皮质酮和生殖反应所必需的。NE/E神经元介导的葡萄糖调节反应的具体亚群尚不清楚。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葡萄糖调节反应中的每一种。几种实验方法，都利用有针对性的神经毒素，将采用病变的特定的儿茶酚胺细胞群，以确定他们的贡献，这些glucoregulatory反应。通过利用不同靶向神经毒素的独特性质，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对葡萄糖缺乏的反射行为和内分泌反应所需的基本神经元素和连接。我们以前的工作表明，食欲和反射消耗的葡萄糖消耗喂养的组成部分依赖于后脑NE或E神经元。在这一目标的实验将利用免疫毒性病变和免疫组织化学方法应用与去大脑，以进一步测试的假设，即完善的进食反应，葡萄糖匮乏是由后脑侧支相同的儿茶酚胺神经元，介导的食欲反应。研究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，哪些是由前脑下行投射激活的。最后，由这些实验产生的前脑激活图可以识别直接激活的内在前脑葡萄糖感受神经元的电路。确定控制糖调节反应的特定神经回路对于开发临床方法以减少低血糖相关自主神经功能衰竭（HAAF）的发生可能是重要的，HAAF是胰岛素治疗的潜在致命副作用，其中中枢糖调节反应不是由低血糖引起的。

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.