Neural Pathways for Metabolic Control of Ingestion

描述(申请人提供)：维持充足的葡萄糖供应，这是大脑的基本代谢燃料，需要受体细胞监测大脑葡萄糖的供应，并启动神经电路，当水平下降时，能够引发内分泌、自主神经和行为反应来恢复血糖。我们的工作表明，后脑儿茶酚胺(NE/E)神经元是诱发对葡萄糖缺乏的一系列关键反应所必需的，包括刺激摄食、皮质酮(CORT)和肾上腺髓质分泌以及抑制生殖反应。了解后脑的糖调节回路一直是我们实验室的一项持续努力，也是这项应用的重点。这项提议将解决我们对这一后脑系统认识上的两个主要差距。首先，我们不了解头端投射的NE/E神经元调节摄食和皮质酮对葡萄糖缺乏反应(“葡萄糖营养”)的回路。其次，尽管我们已经证明，在缺糖时，NE/E神经元是激发和协调糖调节反应所必需的，但我们不知道E/NE神经元本身是否是葡萄糖感受器。这项工作将确定腹侧被盖(VTA)多巴胺(DA)系统的NE/E神经支配在全身性糖营养引起的食欲摄食反应中的作用，并确定这种VTA神经支配是否来自相同的NE/E神经元，这些神经元介导皮质醇对糖营养的反应。实验将利用逆行运输的靶向免疫毒素抗多巴胺β羟基酶皂苷(DSAP)选择性地损毁支配VTA的NE/E神经元，而不损害VTA DA神经元。这项拟议的工作还将使用基因沉默来进一步描述特定的后脑NE/E细胞组，这些细胞组介导了葡萄糖普利诱导的摄食和/或皮质酮的分泌。最后，本研究将探讨细胞能量感受器和调节器--5‘-腺苷一磷酸活化蛋白激酶(AMPK)在缺糖时对后脑NE/E神经元功能的影响，以及这些神经元作为葡萄糖感受器的可能性。我们的长期目标是确定后脑NE/E神经元作为葡萄糖感受器的潜力，并确定它们的传入输入和传出输出在对葡萄糖缺乏的整体生理反应中的作用。我们相信，我们的工作将对人类健康产生重大影响。解开糖调节回路将有助于评估它们参与代谢紊乱的情况，如2型糖尿病、肥胖和糖尿病患者胰岛素治疗的潜在致命并发症(称为低血糖相关自主神经衰竭，或HAF)，在这些并发症中，葡萄糖供应的严重减少无法触发救命的糖调节反应。 与公众健康相关：葡萄糖是大脑必不可少的代谢燃料。这项建议侧重于大脑保护其葡萄糖供应的机制，并扩展了我们之前的工作，证明了后脑儿茶酚胺神经元在保护和恢复对葡萄糖缺乏的反应中所需的参与。这项拟议的工作将描绘儿茶酚胺的投射，这些投射介导对葡萄糖缺乏的两个关键反应，即摄食和皮质酮分泌，并将研究后脑儿茶酚胺神经元作为葡萄糖传感器的潜在作用。研究结果将为后脑糖调节机制在肥胖、糖尿病和其他代谢性疾病中促进或改变的方式提供新的见解。

DESCRIPTION (provided by applicant): Maintaining an adequate supply of glucose, the brain's essential metabolic fuel, requires receptor cells that monitor brain glucose availability and engage neural circuitry capable of eliciting endocrine, autonomic and behavioral responses to restore glucose when levels fall. Our work has revealed that hindbrain catecholamine (NE/E) neurons are required for elicitation of a number of key responses to glucose deficit, including stimulation of feeding, corticosterone (CORT) and adrenal medullary secretion and suppression of reproductive responses. Understanding hindbrain glucoregulatory circuitry has been a continuing effort in our lab and is the focus of this application. Two major gaps in our knowledge of this hindbrain system will be addressed by this proposal. First, we do not understand the circuitry by which rostrally-projecting NE/E neurons mediate feeding and corticosterone responses to glucose deficit ("glucoprivation"). Second, although we've shown that NE/E neurons are required for elicitation and coordination of glucoregulatory responses during glucose deficit, we do not know whether E/NE neurons are themselves glucose- sensors. The proposed work will determine the contribution of NE/E innervation of the ventral tegmental (VTA) dopamine (DA) system to elicitation of appetitive feeding responses by systemic glucoprivation and determine whether this VTA innervation arises from the same NE/E neurons mediating the CORT response to glucoprivation. Experiments will utilize the retrogradely transported targeted immunotoxin, anti-dopamine beta hydroxylase saporin (DSAP) to selectively lesion NE/E neurons innervating the VTA without damaging the VTA DA neurons. The proposed work will also use gene silencing to further delineate the specific hindbrain NE/E cell groups that mediate glucoprivation-induced feeding and/or corticosterone secretion. Finally, the proposed work will examine the contribution of 5' adenosine monophosphate-activated protein kinase (AMPK), a cellular energy sensor and regulator, to the function of hindbrain NE/E neurons during glucose deficit and the possibility that these neurons are glucose sensors. Our long-term goal is to determine the potential of hindbrain NE/E neurons to serve as glucose sensors and to establish the roles of their afferent inputs and efferent outputs in the overall physiological response to glucose deficit. We believe that our work will have a significant impact on human health. Unraveling glucoregulatory circuits will enable assessment of their involvement in metabolic disorders such as Type 2 diabetes, obesity and the potentially lethal complication of insulin therapy in diabetics (known as Hypoglycemia Associated Autonomic Failure, or HAAF), in which severe reductions in glucose availability fail to trigger life-saving glucoregulatory responses. PUBLIC HEALTH RELEVANCE: Glucose is the brain's essential metabolic fuel. This proposal is focused on mechanisms by which the brain protects its glucose supply and extends our previous work demonstrating the required participation of hindbrain catecholamine neurons in protective and restorative responses to glucose deficit. The proposed work will delineate the catecholamine projections that mediate two critical responses to glucose deficit, feeding and corticosterone secretion, and will examine the potential role of hindbrain catecholamine neurons as glucose sensors. Results will provide new insights into the ways in which hindbrain glucoregulatory mechanisms contribute to or are altered by obesity, diabetes and other metabolic diseases.