NEURAL PATHWAYS FOR METABOLIC CONTROL OF INGESTION

说明(申请人摘要)：葡萄糖是必需的代谢燃料 对大脑来说。大脑不储存葡萄糖，但受到保护，不受 糖基化的致死后果通过敏感的受体机制 早期发现葡萄糖缺乏症。葡萄糖受体机制耦合到 强大的神经、神经内分泌和行为控制，可恢复 血糖正常。糖受体缺陷危及生命，可能是 低血糖相关性自主神经衰竭的发病机制--a 观察到糖尿病患者对低血糖的反应减退 强化胰岛素治疗。糖感受性神经元也会刺激食欲，并可能 导致体重调节紊乱。这项提案将重点放在 两种基本的糖调节控制的神经回路：增加 肾上腺髓质分泌，通过促进血糖升高 糖原分解和食物摄入量增加，从而通过吸收提高葡萄糖 从摄入的碳水化合物和补充耗尽的糖原储存。引人入胜 新数据表明，后脑儿茶酚胺神经元是必不可少的 摄食和肾上腺髓质对葡萄糖普利反应的媒介， 在后脑和前脑之间提供糖感受部位和前脑之间的耦合 这些反应的脊髓输出神经元。这笔赠款的具体目的 应用是鉴定参与儿茶酚胺的特异神经元 葡萄糖摄取和肾上腺髓质分泌，并确定 它们各自的吻部和脊柱投射的功能组织。 研究将利用一些实验方法，包括测量 葡萄糖摄取和肾上腺髓质分泌，免疫毒素损伤， Fos免疫反应、逆行追踪和原位杂交鉴定 确切地说，参与每一项运动的特定儿茶酚胺神经元 糖调节反应及其侧支过程的分布。在……里面 此外，上升儿茶酚胺神经元激活的能力 含促食欲素多肽NPY、AgRP、ORX和MCH的下丘脑神经元 将使用原位杂交和选择性的 儿茶酚胺免疫毒素。参与脊髓投射的儿茶酚胺神经元 在葡萄糖治疗中，控制肾上腺髓质的特征将是 共定位多肽的鉴定、逆行示踪和原位检测 杂交。儿茶酚胺能神经元的功能关系 其他大脑部位提供肾上腺髓质的直接神经支配 将对节前神经元进行研究。

DESCRIPTION (applicant's abstract): 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.