Hindbrain mechanisms of hypoglycemia unawarness

描述（由申请人提供）：该项目的总体目标是了解低血糖相关自主神经衰竭（HAAF）的潜在机制，HAAF是一种危及生命的临床综合征，由先前的低血糖发作引起的行为、自主神经和神经内分泌对低血糖的反应性降低。令人信服的证据表明，糖皮质激素参与HAAF的发病机制，因为糖皮质激素在糖活化作用下显著升高，并且外源性糖皮质激素的使用可重现HAAF的症状。本文将重点研究HAAF的后脑机制。后脑糖受体控制两个重要的糖调节反应，增加食物摄入和肾上腺髓质分泌。第一个具体目的是确定后脑糖受体是否也介导糖皮质激素分泌的糖醛酸控制。第二个具体目标是后脑NE/E神经元。这些神经元对葡萄糖化的摄食、肾上腺髓质和皮质酮反应至关重要，其功能受损可导致类似HAAF的症状。本研究将探讨多种途径，通过它们控制皮质酮分泌可能介导。第三个具体目标是研究NE/E神经元作为皮质酮反馈效应位点的重要性，皮质酮反馈效应可能导致HAAF期间NE/E神经元活性的抑制。这些神经元中有许多具有糖皮质激素受体。这项工作将试图将特定NE/E神经元群上糖皮质激素受体的存在与它们在HAAF中的功能和参与联系起来。最后一个具体目的是确定导致HAAF的糖皮质激素升高的参数，特别关注分泌事件的大小和持续时间。皮质酮输注和对皮质酮分泌有不同影响的特定应激源将检查其诱导HAAF的能力。

DESCRIPTION (provided by applicant): The overall aim of this project is to understand the mechanisms underlying Hypoglycemia-Associated Autonomic Failure (HAAF), a life-threatening clinical syndrome of reduced behavioral, autonomic and neuroendocrine responsiveness to hypoglycemia resulting from prior hypoglycemic bouts. Compelling evidence indicates that glucocorticoids are involved in the pathogenesis of HAAF, because they are dramatically elevated by glucoprivation and because administration of exogenous glucocorticoids can reproduce the symptoms of HAAF. This proposal will focus on hindbrain mechanisms involved in HAAF. Hindbrain glucoreceptors control two important glucoregulatory responses, increased food intake and adrenal medullary secretion. The first specific aim is to determine whether hindbrain glucoreceptors also mediate the glucoprivic control of glucocorticoid secretion. The second specific aim focuses on hindbrain NE/E neurons. These neurons are crucial for feeding, adrenal medullary and corticosterone responses to glucoprivation and impairment in their function results in symptoms similar to HAAF. This proposal will investigate the multiple pathways through which their control of corticosterone secretion may be mediated. The third specific aim will investigate the importance of NE/E neurons as a site for corticosterone feedback effects that could result in suppression of their activity during HAAF. Many of these neurons possess glucocorticoid receptors. The proposed work will attempt to relate the presence of glucocorticoid receptors on specific populations of NE/E neurons with their functions and involvement in HAAF. The last specific aim is to identify the parameters of glucocorticoid elevation that result in HAAF with particular focus on the magnitude and duration of the secretory event. Corticosterone infusions and specific stressors with differing effects on corticosterone secretion will be examined for their ability to induce HAAF.