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，这是一种危及生命的临床综合征，表现为因先前的低血糖发作而导致对低血糖的行为、自主和神经内分泌反应性降低。令人信服的证据表明，糖皮质激素参与了 HAAF 的发病机制，因为糖缺乏会显着升高糖皮质激素水平，并且外源性糖皮质激素的施用可以重现 HAAF 的症状。该提案将重点关注 HAAF 涉及的后脑机制。后脑葡萄糖感受器控制两种重要的葡萄糖调节反应，增加食物摄入和肾上腺髓质分泌。第一个具体目标是确定后脑糖受体是否也介导糖皮质激素分泌的糖皮质激素控制。第二个具体目标集中在后脑 NE/E 神经元。这些神经元对于进食、肾上腺髓质和皮质酮对糖缺乏的反应至关重要，其功能受损会导致类似于 HAAF 的症状。该提案将研究它们可能介导的皮质酮分泌控制的多种途径。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，这可能导致 HAAF 期间抑制其活动。许多这些神经元具有糖皮质激素受体。拟议的工作将尝试将特定 NE/E 神经元群上糖皮质激素受体的存在与它们的功能和参与 HAAF 联系起来。最后一个具体目标是确定导致 HAAF 的糖皮质激素升高的参数，特别关注分泌事件的幅度和持续时间。将检查皮质酮输注和对皮质酮分泌具有不同影响的特定应激源诱导 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.