Hindbrain mechanisms of hypoglycemia unawarness

描述(由申请人提供)：本项目的总体目标是了解低血糖相关自主神经衰竭(HAAF)的机制，HAAF是一种危及生命的临床综合征，其行为、自主神经和神经内分泌反应对先前的低血糖发作导致的低血糖反应降低。令人信服的证据表明，糖皮质激素参与了HAAF的发病机制，因为糖皮质激素可显著升高它们的水平，而且外源性糖皮质激素的应用可以重现HAAF的症状。这项提案将重点放在HAAF涉及的后脑机制上。后脑糖受体控制两个重要的糖调节反应，增加食物摄入量和肾上腺髓质分泌。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。这些神经元在进食、肾上腺髓质和皮质酮对葡萄糖代谢的反应中起着至关重要的作用，它们的功能受损会导致类似HAF的症状。这项建议将调查他们控制皮质酮分泌的多种途径。第三个具体目标将调查NE/E神经元作为皮质酮反馈效应的重要性，皮质酮反馈效应可能导致在HAAF期间其活动受到抑制。这些神经元中有许多具有糖皮质激素受体。这项拟议的工作将试图将NE/E神经元特定群体上糖皮质激素受体的存在与它们的功能和参与HAF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大小和持续时间。皮质酮注射和对皮质酮分泌有不同影响的特定应激源将被检测其诱发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.