CNS Stress Pathways and the Development of Acute HAAF

CNS 应激通路与急性 HAAF 的发展

• 批准号: 6548808
• 负责人: DIANNE FIGLEWICZ LATTEMANN
• 金额: $ 12.34万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6548808
• 关键词: autonomic disorder; autonomic nervous system; benzodiazepines; blood glucose; central nervous system; disease /disorder model; hypoglycemia; immunocytochemistry; inhibitor /antagonist; insulin dependent diabetes mellitus; laboratory rat; medical complication; neuroendocrine system; neurotransmitter transport; paraventricular nucleus; physiologic stressor; thalamus

DESCRIPTION (provided by applicant): A major complication for insulin-requiring diabetic individuals is the development of Hypoglycemia Associated Autonomic Failure, or HAAF. In the acute form of the syndrome the experience of two or more bouts of hypoglycemia within a 24-hour period results in a blunting of the neuroendocnne counterregulatory response which would normally correct plasma glucose levels. This phenomenon can be modeled in non-diabetic humans and experimental animals, and appears to represent a form of 'stress adaptation'. With other stressors, repeated exposure to the same stressor results in a blunting of the neuroendocrine stress response to that stress. We have developed a rat model of HAAF and have found that, concomitant with the blunted neuroendocnne response, patterns of brain activation (reflected in expression of c-fos) are altered when rats are exposed to three (vs. one) bouts of hypoglycemia in a 24-hr period. Specifically c-fos was decreased in the paraventricular (PVN) and dorsomedial (DMH) hypothalamic areas, with no change in activation of the posterior paraventricular nucleus of the thalamus (THPVP), a region which has net inhibitory input to the PVN. We concluded that a combination of decreased stimulatory input (DMH) and unchanged inhibitory input (THPVP) to the PVN may play a significant role in the decreased neural activation of the PVN and thus decreased downstream neuroendocrine activation. In this series of studies we propose to test the roles of these two brain areas, which are important in the mediation of neuroendocnne responses to other types of stressors, in the neuroendocrine response to hypoglycemic stress and in the development of HAAF. We will reversibly inactivate the THPVP and the DMH with lidocaine or the inhibitory GABA analog muscimol and measure neuroendocnne responses to hypoglycemia, with hypothesized outcomes of reversal of HAAF or simulation of HAAF, respectively. Additionally, we will test the hypothesis that a net increase of inhibitory input at the PVN (reflected by GABAergic transmission) causes the expression of HAAF, by blocking GABAergic activity in the PVN in rats that are experiencing a third bout of hypoglycemia. Together these studies will provide new insight into the role of two stress-regulatory brain regions in the normal counterrregulatory response to hypoglycemia, and in the expression of HAAF; and they will further validate the role of the PVN in mediating counterregulation to hypoglycemia.

描述（由申请人提供）：需要胰岛素的糖尿病患者的一个主要并发症是低血糖相关自主神经衰竭（HAAF）的发生。在该综合征的急性形式中，24小时内经历两次或多次低血糖会导致通常纠正血浆葡萄糖水平的神经内分泌反调节反应减弱。这种现象可以在非糖尿病人类和实验动物中进行模拟，并且似乎代表了一种“压力适应”形式。对于其他压力源，重复暴露于相同的压力源会导致神经内分泌应激反应减弱。我们开发了一种 HAAF 大鼠模型，并发现，当大鼠经历 3 次（相对于 1 次）低血糖时，伴随神经内分泌反应减弱，大脑激活模式（反映在 c-fos 的表达中）会发生改变。 24 小时期间。具体而言，下丘脑室旁 (PVN) 和背内侧 (DMH) 区域的 c-fos 减少，但丘脑室旁核后部 (THVP) 的激活没有变化，该区域对 PVN 具有净抑制输入。我们的结论是，PVN 刺激输入 (DMH) 减少和抑制输入不变 (THVP) 的组合可能在 PVN 神经激活减少中发挥重要作用，从而减少下游神经内分泌激活。在这一系列研究中，我们建议测试这两个脑区的作用，这两个脑区在调节神经内分泌对其他类型应激源的反应、对低血糖应激的神经内分泌反应以及 HAAF 的发展中发挥着重要作用。我们将用利多卡因或抑制性 GABA 类似物蝇蕈醇可逆地灭活 THPVP 和 DMH，并测量神经内分泌对低血糖的反应，并分别假设逆转 HAAF 或模拟 HAAF 的结果。此外，我们将测试以下假设：PVN 抑制输入的净增加（通过 GABA 能传递反映）通过阻断正在经历第三次低血糖的大鼠 PVN 中的 GABA 能活性来导致 HAAF 的表达。这些研究共同将为两个压力调节大脑区域在低血糖正常反调节反应以及 HAAF 表达中的作用提供新的见解。他们将进一步验证 PVN 在介导低血糖反调节中的作用。