HPA REGULATION IN STRESS: THE DORSOMEDIAL HYPOTHALAMUS

压力下的 HPA 调节：下丘脑背内侧

• 批准号: 6033362
• 负责人: JOSEPH A DIMICCO
• 金额: $ 4.68万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6033362
• 关键词: GABA receptor; behavioral /social science research tag; bicuculline; biological models; cardiovascular function; circadian rhythms; corticosteroids; disease /disorder model; early experience; glucocorticoids; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; hypothalamus; laboratory rat; lipopolysaccharides; microinjections; muscimol; neuroendocrine system; neurons; newborn animals; panic disorder; psychological stressor; psychophysiology; stress

Stress elicits a pattern of physiological and behavioral changes that are remarkably similar in different mammalian species. A salient feature of this response is recruitment of the hypothalamic-pituitary adrenal (HPA) axis, and alterations in HPA function are seen in a number of human psychopathologic states. Recently, neurons in the dorsomedial hypothalamus (DMH) have been implicated in the generation of a host of stress-induced physiologic and behavioral changes in rats including recruitment of the HPA axis in an experimental paradigm for emotional stress. These potential "command neurons" for the stress response are under tonic GABAA receptor-mediated inhibition. Intriguingly, chronic dysfunction of GABAergic inhibition in this region in rats results in a condition bearing striking similarities to panic disorder in humans. GABAergic mechanisms in the hypothalamus - and particularly GABAA receptors - appear to be subject to a remarkable degree of plasticity; In fact, experimental evidence suggests that circulating glucocorticoids may influence the subunit composition of GABAA receptors to alter their function. These findings support the hypothesis that perinatal events that alter responsivity of the HPA axis in adult rats do so by altering GABAergic mechanisms in the DMH - perhaps through influencing the subunit composition of local GABAA receptors - and that such a mechanism may play a role in human psychopathology, including susceptibility to panic attack and anxiety disorders. This proposal is to facilitate the interaction of a group of investigators, many of whom have contributed important elements of this story, in pursuit of key preliminary data that would shed light on the regulation of the HPA axis in stress and at the same time provide potential support for this hypothesis. Included among their collective expertise are perspectives and approaches ranging from molecular biology, electrophysiology, neuroendocrinology and neuroimmunology, and behavioral paradigms to clinical experience and study of anxiety, panic disorder, and related psychopathologies in humans. Pilot studies are planned to (a) examine the regulation of HPA function in an animal model for panic disorder based on chronic dysfunction of GABAergic inhibition in the DMH, and (b) assess the effect of neonatal treatment with bacterial lipopolysaccharide (LPS), an intervention that has been shown to cause hyperresponsivity of the HPA axis to experimental stress in these rats as adults, on GABAA receptors in this region.

压力引起的一种生理和行为变化的模式在不同的哺乳动物物种中非常相似。 这种反应的一个显着特征是募集下丘脑 - 垂体肾上腺（HPA）轴，并且在许多人类心理病理状态下都可以看到HPA功能的改变。最近，背侧下丘脑（DMH）中的神经元与大鼠的大量胁迫诱导的生理和行为变化有关，包括在情绪压力的实验范式中募集HPA轴。这些潜在的“指挥性神经元”用于应激反应，在补品GABAA受体介导的抑制下。 有趣的是，该区域中GABA能抑制的慢性功能障碍导致与人类恐慌症相似的条件。 下丘脑，尤其是GABAA受体的GABA能机制似乎具有显着的可塑性。实际上，实验证据表明，循环的糖皮质激素可能会影响GABAA受体的亚基组成以改变其功能。 这些发现支持以下假设：成年大鼠中改变HPA轴的围产期事件是通过改变DMH中的GABA能机制来做到的，这也许是通过影响局部GABAA受体的亚基组成的，并且这种机制可能在人类心理病理学中起作用，包括对人类心理病理学的作用，包括对泛滥和焦虑症的敏感性。 该提议是为了促进一组研究人员的相互作用，其中许多人贡献了这个故事的重要要素，以追求关键的初步数据，这些数据将揭示压力下的HPA轴的调节，同时为这一假设提供了潜在的支持。 他们的集体专业知识包括分子生物学，电生理学，神经内分泌学和神经免疫学以及行为范式到临床经验以及对人类焦虑症，恐慌症以及相关的精神病理学的临床经验和研究。 计划（a）基于DMH中GABA能抑制作用的长期功能障碍，研究动物模型中HPA功能的调节，以及（b）评估新生儿治疗对细菌脂多糖（LPS）（LPS）的影响，这是对高度质量hPASAS a axis axis axis axiS axis axiS axiS axiS axia axiS axi a x axiS axi a x axiS axiS axiS axis axiS axiS axiS axiS axi a x axi a x axi a x axi as axis axis axi axiS的影响。该地区的受体。