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.

压力引起的生理和行为变化模式在不同哺乳动物物种中非常相似。 这种反应的一个显着特征是下丘脑-垂体肾上腺 (HPA) 轴的募集，并且在许多人类精神病理学状态中都可以看到 HPA 功能的改变。最近，下丘脑背内侧 (DMH) 的神经元与大鼠应激引起的一系列生理和行为变化的产生有关，包括在情绪应激实验范式中招募 HPA 轴。这些潜在的应激反应“命令神经元”受到 GABAA 受体介导的强直性抑制。 有趣的是，大鼠该区域 GABA 能抑制的慢性功能障碍会导致与人类惊恐障碍惊人相似的病症。 下丘脑中的 GABA 能机制——尤其是 GABAA 受体——似乎具有显着的可塑性。事实上，实验证据表明循环中的糖皮质激素可能会影响 GABAA 受体的亚基组成，从而改变其功能。 这些发现支持以下假设：改变成年大鼠 HPA 轴反应性的围产期事件是通过改变 DMH 中的 GABA 能机制（可能是通过影响局部 GABAA 受体的亚基组成）来实现的，并且这种机制可能在人类中发挥作用。精神病理学，包括对惊恐发作和焦虑症的易感性。 该提案旨在促进一组研究人员的互动，其中许多人为这个故事做出了重要贡献，以寻求关键的初步数据，这些数据将揭示压力下 HPA 轴的调节，同时提供潜在的支持这一假设。 他们的集体专业知识包括从分子生物学、电生理学、神经内分泌学和神经免疫学、行为范式到人类焦虑、恐慌症和相关精神病理学的临床经验和研究的观点和方法。 试点研究计划 (a) 在基于 DMH 中 GABA 能抑制的慢性功能障碍的惊恐障碍动物模型中检查 HPA 功能的调节，以及 (b) 评估用细菌脂多糖 (LPS) 治疗新生儿的效果，LPS 是一种研究表明，这种干预措施会导致这些成年大鼠的 HPA 轴对该区域的 GABAA 受体的实验应激反应过度。