Significance of Stress-Induced Hippocampal Atrophy

压力引起的海马萎缩的意义

• 批准号: 6909975
• 负责人: CHERYL D CONRAD
• 金额: $ 19.55万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-12 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909975
• 关键词: atrophy; behavioral /social science research tag; corticosteroids; corticosterone; hippocampus; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; laboratory rat; memory disorders; neural degeneration; psychological stressor; stress

DESCRIPTION (provided by applicant): Chronic stress and the adrenal steroids secreted in response to stress (e.g. cortisol, corticosterone) are associated with hippocampal atrophy in several conditions including Cushing's Syndrome, recurrent depressive disorder, and aging. Even veterans with posttraumatic stress disorder, a condition with reduced cortisol at the time of diagnosis, display reduced hippocampi, leaving open the possibility that cortisol was elevated during the period of hippocampal shrinkage. A recent study suggests that cortisol elevations contribute to hippocampal shrinkage because reducing chronically elevated cortisol in Cushing's patients reverses hippocampal atrophy. Given the breadth and significance of these cortisol-related afflictions, the long-term objective of this proposal is to understand the consequences and mechanisms by which chronic stress and cortisol hypersecretion cause hippocampal atrophy. Dendritic retraction of CA3 neurons in rats provides a useful model to study the effects of chronic stress and elevated corticosterone on the hippocampus. Chronic stress-induced changes in CA3 dendrites parallel the human condition by shrinking after chronic stress/corticosterone treatment and reversing when the stress subsides. Thus, the mechanisms underlying stress-induced dendritic retraction are conserved across species. The objectives of this proposal are to determine the effects of chronic stress or elevated corticosterone on mechanisms of CA3 dendritic retraction and their functional significance. To achieve this goal, this proposal has three specific aims. First, to determine whether chronic stress-induced CA3 dendritic retraction is indicative of neuronal degeneration or a protective response. Second, to ascertain the levels of corticosterone that are sufficient to cause CA3 dendritic retraction and memory impairment. Third, to determine whether psychosocial stress produces CA3 dendritic retraction and to reveal the components of hippocampal-dependent memory (such as acquisition, consolidation, retrieval) that are disrupted. In all studies, corticosterone, corticosterone binding globulin, and dehydroepiandrosterone will be measured to determine whether other components of the hypothalamic-pituitary-adrenal axis are disrupted by chronic stress and whether they correlate with CA3 dendritic retraction and memory deficits.

描述（由申请人提供）：慢性应激和针对胁迫分泌的肾上腺固醇（例如皮质醇，皮质酮）在多种疾病中与海马萎缩有关，包括库欣综合征，经常性抑郁症和衰老。甚至具有创伤后应激障碍的退伍军人，诊断时皮质醇降低的疾病，海马降低，使皮质醇在海马收缩期间升高的可能性。最近的一项研究表明，皮质醇升高有助于海马收缩，因为库欣患者的长期升高皮质醇会逆转海马萎缩。鉴于这些与皮质醇相关的苦难的广度和意义，该提案的长期目标是了解慢性应激和皮质醇过度分泌引起海马萎缩的后果和机制。大鼠CA3神经元的树突缩回提供了一个有用的模型，以研究慢性应激和升高皮质酮对海马的影响。慢性应激诱导的CA3树突变化通过在慢性应激/皮质酮治疗后缩小并在压力消退时逆转来平行人类状况。因此，在物种之间，应激诱导的树突缩回的基础机制是保守的。该提案的目标是确定慢性应激或皮质酮升高对CA3树突回收机制及其功能意义的影响。为了实现这一目标，该提案具有三个具体目标。首先，确定慢性应激诱导的CA3树突回收是指示神经元变性还是保护性反应。其次，为了确定足以引起CA3树突缩回和记忆障碍的皮质酮的水平。第三，确定社会心理应力是否会产生CA3树突缩回，并揭示受破坏的海马依赖性记忆（例如获取，合并，检索）的组成部分。在所有研究中，将测量皮质酮，皮质酮结合球蛋白和脱氢表二耐甲蛋白，以确定下丘脑 - 垂体 - 肾上腺肾上腺轴的其他成分是否受到慢性应激的破坏，以及它们是否与CA3树突恢复和记忆缺陷相关。