FEAR, STRESS AND HIPPOCAMPAL PLASTICITY

恐惧、压力和海马可塑性

• 批准号: 6336698
• 负责人: Bruce S. McEwen
• 金额: $ 29.64万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6336698
• 关键词: AMPA receptors; NMDA receptors; amygdala; atrophy; behavioral /social science research tag; bioimaging /biomedical imaging; brain mapping; clinical research; conditioning; corticosteroid receptors; dentate gyrus; fear; functional magnetic resonance imaging; gene expression; hormone regulation /control mechanism; human subject; laboratory rat; long term potentiation; neural plasticity; neurogenesis; pyramidal cells; receptor expression; restraint; stress

DESCRIPTION (Adapted from applicant's abstract): McEwen and colleagues have recently found that granule neurons are replaced in the dentate gyrus (DG) of the adult brain and that this occurs not only in rodents but also in tree shrews and primates. Moreover, they found that acute and chronic stress inhibit neurogenesis in the DG. The amygdala exerts an important influence on excitability and long-term potentiation (LTP) in the DG, and both the amygdala and DG are targets for stress and contain receptors for stress hormones. The central hypothesis of Project 4 is that stressors facilitate mechanisms subserving fear in the arnygdala and inhibit neurogenesis in granule neurons of the DG, both acutely and chronically; moreover, chronic stress results in decreased DG volume and altered connectivity and function that impairs the ability of the hippocampus to participate in context-dependent fear. The sequence of studies is as follows. First, in collaboration with LeDoux (Project 1), amygdala and DG LTP will be explored, especially focusing on amygdala influences on DG LTP. Next, also with LeDoux (Project 1), we plan to investigate the effects of restraint stress and contextual fear conditioning on DG neurogenesis. Third, in collaboration with LeDoux (Project 1) and the Quantitative Morphology Core, the effects of repeated stress on DG neurogenesis and structure will be examined in relation to the amygdala and fear. Fourth, in collaboration with Morrison (Project 3), the effects of stress and glucocorticoid manipulations on the expression and distribution of NMDA and other excitatory amino acid receptors in the DG will be determined. Based upon the neurogenesis findings, we plan to determine if turnover of DG neurons affects stability of fear conditioning, again in collaboration with LeDoux (Project 1). Concurrently, with these studies, and based upon our initial results, we plan to assess changes in DG gene expression during contextual fear conditioning. Finally, in collaboration with Mony de Leon of NYU, and later in conjunction with Silbersweig, Stern, and Gorman (Project 2), we plan to investigate the anatomical basis of hippocampal atrophy in the human brain with MRI and eventually compare this with animal brain MRI, in particular, establishing and validating methods for measuring DG volume.

描述（改编自申请人的摘要）：McEwen及其同事最近发现，成人大脑的牙齿回（DG）中替换了颗粒神经元，这不仅发生在啮齿动物中，而且发生在树丛和灵长类动物中。此外，他们发现急性和慢性应激抑制了DG中的神经发生。杏仁核对DG中的兴奋性和长期增强（LTP）产生了重要影响，而杏仁核和DG均为应力的靶标，并含有应力激素的受体。项目4的中心假设是，压力源促进了ARNYGDALA中恐惧的机制，并抑制DG颗粒神经元的神经发生，无论是急性而慢性地还是长期以来。此外，慢性应激会导致DG体积减少，并改变了连通性和功能，从而损害了海马参与上下文依赖性恐惧的能力。研究顺序如下。首先，将探讨与Ledoux（项目1）合作，Amygdala和DG LTP，尤其是专注于杏仁核对DG LTP的影响。接下来，同样在Ledoux（项目1）的情况下，我们计划研究约束压力和情境恐惧调节对DG神经发生的影响。第三，与Ledoux（项目1）和定量形态核心合作，将根据杏仁核和恐惧研究重复应力对DG神经发生和结构的影响。第四，与莫里森（项目3）合作，将确定应力和糖皮质激素操纵对DG中NMDA和其他兴奋性氨基酸受体的表达和分布的影响。基于神经发生的结果，我们计划确定DG神经元的营业额是否影响恐惧调节的稳定性，再次与Ledoux合作（项目1）。同时，与这些研究并基于我们的最初结果，我们计划在上下文恐惧条件下评估DG基因表达的变化。最后，与纽约大学的Mony de Leon合作，后来与Silbersweig，Stern和Gorman（项目2）结合使用，我们计划研究人脑中海马萎缩的解剖学基础与MRI的解剖学基础，并最终与动物脑MRI相比，尤其是与动物脑MRI相比，尤其是用于测量DG量的方法。