FEAR, STRESS AND HIPPOCAMPAL PLASTICITY

描述（改编自申请人的摘要）：麦克尤恩及其同事最近发现，成年大脑的齿状回（DG）中的颗粒神经元被替换，这不仅发生在啮齿动物中，也发生在树鼩和灵长类动物中。此外，他们发现急性和慢性应激抑制DG中的神经发生。杏仁核对DG的兴奋性和长时程增强（LTP）有重要影响，杏仁核和DG都是应激的靶点，并含有应激激素的受体。项目4的中心假设是，应激促进机制subserving恐惧的arnygdala和抑制颗粒神经元的DG的神经发生，急性和慢性;此外，慢性应激导致DG体积减少和改变连接和功能，损害海马体的能力，参与上下文相关的恐惧。研究顺序如下。首先，与LeDoux（项目1）合作，杏仁核和DG LTP将被探索，特别是集中在杏仁核对DG LTP的影响。接下来，也与LeDoux（项目1），我们计划调查约束压力和情境恐惧条件反射对DG神经发生的影响。第三，与LeDoux（项目1）和定量形态学核心合作，将研究反复应激对DG神经发生和结构的影响与杏仁核和恐惧的关系。第四，与莫里森（项目3）合作，将确定应激和糖皮质激素操作对DG中NMDA和其他兴奋性氨基酸受体的表达和分布的影响。基于神经发生的发现，我们计划再次与LeDoux合作，确定DG神经元的周转是否影响恐惧条件反射的稳定性（项目1）。与此同时，这些研究，并根据我们的初步结果，我们计划评估DG基因表达的变化在上下文恐惧条件反射。最后，与纽约大学的Mony德莱昂合作，后来与Silbersweig，Stern和Gorman（项目2）合作，我们计划用MRI研究人脑海马萎缩的解剖学基础，并最终将其与动物脑MRI进行比较，特别是建立和验证测量DG体积的方法。

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.