FEAR, STRESS AND HIPPOCAMPAL PLASTICITY

描述（改编自申请人摘要）：McEwen和同事最近发现，颗粒神经元在成年大脑的齿状回（DG）中被取代，这种情况不仅发生在啮齿动物身上，也发生在树鼩和灵长类动物身上。此外，他们发现急性和慢性应激抑制DG的神经发生。杏仁核对DG的兴奋性和长期增强（LTP）有重要影响，杏仁核和DG都是应激的靶点，含有应激激素受体。项目4的中心假设是，应激源促进了杏仁核中的恐惧机制，并抑制了DG颗粒神经元的神经发生，无论是急性的还是慢性的；此外，慢性应激导致DG体积减少，连通性和功能改变，从而损害海马体参与情境依赖性恐惧的能力。研究的顺序如下。首先，与LeDoux （Project 1）合作，探索杏仁核和DG LTP，特别是杏仁核对DG LTP的影响。接下来，我们计划利用LeDoux （Project 1）研究约束应激和情境恐惧条件反射对DG神经发生的影响。第三，与LeDoux （Project 1）和Quantitative Morphology Core合作，反复应激对DG神经发生和结构的影响将与杏仁核和恐惧有关。第四，与Morrison （Project 3）合作，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（项目1）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。同时，在这些研究的基础上，我们计划评估情境恐惧条件反射中DG基因表达的变化。最后，我们计划与NYU的Mony de Leon合作，随后与Silbersweig， Stern， and Gorman合作（Project 2），利用MRI研究人脑海马萎缩的解剖学基础，并最终与动物脑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.