FEAR, STRESS AND HIPPOCAMPAL PLASTICITY

描述(摘自申请者的摘要)：McEwen和他的同事最近发现，颗粒神经元被替换在成年大脑的齿状回(DG)中，这不仅发生在啮齿动物身上，也出现在树鼠和灵长类动物身上。此外，他们发现，急性和慢性应激抑制了DG内的神经发生。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，应激源促进杏仁核中服从恐惧的机制，并抑制DG颗粒神经元中的神经发生，无论是急性还是慢性；此外，慢性应激导致DG体积减少，连接和功能改变，从而削弱海马体参与上下文依赖性恐惧的能力。研究的顺序如下。首先，与LeDoux合作(项目1)，将探索杏仁核和DG LTP，特别是杏仁核对DG LTP的影响。下一步，也是与LeDoux(项目1)一起，我们计划研究束缚应激和情境恐惧条件作用对DG神经发生的影响。第三，与LeDoux(项目1)和Quantity Morphology Core合作，将研究重复应激对DG神经发生和结构的影响与杏仁核和恐惧的关系。第四，与莫里森合作(项目3)，将确定应激和糖皮质激素操作对DG内NMDA和其他兴奋性氨基酸受体表达和分布的影响。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)。同时，在这些研究的基础上，基于我们的初步结果，我们计划评估DG基因在情景恐惧条件反射过程中的表达变化。最后，与纽约大学的Mony De Leon合作，以及后来与SilberSweig、Stern和Gorman(项目2)的合作，我们计划用MRI研究人脑中海马体萎缩的解剖学基础，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.