Fear, Stress and Neural Structural Plasticity

GRANT=P50MH58911-06-0004 压力经历会引发精神疾病，包括抑郁症和创伤后应激障碍。应激包括焦虑和恐惧，其中杏仁核是大脑的关键区域，而下丘脑-垂体-肾上腺(HPA)轴通过糖皮质激素调节基因表达并导致与其他介质(如兴奋性氨基酸神经递质)相互作用的下游效应，在调节应激对大脑和身体其他部分的影响方面发挥着重要作用。我们发现，急性和慢性应激会增加恐惧和焦虑，我们认为这至少部分是通过我们在海马体中发现的应激诱导的结构可塑性(树突重塑、脊突突触形成和神经发生抑制)来实现的。我们发现，应激还会导致杏仁核和前额叶皮质的结构可塑性(树突重塑、棘突突触形成)。在与项目1和3以及成像核心的合作下，我们打算研究这些大脑区域之间在调节结构可塑性方面的相互作用，因为杏仁核与这些和其他大脑区域进行通信，并共同调节作为项目1主题的未习得恐惧、恐惧条件反射、再巩固和灭绝的复杂影响。 项目4使用成像核心的定量形态方法和技术，如原位杂交、免疫细胞化学和向杏仁核立体定向递送药物，在细胞和分子水平上检查应激诱导的结构可塑性。其中包括将基因输送到特定大脑区域的病毒载体。在动物模型中，急性和慢性应激的一些影响在雄性和雌性之间有所不同，至少部分原因是性腺激素在成年生活和发育过程中的作用。因此，还将与所有其他项目合作调查这些性别差异的各个方面。在与Proj.2的合作中，我们将努力将这些发现转化为人类大脑，因为在人类抑郁症和焦虑症中发现杏仁核、海马体和前额叶皮质的活动和结构发生了长期的变化。

GRANT=P50MH58911-06-0004 Stress experiences can precipitate psychiatric illnesses, including depression and post-traumatic stress disorder. Stress includes anxiety and fear, for which the amygdala is a key brain region, and the hypothalamo-pituitary-adrenal (HPA) axis plays an important role in mediating the effects of stress both on the brain and the rest of the body via the ability of glucocorticoids to regulate gene expression and lead to downstream effects that interact with other mediators, such as excitatory amino acid neurotransmitters. We have found that acute and chronic stress increases fear and anxiety and we propose that they do so, at least in part, by stress-induced structural plasticity (dendritic remodeling, spine synapse formation and suppression of neurogenesis) that we have found in hippocampus. We have found that stress also cause structural plasticity (dendritic remodeling, spine synapse formation) in amygdala and prefrontal cortex. In collaboration with Proj 1 and 3 and the Imaging Core, we intend to study the interactions between these brain areas in regulating structural plasticity because the amygdala communications with these and other brain areas and together they mediate the complex effects on unlearned fear, fear conditioning, reconsolidation and extinction that are the topic of Proj.1. Project.4 examines stress-induced structural plasticity at the cellular and molecular levels using quantitative morphological methods with the Imaging Core and techniques such as in situ hybridization, immunocytochemistry and stereotaxic delivery of agents into the amygdala. These include viral vectors for delivering genes to specific brain regions. Some of the effects of acute and chronic stress in animal models differ between males and females, at least in part because of the actions of gonadal hormones in adult life and also during development. As a result, aspects of these gender differences will also be investigated in collaboration with all of the other projects. In collaboration with Proj.2, we will endeavor to translate these findings to the human brain, because long lasting changes in activity and structure of the amygdala, hippocampus and prefrontal cortex have been found in human depressive illness and anxiety disorders.