Stress, Adrenal Steroids and the Brain

描述(申请人提供)：对应激源的反应包括基本的、综合的大脑行为反应，这些反应是为了确保生存，最初对许多过程具有保护性和适应性，如避免和警惕威胁，以及记忆、免疫功能和新陈代谢。压力也可能有有害的影响，包括情绪变化和焦虑，如果在应激源终止后持续存在，可能会成为焦虑或抑郁障碍。大脑对压力的一个显著反应是结构可塑性，这种可塑性在海马体结构中得到了最广泛的研究，现在在前额叶皮质(PFC)和杏仁核中也发现了这种可塑性。在幼年动物中，这种可塑性在慢性应激后在很大程度上是可逆的，但在年长的动物中就失去了这种可塑性。因此，我们认为慢性压力会导致一种“加速衰老”，即弹性丧失。如果这些行为和结构变化不能自发恢复，不适当的神经行为功能，如焦虑或抑郁，可能会持续存在，并变得不适应。应激对结构可塑性和其他功能的影响涉及内源性大麻素、兴奋性氨基酸、糖皮质激素和神经保护剂之间的相互作用，如伴侣BAG1。这一建议的中心假设是，除了适应行为赋予的韧性之外，海马体和前额叶皮质以结构可塑性形式表现的韧性是健康大脑对压力反应的一个特征。相比之下，弹性丧失是情绪和焦虑障碍的一个特征，可能是反复应激的结果，反复应激是糖皮质激素(GC)和兴奋性氨基酸(EAA)反复升高的结果，这些激素共同激活与氧化应激和可能的炎症相关的基因，还改变神经传递和细胞骨架。我们计划通过干扰内源性大麻素(ECB)和BAG1伴侣系统来识别与应激和GC效应相关的基因和基因产物，这些系统调节海马区和应激敏感的mPFC中的糖皮质激素和EAA的作用。我们推测，ECB和BAG1信号的减少将增加CA3和mPFC神经元的脆弱性，并导致弹性丧失。我们还计划使用BAC转基因小鼠深入研究易受压力影响的CA3神经元。目的1.慢性应激和慢性糖皮质激素暴露如何改变行为和PFC和CA3的形态，并影响脆弱的CA3神经元的基因表达模式？目的2.内源性大麻素CB1受体在缓解慢性应激的负面影响以及在海马区和前额叶皮质中的作用是什么？目的3.神经保护因子和糖皮质激素受体(GR)伴侣蛋白BAG1在慢性应激对海马区和前额叶皮质的行为、形态和基因表达的影响中有何调节作用？我们的工作对生物精神病学领域产生了重大影响，因为我们将注意力集中在压力导致的大脑结构变化上。

DESCRIPTION (provided by applicant): The response to stressors involves essential, integrative brain-behavior reactions that are engaged in order to ensure survival and are initially protective and adaptive for many processes such as avoidance of, and vigilance towards, threat, as well as memory, immune function and metabolism. Stress can also have deleterious effects, including mood alterations and anxiety that, if they persist after the stressor is terminated, can become an anxiety or depressive disorder. One salient response of the brain to stress can be seen in the form of structural plasticity that has been most extensively studied in the hippocampal formation and is now found in prefrontal cortex (PFC) and amygdala. In young animals, this plasticity is largely reversible after chronic stress but the reversal is lost in older animals. Thus we propose that chronic stress causes a type of "accelerated aging", i.e., a loss of resilience. If these behavioral and structural changes do not spontaneously recover, inappropriate neurobehavioral functions, such as anxiety or depression, can persist and become maladaptive. Stress effects on structural plasticity and other functions involve interactions among endocannabinoids, excitatory amino acids and glucocorticoids and neuroprotective agents, such as the chaperone, BAG1. The central hypothesis of this proposal is that, along with resilience conferred by adaptive behaviors, resilience in the form of structural plasticity in the hippocampus and prefrontal cortex is a feature of the healthy brain's response to stress. In contrast, loss of resilience is a feature of mood and anxiety disorders and may be a consequence of repeated stress that is mediated by repeated elevation of glucocorticoids (GC's) and excitatory amino acids (EAA) that, together, activate genes related to oxidative stress and possibly inflammation and also alter neurotransmission and cytoskeleton. We plan to identify genes and gene products related to stress and GC effects by perturbing the endocannabinoid (eCB) and BAG1 chaperone systems that modulate glucocorticoid and EAA actions in hippocampus and also in the stress-sensitive mPFC. We postulate that reduced eCB and BAG1 signaling will increase the vulnerability of CA3 and mPFC neurons and confer a loss of resilience. We also plan to look in depth at stress-vulnerable CA3 neurons using a BAC transgenic mouse. There are three Specific Aims: Aim 1. How do chronic stress and exposure to chronic glucocorticoid alter behavior and PFC and CA3 morphology and affect the pattern of gene expression in vulnerable CA3 neurons? Aim 2. What is the role of endocannabinoid CB1 receptors in moderating negative effects of chronic stress and in hippocampus and prefrontal cortex? Aim 3. What is the moderating role of the neuroprotective factor and glucocorticoid receptor (GR) chaperone, BAG1, in effects of chronic stress on behavior, morphology and gene expression in hippocampus and prefrontal cortex? Our work has had major impact on the field of biological psychiatry by directing attention to structural changes in the brain as a result of stress.