Stress, Adrenal Steroids and the Brain

压力、肾上腺类固醇和大脑

• 批准号: 8270477
• 负责人: Bruce S. McEwen
• 金额: $ 42.38万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270477
• 关键词: Adaptive Behaviors; Adrenal Glands; Affect; Aggressive behavior; Aging; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; BAG1 gene; Behavior; Behavioral; Biological Psychiatry; Brain; Brain Diseases; Brain region; CNR1 gene; Cell Nucleus; Chronic; Chronic stress; Cognitive; Cytoskeleton; Decision Making; Depressive disorder; Endocannabinoids; Ensure; Excitatory Amino Acids; Exposure to; Failure; Gene Expression; Gene Expression Profile; Genes; Glucocorticoid Receptor; Glucocorticoids; Growth; Health; Health Care Costs; Hippocampal Formation; Hippocampus (Brain); Hormones; Inflammation; Lead; Medial; Mediating; Memory; Mental Depression; Mental disorders; Metabolism; Mitochondria; Modeling; Molecular Chaperones; Mood Disorders; Moods; Morphology; National Institute of Mental Health; Nature; Neurons; Neuroprotective Agents; Oxidative Stress; Prefrontal Cortex; Prevention; Process; Productivity; Proteins; Reaction; Role; Short-Term Memory; Signal Transduction; Steroids; Strategic Planning; Stream; Stress; System; Transgenic Mice; Work; brain behavior; cognitive function; computerized data processing; dentate gyrus; directed attention; disturbance in affect; executive function; flexibility; immune function; indexing; information processing; juvenile animal; neurobehavioral; neurotransmission; protective effect; receptor; resilience; response; stressor; vigilance

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.

描述（由申请人提供）：对压力源的反应涉及为了确保生存而进行的必要的，综合性的脑行为反应，最初具有保护性并适应许多过程，例如避免，对威胁，记忆，免疫功能和代谢的避免和警惕。压力也会产生有害的影响，包括情绪改变和焦虑，如果压力终止后持续存在，则会成为焦虑或抑郁症。大脑对压力的一种显着反应可以以结构可塑性的形式看到，这在海马形成中最广泛地研究了，现在在额叶皮层（PFC）和杏仁核中发现。在年轻动物中，这种可塑性在慢性压力后在很大程度上是可逆的，但在老年动物中逆转损失。因此，我们建议慢性应激会导致一种“加速衰老”，即弹性丧失。如果这些行为和结构性变化不会自发恢复，那么诸如焦虑或抑郁之类的不适当神经行为功能会持续并变得适应不良。压力对结构可塑性和其他功能的影响涉及内源性大麻素，兴奋性氨基酸和糖皮质激素和神经保护剂之间的相互作用，例如伴侣蛋白，Bag1。该提议的中心假设是，与适应性行为所赋予的弹性一起，海马和前额叶皮层的结构可塑性形式是健康大脑对压力的反应的特征。相比之下，弹性的丧失是情绪和焦虑症的特征，可能是反复压力的结果，这是由于糖皮质激素（GC）（GC）和兴奋性氨基酸（EAA）的反复介导的，它们共同激活了与氧化应激有关的基因，可能与氧化应激有关，可能是可能的炎症以及可能会改变神经氟胰者以及改变神经转培养和Cytosskeleton。我们计划通过扰动内源性大麻素（ECB）和BAG1伴侣系统来鉴定与胁迫和GC效应有关的基因和基因产物，这些系统在海马以及在压力敏感的MPFC中调节糖皮质激素和EAA作用。我们假设减少的欧洲央行和BAG1信号传导将增加CA3和MPFC神经元的脆弱性，并赋予弹性丧失。我们还计划深入探究使用BAC转基因小鼠的可应激构成CA3神经元。有三个特定的目的：目标1。慢性应激和暴露于慢性糖皮质激素改变行为和PFC和CA3形态，并影响脆弱的CA3神经元中基因表达的模式？目标2。内源性大麻素CB1受体在调节慢性应激以及海马和前额叶皮层的负面影响中的作用是什么？目标3。神经保护因子和糖皮质激素受体（GR）伴侣BAG1的调节作用在慢性应激对海马和前额叶皮质中行为，形态和基因表达的影响？由于压力，我们的工作对生物精神病学领域产生了重大影响。