Neural Mechanisms Underlying Stress-Induced Changes In Behavior

描述（由申请人提供）：暴露于压力，心理社会刺激可导致各种情感障碍，包括抑郁症，广泛性焦虑症和创伤后应激障碍。血清素是一种关键的神经化学信号，在应激敏感性精神病理学的表达和治疗中起着关键作用。在动物模型中，5-羟色胺作用于几个大脑区域，包括基底外侧杏仁核（BLA），以调节压力诱导的焦虑和抑郁行为变化。在目前的建议中，我们将使用叙利亚仓鼠的社会失败模型，称为条件性失败，在心理社会背景下调查压力引起的行为变化。在我们的条件性失败模型中，当个体后来与一个较小的、非攻击性的对手进行测试时，社会性失败导致物种典型的领土攻击性完全丧失，顺从和防御行为大幅增加。在我们的工作模型中，我们提出，社会失败激活5-HT神经元，5-羟色胺反过来调节条件性失败的形成，通过影响关键因素，调节BLA的神经可塑性，如cAMP反应元件结合蛋白（CREB）和脑源性神经营养因子（BDNF）。更具体地说，我们建议，5-羟色胺调节条件性失败的形成，通过在5-HT 1A受体在BLA的损害CREB-BDNF通路和5-HT 2C受体在BLA的作用，以促进CREB-BDNF通路。在本报告中，我们将测试四个预测。首先，我们将测试的预测，5-HT 1A受体拮抗剂注射到BLA将增强收购和条件性失败的表达。第二，我们将测试的预测，即5-HT 2C受体激动剂的全身给药将提高收购和条件性失败的表达，和5-HT 2C受体激动剂的效果将被阻断的5-HT 2C受体拮抗剂注射到BLA。第三，我们将测试的预测，5-HT 1A的中缝背核中的自身受体的药理学激活将阻止失败引起的增加磷酸化CREB免疫反应性内的BLA。第四，我们将测试的预测，药理学激活中缝背核5-HT 1A自身受体将阻止失败诱导的BLA内BDNF mRNA表达的增加。 公共卫生相关性：暴露于压力，心理社会刺激可导致各种情绪障碍，包括重度抑郁症，广泛性焦虑症和创伤后应激障碍。在这项提案中，我们正在研究选择大脑区域的神经化学信号如何控制社交失败经历后发生的行为变化。研究失败引起的行为变化背后的神经机制应该会更好地理解与压力相关的精神病理学，并最终为这些精神障碍提供更好的治疗方案。

DESCRIPTION (provided by applicant): Exposure to stressful, psychosocial stimuli can lead to a variety of affective disorders, including depression, generalized anxiety disorder, and post-traumatic stress disorder. Serotonin is a key neurochemical signal that plays a pivotal role in the expression and treatment of stress-sensitive psychopathologies. In animal models, serotonin acts in several brain regions, including the basolateral amygdala (BLA), to regulate stress-induced changes in behavior indicative of anxiety and depression. In the current proposal, we will use a social defeat model in Syrian hamsters, called conditioned defeat, to investigate stress-induced changes in behavior within a psychosocial context. In our conditioned defeat model, social defeat results in a complete loss of species-typical territorial aggression and a substantial increase in submissive and defensive behavior when individuals are later tested with a smaller, non-aggressive opponent. In our working model, we propose that social defeat activates 5-HT neurons and that serotonin in turn modulates the formation of conditioned defeat by affecting key factors that regulate neural plasticity in the BLA such as cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF). More specifically, we propose that serotonin modulates the formation of conditioned defeat by acting at 5-HT1A receptors in the BLA to impair the CREB-BDNF pathway and acting at 5-HT2C receptors in the BLA to facilitate the CREB-BDNF pathway. In the current proposal we will test four predictions. First, we will test the prediction that injection of a 5-HT1A receptor antagonist into the BLA will enhance the acquisition and expression of conditioned defeat. Second, we will test the prediction that systemic administration of a 5-HT2C receptor agonist will enhance the acquisition and expression of conditioned defeat, and that the effects of the 5-HT2C receptor agonist will be blocked by injection of a 5-HT2C receptor antagonist into the BLA. Third, we will test the prediction that pharmacological activation of 5-HT1A autoreceptors in the dorsal raphe nucleus will block defeat-induced increases in phosphorylated CREB immunoreactivity within the BLA. Fourth, we will test the prediction that pharmacological activation of 5-HT1A autoreceptors in the dorsal raphe nucleus will block defeat-induced increases in BDNF mRNA expression within the BLA. PUBLIC HEALTH RELEVANCE: Exposure to stressful, psychosocial stimuli can lead to a variety of mood disorders, including major depression, generalized anxiety disorder, and post-traumatic stress disorder. In this proposal, we are investigating how neurochemical signals in select brain regions control the behavioral changes that occur following social defeat experience. Studying the neural mechanisms underlying defeat-induced changes in behavior should lead to a better understanding of stress-related psychopathologies, and ultimately to the development of better treatment options for these mental disorders.