Neural Mechanisms Underlying Stress-Induced Changes In Behavior

描述（由申请人提供）：暴露于压力，社会心理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，在应激性精神病理的表达和治疗中起着关键作用。在动物模型中，血清素作用于大脑的几个区域，包括基底外侧杏仁核（BLA），以调节压力引起的焦虑和抑郁行为变化。在目前的提案中，我们将使用叙利亚仓鼠的社会失败模型，称为条件失败，来调查心理社会背景下压力引起的行为变化。在我们的条件失败模型中，社会失败导致物种典型的领土侵略行为完全丧失，当个体随后与一个较小的、不具攻击性的对手进行测试时，服从和防御行为会大幅增加。在我们的工作模型中，我们提出社交失败激活5-HT神经元，而血清素反过来通过影响调节BLA中神经可塑性的关键因素，如cAMP反应元件结合蛋白（CREB）和脑源性神经营养因子（BDNF），来调节条件性失败的形成。更具体地说，我们提出5-羟色胺通过作用于BLA中的5-HT1A受体来破坏CREB-BDNF通路，并通过作用于BLA中的5-HT2C受体来促进CREB-BDNF通路，从而调节条件失败的形成。在当前的提案中，我们将测试四个预测。首先，我们将验证向BLA注射5-HT1A受体拮抗剂将增强条件失败的获得和表达的预测。其次，我们将验证系统给药5-HT2C受体激动剂将增强条件失败的获得和表达的预测，并且5-HT2C受体激动剂的作用将通过向BLA注射5-HT2C受体拮抗剂来阻断。第三，我们将验证中缝背核中5-HT1A自身受体的药理激活将阻止失败诱导的BLA内磷酸化CREB免疫反应性的增加。第四，我们将验证中缝背核中5-HT1A自受体的药理激活将阻止失败诱导的BLA内BDNF mRNA表达的增加的预测。

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.