Neural Mechanisms Underlying Stress-Induced Changes In Behavior

描述(由申请人提供)：暴露在应激性心理社会刺激下可导致各种情感障碍，包括抑郁、广泛性焦虑症和创伤后应激障碍。5-羟色胺是一种关键的神经化学信号，在应激敏感型精神病的表达和治疗中发挥着关键作用。在动物模型中，5-羟色胺在包括杏仁基底外侧核(BLA)在内的几个大脑区域发挥作用，以调节压力导致的焦虑和抑郁行为的变化。在目前的提案中，我们将使用叙利亚仓鼠的社会失败模型，称为条件性失败，在心理社会背景下研究压力诱导的行为变化。在我们的条件性失败模型中，社会失败导致物种的完全丧失--典型的领土攻击，以及当个体稍后与较小的、非侵略性的对手进行测试时，顺从和防御行为的大幅增加。在我们的工作模型中，我们认为社会挫折激活了5-羟色胺神经元，而5-羟色胺通过影响调节大脑白质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)，进而调节条件性失败的形成。更具体地说，我们认为，5-羟色胺通过作用于BLA中的5-HT1A受体来破坏CREB-BDNF途径，并作用于BLA中的5-HT2C受体来促进CREB-BDNF途径，从而调节条件性失败的形成。在目前的提案中，我们将测试四个预测。首先，我们将验证这样的预测，即在BLA中注射5-HT1A受体拮抗剂将增强条件性失败的获得和表达。其次，我们将检验以下预测：全身给予5-HT2C受体激动剂将增强条件性失败的获得和表达，并且向BLA内注射5-HT2C受体拮抗剂将阻断5-HT2C受体激动剂的作用。第三，我们将测试中缝背核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免疫反应性增加的预测。第四，我们将验证中缝背核5-HT1A自身受体的药理激活将阻断失败诱导的BDNF mRNA在BLA内表达增加的预测。 公共卫生相关性：暴露在应激性心理社会刺激下可导致各种情绪障碍，包括严重抑郁、广泛性焦虑症和创伤后应激障碍。在这项研究中，我们正在研究特定大脑区域中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。研究失败导致行为变化的神经机制将有助于更好地理解与应激相关的精神病理，并最终开发出更好的治疗这些精神障碍的选择。

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.