Kappa opioid receptor modulation of depression-like behaviors through mTOR signaling

项目摘要 压力是临床抑郁症的已知危险因素，而压力会加剧抑郁症状。 在脆弱的个体中。通过更好地理解应激可以 推动亲抑郁行为，我们将能够产生新的/量身定做的疗法来对抗这一点 流行的疾病。雷帕霉素的kappa-阿片受体(KOR)和哺乳动物靶标 (MTOR)系统已被证明可以调节应激诱导的抑郁样行为的元素 在老鼠身上。然而，这两个系统从未联系在一起，这是我们在 了解从应激到病理生理和行为的完整途径。了解如何 KOR活性与mTOR功能有关，这将是提纯针对这些系统的药物的关键。 这些通路中一个可能的中间蛋白是p38MAPK，它被KOR和 它们的活动对于压力诱导的静止、厌恶和社交回避是必要的。这个 拟议的实验将直接测试KOR、p38 MAPK和mTOR之间的关系，作为 调节抑郁样行为和神经元可塑性的功能信号通路。具体来说， 我们建议首先验证证明mTOR水平受KOR调制的初步数据 激活。在目标1中，我们将使用药物抑制剂/拮抗剂和遗传模型来测试 KOR激活后mTOR水平的变化是否需要p38MAPK。到时候我们会的 评估mTOR是否介导KOR/p38诱导的场所厌恶和游泳应激的变化 一动不动。在目标2中，我们将测试KOR是否会改变神经元可塑性的标志，包括 树突长度、棘突密度/形状和突触蛋白。我们将使用这两种药物 激活KOR和应激以检测p38MAPK和mTOR的依赖性，最终确定是否 KOR拮抗能够减弱应力诱导的可塑性的变化。建议进行的研究 这里描述的将更好地定义从应激暴露到类似抑郁症的分子途径 行为，并可能发现可用于临床的治疗行动的新靶点 用来治疗易受压力的个体。

Project Summary Stress is a known risk factor for clinical depression, and stress can exacerbate depressive symptoms in vulnerable individuals. By better understanding the molecular mechanisms by which stress can drive pro-depressive behaviors, we will be able to generate novel/tailored therapeutics to combat this prevalent disease. Both the kappa-opioid receptor (KOR) and mammalian target of rapamycin (mTOR) systems have been shown to mediate elements of stress-induced, depression-like behaviors in mice. However, these two systems have never been linked, representing a major gap in our knowledge of a complete pathway from stress to pathophysiology and behavior. Understanding how KOR activity is related to mTOR function will be critical in refining drugs that target these systems. One possible intermediate protein in these pathways is p38 MAPK, which is activated by KOR and whose activity is necessary for stress-induced immobility, aversion, and social avoidance. The proposed experiments will directly test the relationship between KOR, p38 MAPK, and mTOR as a functional signaling pathway mediating depression-like behaviors and neuronal plasticity. Specifically, we propose to first validate preliminary data demonstrating that mTOR levels are modulated by KOR activation. In Aim 1, we will use pharmacological inhibitors/antagonists and genetic models to test whether p38 MAPK is necessary for the changes in mTOR level seen by KOR activation. We will then assess whether mTOR mediates KOR/p38-induced place aversion and changes in swim stress immobility. In aim 2, we will test whether KOR changes markers of neuronal plasticity including dendrite length, spine density/shape, and synaptic proteins. We will use both pharmacological activation of KOR and stress to test dependence of p38 MAPK and mTOR, and finally determine if KOR antagonism is able to attenuate changes in stress-induced plasticity. The proposed studies described here will better define the molecular pathways from stress exposure to depression-like behaviors, and possibly uncover novel targets for therapeutic action that could be used in the clinical population to treat stress-vulnerable individuals.