Cellular and molecular mechanisms of vasopressin in anxiety

项目摘要/摘要 焦虑症是影响约2000万美国人的最常见的精神疾病之一 人民。因为目前的药物只对50%到60%的患者有效，而且有一定的副作用或 耐受或依赖问题，探索新的神经生物学机制和治疗 治疗焦虑症的方法仍然是一项艰巨的任务。我们的长期目标是探索新的机制，通过 可以为焦虑症开发哪些创新的治疗策略。积累证据 表明加压素(又称精氨酸加压素，AVP；抗利尿激素)升高 系统通过激活V1a受体(V1aRs)促进焦虑。然而，通过这些机制 V1aRs的激活增加了焦虑，这一点尚未确定。这项提案的目标是确定 V1aR激活促进焦虑的细胞和分子机制。我们的理由是 确定V1aR激活增加焦虑的机制将刺激发育和 V1aR拮抗剂和靶向V1aR下游信号分子的药物在治疗中的应用 焦虑。因为谷氨酸能功能的升高是焦虑产生的基础，我们正在测试 核心假设认为，V1aRs的激活通过增加谷氨酸能功能来促进焦虑。这个 这一假说的形成也是基于我们的初步结果，即V1aRs的激活 促进腹侧海马区主神经元的兴奋性和谷氨酸能传递 与类似焦虑的反应密切相关。我们进一步证明腹侧微量注射AVP 海马区或光基因刺激内源性AVP释放可诱导焦虑效应 高架迷宫(EPM)、旷场试验(OFT)和暗箱试验(LDB)。目标1将确定 AVP兴奋海马腹侧主神经元的机制。我们将测试 假设V1aR的激活通过PLCβ1介导的PIP2耗竭来增加神经元的兴奋性， 促进TRPC4/5通道功能和钙内流。目标2将定义AVP的机制 促进谷氨酸在海马腹侧突触的释放。我们将检验V1aR的假设 激活通过相互作用增加量子大小、释放部位和/或多囊释放的数量 与PLCβ1、TRPC4/5通道、钙/钙调蛋白依赖性激酶II(CaMKII)和突触素I有关。 阐明V1aR激活诱导焦虑效应的机制。我们将检验这一假设 PLCβ1、TRPC4/5通道、CaMKII和突触素I参与V1aR介导的焦虑效应 使用EPM、OFT和LDB。我们认为，确定V1aR介导的增加的机制 将为焦虑症治疗提供新的方法。

Project Summary/Abstract Anxiety disorders are among the most common psychiatric disorders affecting ~20 million American people. Because current medications are effective for only 50~60% of patients and have certain side effects or problems with tolerance or dependence, exploring novel neurobiological mechanisms and therapeutic approaches for anxiety disorders is still an arduous task. Our long-term goal is to explore novel mechanisms by which innovative therapeutic strategies for anxiety disorders can be developed. Accumulating evidence demonstrates that elevation of vasopressin (also known as arginine vasopressin, AVP; antidiuretic hormone) system facilitates anxiety via activation of V1a receptors (V1aRs). However, the mechanisms whereby activation of V1aRs increases anxiety have not been determined. The objective of this proposal is to determine the cellular and molecular mechanisms whereby V1aR activation facilitates anxiety. Our rationale is that determining the mechanisms whereby V1aR activation augments anxiety would stimulate the development and uses of V1aR antagonists and drugs targeting the downstream signaling molecules of V1aRs for the treatment of anxiety. Because elevation in glutamatergic functions underlies the generation of anxiety, we are testing the central hypothesis that activation of V1aRs facilitates anxiety by increasing the glutamatergic functions. The formation of the hypothesis is also based on our preliminary results demonstrating that activation of V1aRs facilitates the excitability of principal neurons and glutamatergic transmission in the ventral hippocampus which is closely involved in anxiety-like responses. We further showed that microinjection of AVP into the ventral hippocampus or optogenetically stimulating endogenous AVP release induces anxiogenic effects assessed by Elevated-Plus Maze (EPM), Open Field Test (OFT) and Light-Dark Box (LDB). Aim 1 will identify the mechanisms underlying AVP-induced excitation of ventral hippocampal principal neurons. We will test the hypothesis that V1aR activation increases neuronal excitability via PLCβ1-mediated depletion of PIP2, facilitating TRPC4/5 channels function and Ca2+ influx. Aim 2 will define the mechanisms whereby AVP facilitates glutamate release at the ventral hippocampal synapses. We will test the hypothesis that V1aR activation increases the quantal size, the number of release site and/or multivesicular release via interaction with PLCβ1, TRPC4/5 channels, calcium/calmodulin-dependent kinase II (CaMKII) and synapsin I. Aim 3 will elucidate the mechanisms by which V1aR activation induces anxiogenic effects. We will test the hypothesis that PLCβ1, TRPC4/5 channels, CaMKII and synapsin I are involved in V1aR-mediated anxiogenic effects using EPM, OFT and LDB. We believe that determining the mechanisms underlying V1aR-mediated increases in anxiety would provide novel approaches for anxiety therapy.