Cellular and molecular mechanisms of vasopressin in anxiety

项目总结/摘要 焦虑症是最常见的精神疾病之一，影响约2000万美国人。 人因为目前的药物治疗仅对50~60%的患者有效，且有一定的副作用或 耐受性或依赖性问题，探索新的神经生物学机制和治疗 焦虑症的治疗仍然是一项艰巨的任务。我们的长期目标是探索新的机制， 可以开发出哪些创新的焦虑症治疗策略。越来越多的证据 表明加压素（也称为精氨酸加压素，AVP;抗利尿激素）的升高 系统通过激活V1 a受体（V1 aRs）促进焦虑。然而， V1 aR的激活增加焦虑尚未确定。本提案的目的是确定 V1 aR激活促进焦虑的细胞和分子机制。我们的理由是， 确定V1 aR激活增强焦虑的机制将刺激发展， V1 aR拮抗剂和靶向V1 aR下游信号分子的药物在治疗中的用途 焦虑因为脑功能的提升是焦虑产生的基础，我们正在测试 中心假设，激活V1 aRs通过增加神经元功能促进焦虑。的 该假说的形成也是基于我们的初步结果，表明V1 aRs的激活 促进腹侧海马中主要神经元的兴奋性和海马能传递， 与焦虑反应密切相关我们进一步表明，在腹侧注射AVP， 海马或光遗传学刺激内源性AVP释放诱导焦虑作用， 高架迷宫、旷场试验和明暗箱试验。目标1将确定 AVP诱导的腹侧海马主要神经元兴奋的机制。我们将测试 假设V1 aR激活通过PLCβ1介导的PIP 2耗竭增加神经元兴奋性， 促进TRPC 4/5通道功能和Ca 2+内流。目标2将定义AVP 促进腹侧海马突触处的谷氨酸释放。我们将检验V1 aR 活化通过相互作用增加了量子尺寸、释放位点的数量和/或多泡释放 与PLCβ1、TRPC 4/5通道、钙/钙调蛋白依赖性激酶II（CaMK II）和突触蛋白I。目标3将 阐明V1 aR激活诱导抗焦虑作用的机制。我们将检验这个假设 PLCβ1、TRPC 4/5通道、CaMK Ⅱ和突触蛋白I参与了V1 aR介导的抗焦虑作用 使用了OFT、OFT和LDB。我们认为，确定V1 aR介导的增加的潜在机制， 将为焦虑症的治疗提供新的途径。

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.