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Cellular and molecular mechanisms of vasopressin in anxiety

加压素抗焦虑的细胞和分子机制

基本信息

批准号：
10663878
负责人：
Saobo Lei
金额：
$ 11.58万
依托单位：
UNIVERSITY OF NORTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-06 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663878
关键词：
AVPR2 gene Affect American Anti-Anxiety Agents Anxiety Anxiety Disorders Argipressin Axon Bathing Blood Brain region Calcium Calmodulin Chemicals Darkness Data Dependence Development Dimerization Disease remission Down-Regulation Drug Targeting Duct (organ) structure Fiber G-Protein-Coupled Receptors Generations Glutamates Goals Hippocampus Hypothalamic structure Kidney Knockout Mice Knowledge Light Literature Mediating Mental disorders Microinjections Molecular Neurobiology Neurons Pathogenesis Patients Permeability Persons Pharmaceutical Preparations Phosphatidylinositol 4,5-Diphosphate Phosphorylation Phosphotransferases Posterior Pituitary Gland Public Health Receptor Activation Research Role Signaling Molecule Site Slice Structure Synapses Synapsin I System Testing Therapeutic Urine V1 Receptors V1a vasopressin receptor V2 Receptors Vascular Smooth Muscle Vasopressins Water antagonist anxiety treatment anxiety-like behavior dentate gyrus field study granule cell hippocampal pyramidal neuron innovation magnocellular neurobiological mechanism neuronal excitability novel novel strategies optogenetics paraventricular nucleus parvocellular peptide hormone pharmacologic pressure prevent receptor receptor function response side effect supraoptic nucleus transmission process vasoconstriction vesicular release

项目摘要

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.

项目概要/摘要焦虑症是最常见的精神疾病之一，影响约 2000 万美国人人们。因为目前的药物治疗仅对50~60%的患者有效，并且有一定的副作用或耐受或依赖性问题，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可以开发出针对焦虑症的创新治疗策略。积累证据表明加压素（也称为精氨酸加压素，AVP；抗利尿激素）升高系统通过激活 V1a 受体 (V1aR) 来促进焦虑。然而，其机制 V1aR 的激活是否会增加焦虑尚未确定。该提案的目的是确定 V1aR 激活促进焦虑的细胞和分子机制。我们的理由是确定 V1aR 激活增强焦虑的机制将刺激发育和使用V1aR拮抗剂和靶向V1aR下游信号分子的药物进行治疗的焦虑。由于谷氨酸能功能的升高是焦虑产生的基础，因此我们正在测试中心假设是 V1aR 的激活通过增加谷氨酸能功能来促进焦虑。这该假设的形成还基于我们的初步结果，表明 V1aR 的激活促进腹侧海马主要神经元的兴奋性和谷氨酸能传递与焦虑样反应密切相关。我们进一步表明，将 AVP 显微注射到腹侧海马或光遗传学刺激内源性 AVP 释放诱导焦虑效应高架迷宫 (EPM)、旷场测试 (OFT) 和明暗盒 (LDB)。目标 1 将确定 AVP 诱导腹侧海马主要神经元兴奋的机制。我们将测试假设 V1aR 激活通过 PLCβ1 介导的 PIP2 耗竭增加神经元兴奋性，促进 TRPC4/5 通道功能和 Ca2+ 流入。目标 2 将定义 AVP 的机制促进腹侧海马突触释放谷氨酸。我们将检验 V1aR 的假设激活通过相互作用增加量子大小、释放位点和/或多囊泡释放的数量具有 PLCβ1、TRPC4/5 通道、钙/钙调蛋白依赖性激酶 II (CaMKII) 和突触蛋白 I。目标 3 将阐明 V1aR 激活诱导焦虑作用的机制。我们将检验假设 PLCβ1、TRPC4/5 通道、CaMKII 和突触蛋白 I 参与 V1aR 介导的焦虑作用使用 EPM、OFT 和 LDB。我们认为，确定 V1aR 介导的增加的潜在机制焦虑症将为焦虑治疗提供新的方法。