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：
10166945
负责人：
Saobo Lei
金额：
$ 34.75万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10166945
关键词：
AVPR2 gene Affect American Anti-Anxiety Agents Anxiety Anxiety Disorders Argipressin Axon Bathing Blood Brain region Calcium Calmodulin Chemicals Data Dependence Development Dimerization Disease remission Down-Regulation Drug Targeting Duct (organ) structure Fiber G-Protein-Coupled Receptors Generations Glutamates Goals Hippocampus (Brain)Hypothalamic structure Kidney Knockout Mice Knowledge Light Literature Mediating Mental disorders Microinjections Molecular Neurobiology Neurons Pathogenesis Patients Permeability Pharmaceutical Preparations Pharmacology 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 anxiety treatment anxiety-like behavior base dentate gyrus field study granule cell hippocampal pyramidal neuron innovation magnocellular neurobiological mechanism neuronal excitability novel novel strategies optogenetics paraventricular nucleus parvocellular peptide hormone pressure prevent quantum receptor receptor function response side effect supraoptic nucleus transmission process vasoconstriction

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们。因为目前的药物仅对50至60％的患者有效，并且具有一定的副作用或耐受性或依赖性问题，探索新颖的神经生物学机制和治疗焦虑症的方法仍然是一项艰巨的任务。我们的长期目标是通过可以制定哪种动画疾病的创新治疗策略。积累证据证明加压素的升高（也称为精氨酸加压素，AVP；抗利尿激素）系统通过激活V1A受体（V1AR）促进焦虑。但是，该机制的机制 V1AR的激活尚未确定焦虑。该提议的目的是确定 V1AR激活设施动画的细胞和分子机制。我们的理由是确定V1AR激活增强动画的机制将刺激开发和靶向V1AR的下游信号分子的V1AR拮抗剂和药物进行处理动画。因为谷氨酸能函数的抬高是动画产生的基础，所以我们正在测试中心假设，即通过增加谷氨酸能函数，V1AR的激活有助于动画。这假设的形成也基于我们的初步结果，证明了V1AR的激活促进腹侧海马中主要神经元和谷氨酸能传播的兴奋与焦虑症的反应密切相关。我们进一步表明，AVP对腹侧的显微注射海马或光源刺激的内源性AVP释放会诱导通过升高的迷宫（EPM），开放式测试（经常）和灯光盒（LDB）。 AIM 1将确定 AVP引起的通风海马主要神经元的兴奋的机制。我们将测试假设V1AR激活通过PLCβ1介导的PIP2的部署来增加神经元兴奋性，促进TRPC4/5通道功能和Ca2+影响。 AIM 2将定义AVP的机制在腹侧海马突触中促进谷氨酸释放。我们将测试V1AR的假设激活增加了数量大小，释放位点的数量和/或通过相互作用的多释放使用PLCβ1，TRPC4/5通道，钙/钙调蛋白依赖性激酶II（CAMKII）和突触素I. AIM 3 Will Will 阐明V1AR激活诱导焦虑作用的机制。我们将检验假设该PLCβ1，TRPC4/5通道，CAMKII和Sytapsin I参与V1AR介导的抗焦虑作用使用EPM，经常和LDB。我们认为，确定V1AR介导的增加的机制增加了在动画中，将为动画疗法提供新颖的方法。