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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。