Vasopressin in the regulation of serotonin and anxiety

描述(由申请者提供)：社交是生活中重要的一部分。在婴儿期和青春期，我们的生存依赖于其他人，然后在整个一生中，我们一起生活、工作和玩耍。扰乱我们的社会行为的障碍对个人、家庭和整个社会都会造成毁灭性的后果。特别是，焦虑和情绪障碍可能会对社会行为产生破坏性影响，反过来也会受到我们的社会互动的影响，这些疾病的终生发病率非常高(高达五分之一)。在过去的二十年里，许多对啮齿动物的药理学和基因操作研究表明，神经肽加压素(AVP)与社会记忆、父母行为、交配行为和配对联系等社会行为有关。最近在老鼠身上的证据表明，删除特定的AVP受体也会改变焦虑。解剖学证据表明，终纹床核中的AVP神经元投射到中缝背侧，前脑的大部分5-羟色胺(5-HT)在那里产生。随着选择性5-羟色胺再摄取抑制剂(SSRIs)的问世，5-羟色胺系统已成为治疗焦虑和抑郁的有效靶点。根据AVP与5-羟色胺的解剖学联系，推测AVP可能作用于5-羟色胺神经元。应用全细胞电压钳技术，观察到AVP可引起5-羟色胺神经元突触后电流S频率的增加。该建议旨在1)通过结合谷氨酸或GABA受体拮抗剂对分离的PSC进行全细胞电压钳记录，并使用AVP以及谷氨酸和GABA神经元的标记物的免疫组织化学方法，确定AVP介导的效应是由于对GABA或谷氨酸神经元的作用；2)通过全细胞电压钳记录结合应用针对不同AVP受体亚型的拮抗剂来分离相关受体，以确定AVP在中缝背侧的作用与行为的相关性。因为已知交配等附属行为而不是男性间攻击等对抗行为会激活BNST中的AVP细胞，动物将暴露在这些各自的刺激下，随后的焦虑相关行为将在高架的PLUS迷宫中进行测量。随后，如果观察到焦虑相关行为对关联性社会刺激的反应减少，则将AVP拮抗剂注射到中缝背侧，试图在随后的测试中阻止这一效应。这些研究的影响将是：1)表征AVP对5-羟色胺神经元的影响；2)增加我们对中缝背侧局部回路的了解；3)确定对社会刺激敏感的改变5-羟色胺神经元活动的通路；4)确定积极和消极的社交互动如何在细胞和行为水平上影响焦虑。

DESCRIPTION (provided by applicant): Social interactions are an important part of life. During infancy and adolescence, our survival depends on other people, and then throughout life we live, work, and play together. Disorders that disrupt our social behavior have devastating consequences for individuals, families, and society at large. In particular, anxiety and mood disorders can have devastating effects on social behavior and conversely can be impacted by our social interactions, and these disorders have a very high lifetime incidence (as high as 1 in 5). Over the last two decades, a number of pharmacological and gene-manipulation studies in rodents have implicated the neuropeptide vasopressin (AVP) in social behaviors including social memory, parental behavior, mating behavior, and pair-bonding. More recent evidence in mice suggests that deleting specific AVP receptors also alters anxiety. Anatomical evidence suggests that AVP neurons in the bed nucleus of the stria terminalis project to the dorsal raphe, where most of the forebrain's serotonin (5-HT) is produced. The 5-HT system has been an effective target for pharmacological treatment of anxiety and depression, specifically with the advent of selective 5-HT reuptake inhibitors (SSRIs). Based on the anatomical link between AVP and 5-HT, it was hypothesized that AVP would act on 5-HT neurons. Using whole cell voltage clamp electrophysiology, it was found that application of AVP caused an increase in the frequency of post synaptic currents (PSC)s in 5-HT neurons. This proposal aims to 1) determine whether the AVP mediated effects are due to actions on GABA or glutamate neurons using whole cell voltage clamp recordings of isolated PSCs in conjunction with glutamate or GABA receptor antagonists and by using immunohistochemistry for AVP and markers of glutamate and GABA neurons; 2) determine which AVP receptor is responsible for the observed effects using whole cell voltage clamp recording in conjunction with application of antagonists selective for different AVP receptor subtypes to isolate the relevant receptor; and 3) identify the behavioral relevance of AVP action in the dorsal raphe. Because affiliative behaviors such as mating as opposed to antagonistic behaviors such as inter-male aggression are known to activate AVP cells in the BNST, animals will be exposed to these respective stimuli and their subsequent anxiety-related behavior will be measured in the elevated plus maze. Subsequently, if the predicted decrease in anxiety-related behavior in response to affiliative social stimuli is observed, then AVP antagonists will be administered into the dorsal raphe to try to block this effect in subsequent tests. The impact of these studies will be to 1) characterize the effect of AVP on 5-HT neurons, 2) increase our understanding of local circuitry within the dorsal raphe, 3) define pathways sensitive to social stimuli that alter 5-HT neuron activity, and 4) determine how positive and negative social interactions influence anxiety at a cellular and behavioral level.