Vasopressin in the regulation of serotonin and anxiety

加压素调节血清素和焦虑

• 批准号: 8413651
• 负责人: Benjamin David Rood
• 金额: $ 5.22万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413651
• 关键词: AMPA Receptors; Address; Adolescence; Affect; Aggressive behavior; Animal Model; Animals; Antibodies; Anxiety; Anxiety Disorders; Area; Autoreceptors; Behavior; Behavioral; Bicuculline; Biological; Brain; Brain region; Cells; Complex; DNQX; Disease; Dorsal; Drug usage; Effectiveness; Electrophysiology (science); Exposure to; Family; Female; Fiber; Frequencies; GABA Antagonists; Genes; Glutamate Receptor; Glutamates; Health; Immunohistochemistry; Incidence; Individual; Kainic Acid Receptors; Lead; Life; Light; Link; Measures; Mediating; Memory; Mental Depression; Mental disorders; Mood Disorders; Mus; Nature; Neurons; Neuropeptides; Pair Bond; Partner in relationship; Pathway interactions; Pharmacological Treatment; Pharmacology; Phenotype; Plant Roots; Play; Population; Prosencephalon; Regulation; Research; Rodent; Role; Serotonin; Social Behavior; Social Interaction; Societies; Stimulus; Structure of terminal stria nuclei of preoptic region; Synapses; System; Testing; Therapeutic Intervention; Treatment Cost; United States; V2 Receptors; Vasopressins; Work; affiliative behavior; base; gamma-Aminobutyric Acid; infancy; inhibitor/antagonist; male; receptor; research study; response; reuptake; social; voltage clamp

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.

描述（由申请人提供）：社会交往是生活的重要组成部分。在婴儿期和青春期，我们的生存依赖于其他人，然后在整个生命中，我们一起生活，工作和玩耍。扰乱我们社会行为的疾病对个人、家庭和整个社会都有毁灭性的后果。特别是，焦虑和情绪障碍会对社会行为产生破坏性影响，相反，会受到我们社会交往的影响，这些疾病的终生发病率非常高（高达1/5）。在过去的二十年里，许多药理学和基因操作研究表明，神经肽血管加压素（AVP）在社会行为，包括社会记忆，父母的行为，交配行为，和配对。最近在小鼠身上的证据表明，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核，前脑的大部分5-羟色胺（5-HT）是在那里产生的。5-HT系统已成为焦虑和抑郁症药物治疗的有效靶点，特别是随着选择性5-HT再摄取抑制剂（SSRIs）的出现。基于AVP和5-HT之间的解剖学联系，假设AVP作用于5-HT神经元。应用全细胞电压钳电生理技术，发现AVP使5-HT神经元突触后电流（PSC）频率增加。该建议旨在1）使用分离的PSC的全细胞电压钳记录结合谷氨酸或GABA受体拮抗剂并通过使用AVP和谷氨酸和GABA神经元的标记物的免疫组织化学来确定AVP介导的作用是否是由于对GABA或谷氨酸神经元的作用;（二）使用全细胞电压钳记录结合应用对不同AVP具有选择性的拮抗剂来确定哪种AVP受体负责观察到的效应受体亚型，以分离相关受体;和3）确定AVP作用在中缝背核中的行为相关性。因为与诸如雄性间攻击的对抗行为相反，诸如交配的亲和行为已知激活BNST中的AVP细胞，所以动物将暴露于这些相应的刺激，并且将在高架十字迷宫中测量它们随后的焦虑相关行为。随后，如果观察到响应于亲和性社会刺激的焦虑相关行为的预测减少，则将AVP拮抗剂施用到中缝背核中，以在随后的测试中尝试阻断该效应。这些研究的影响将是1）表征AVP对5-HT神经元的影响，2）增加我们对中缝背核内局部回路的理解，3）定义对改变5-HT神经元活动的社会刺激敏感的通路，以及4）确定积极和消极的社会互动如何在细胞和行为水平上影响焦虑。