Vasopressin in the regulation of serotonin and anxiety

加压素调节血清素和焦虑

• 批准号: 8254183
• 负责人: Benjamin David Rood
• 金额: $ 4.84万
• 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/8254183
• 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）：社交互动是生活的重要组成部分。在婴儿期和青春期，我们的生存取决于其他人，然后在整个生命中，我们生活，工作和一起玩耍。破坏我们社会行为的疾病对个人，家庭和整个社会产生了毁灭性的后果。特别是，焦虑和情绪障碍可能会对社会行为产生毁灭性的影响，相反，我们的社交互动会影响，这些疾病的终生发病率很高（高达5分之一）。在过去的二十年中，啮齿动物中的许多药理和基因操纵研究都暗示了神经肽加压素（AVP）在社交行为中，包括社交记忆，父母行为，交配行为和成对键入。小鼠的最新证据表明，删除特定的AVP受体也会改变焦虑。解剖学证据表明，质末端的床核中的AVP神经元向背侧raphe发射，其中大部分前脑的5-羟色胺（5-ht）被产生。 5-HT系统一直是焦虑和抑郁症的药理治疗的有效靶点，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之间的解剖联系，假设AVP会对5-HT神经元作用。使用全细胞电压夹电生理学，发现AVP的应用导致突触后电流（PSC）S在5-HT神经元中的频率增加。该提案的目的是1）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是否是使用全细胞电压夹具对孤立的PSC的记录以及与谷氨酸或GABA受体拮抗剂的结合以及使用免疫组织化学的AVP以及谷氨酸和GABA神经元的标记的； 2）确定哪种AVP受体负责使用全细胞电压夹记录观察到的效应，并与对不同AVP受体亚型选择性的拮抗剂相结合，以隔离相关受体； 3）确定AVP动作在背raphe中的行为相关性。由于已知会激活BNST中的AVP细胞等拮抗行为，例如交配，例如交配等诸如交配的行为，因此将在这些刺激中暴露于这些刺激，并将其随后与焦虑相关的行为衡量。随后，如果观察到与伴侣的社会刺激相关的焦虑相关行为的预测减少，则将将AVP拮抗剂施加到背侧raphe中，以试图在随后的测试中阻止这种影响。这些研究的影响将是1）表征AVP对5-HT神经元的影响，2）增强我们对背侧raphe内局部电路的理解，3）定义对改变5-HT神经元活动的社交刺激敏感的途径，4）4）确定在细胞和行为水平上影响焦虑和负面的社交互动程度如何。