Oxytocin-dependent circuits of social approach and vigilance

催产素依赖的社交方式和警惕性回路

基本信息

批准号：
10576939
负责人：
BRIAN C TRAINOR
金额：
$ 34.36万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576939
关键词：
Affect Agonist Animals Antisense Oligonucleotides Anxiety Disorders Authorization documentation Behavior Behavioral Bioinformatics Brain region California Cells Characteristics Coupling Data Data Set Development Dose Electrophysiology (science)Female GTP-Binding Proteins Human Hypothalamic structure Impairment Individual Infusion procedures Mediating Mental disorders Modeling Molecular Molecular Analysis Mus Neurons Neuropeptides Nucleus Accumbens Oxytocin Oxytocin Receptor Participant Pathway interactions Performance Pharmacology Study Phenotype Physiological Population Potassium Channel Reporting Research Rodent Model Schools Sex Differences Signal Pathway Signal Transduction Pathway Social Anxiety Disorder Social Behavior Social Controls Social Environment Social Interaction Social Phobia Stress Structure of terminal stria nuclei of preoptic region System Testing Therapeutic Transcript United States Viral Viral Vector Virus Visualization Woman Work antagonist authority behavioral study experimental study innovation insight interest male men mesolimbic system molecular phenotype multidisciplinary neural circuit novel novel therapeutic intervention paraventricular nucleus receptor coupling reduce symptoms response sex single cell analysis single-cell RNA sequencing skills social social anxiety social defeat social relationships social stress therapeutic target tool vigilance

项目摘要

Project summary Social anxiety disorder (or social phobia) is the most common form of anxiety disorder in the United States. Affected individuals avoid social contexts, which disrupts social relationships and impairs performance at school or work. New therapeutic approaches are needed because ~40% of affected individuals who seek existing treatments do not respond. Oxytocin is a well-known modulator of social behaviors, and has been put forth as a possible therapeutic. In some studies using human participants, intranasal oxytocin enhances social approach related behaviors. However, other studies (especially in women) report that intranasal oxytocin increases social anxiety. How can the same neuropeptide exert such different effects on behavior? Our central hypothesis is that oxytocin acts in the mesolimbic dopamine system to promote social approach, whereas oxytocin acts in the bed nucleus of the stria terminalis (BNST) to enhance social anxiety. This hypothesis is conceptually innovative because it can reconcile apparently contradictory findings in both human and animal studies of oxytocin function. The proposed studies will test this hypothesis in both males and females because social anxiety disorder is more prevalent in women than men. Our studies will use the California mouse social defeat model, which induces a stronger social anxiety phenotype in females versus males. First, we will use antisense morpholinos to selectively inhibit oxytocin synthesis in neurons within the BNST or hypothalamus (which project to the nucleus accumbens, NAc) to determine how these cells modulate social anxiety and social approach. Next, we will use viral vectors to visualize oxytocin producing cells in the BNST and hypothalamus. We will isolate oxytocin neurons for single-cell RNAseq analyses, and we will also conduct electrophysiological analyses. We will determine the extent to which social stress induces molecular and physiological responses that increase excitability. Finally, we will study the behavioral effects of oxytocin receptor (OTR) in the NAc and BNST using biased agonists that selectively induce OTR coupling of either Gq or Gi pathways. Our research team is ideally suited to execute these studies. Dr. Trainor's lab developed the California mouse social defeat model and collected most of the preliminary data. Dr. Robison is a behavioral neuroscientist with strong molecular and electrophysiology skills. Dr. Settles is an expert in bioinformatics and performed analyses of single-cell RNAseq data. Dr. Chini is a leading authority on OTR G-protein coupling and provides expertise for pharmacology studies. Dr. Grinevich developed viral tools for targeting oxytocin neurons and provides viruses and advice. Our analyses of how stress alters the physiological and molecular phenotypes of distinct populations of oxytocin neurons from males and females are unprecedented, and could lead to novel insights into how to selectively target these cells.

项目概要社交焦虑症（或社交恐惧症）是美国最常见的焦虑症形式。受影响的个人会回避社交环境，从而扰乱社交关系并损害工作表现学校或工作。需要新的治疗方法，因为约 40% 的受影响个体寻求治疗现有的治疗方法没有效果。催产素是众所周知的社会行为调节剂，已被作为一种可能的治疗方法。在一些使用人类参与者的研究中，鼻内催产素增强了社交能力方法相关行为。然而，其他研究（尤其是女性研究）报告称，鼻内催产素增加社交焦虑。相同的神经肽如何对行为产生如此不同的影响？我们的中央假设是催产素在中脑边缘多巴胺系统中起作用以促进社交方式，而催产素作用于终纹床核（BNST），增强社交焦虑。这个假设是概念上的创新，因为它可以调和人类和动物中明显矛盾的发现催产素功能的研究。拟议的研究将在男性和女性中测试这一假设，因为社交焦虑症在女性中比男性更普遍。我们的研究将使用加州小鼠社交失败模型，这会导致女性比男性更强烈的社交焦虑表型。首先，我们将使用反义吗啉选择性抑制 BNST 内神经元的催产素合成或下丘脑（投射到伏隔核，NAc）以确定这些细胞如何调节社交焦虑和社交方法。接下来，我们将使用病毒载体来可视化 BNST 中产生催产素的细胞和下丘脑。我们将分离催产素神经元进行单细胞 RNAseq 分析，我们还将进行电生理学分析。我们将确定社会压力在多大程度上诱发分子和增加兴奋性的生理反应。最后，我们将研究催产素的行为影响 NAc 和 BNST 中的受体 (OTR) 使用偏向激动剂选择性诱导任一 Gq 的 OTR 偶联或 Gi 通路。我们的研究团队非常适合执行这些研究。 Trainor 博士的实验室开发了加州小鼠社交失败模型并收集了大部分初步数据。罗宾逊博士是一位行为具有强大分子和电生理学技能的神经科学家。 Settles 博士是生物信息学领域的专家对单细胞 RNAseq 数据进行分析。 Chini 博士是 OTR G 蛋白偶联和为药理学研究提供专业知识。 Grinevich 博士开发了针对催产素神经元的病毒工具并提供病毒和建议。我们对压力如何改变生理和分子的分析来自男性和女性的不同催产素神经元群体的表型是前所未有的，并且可能从而对如何选择性地靶向这些细胞产生新的见解。