Oxytocin-dependent circuits of social approach and vigilance

项目摘要 社交焦虑症（或社交恐惧症）是美国最常见的焦虑症。 受影响的个人避免社交环境，这会破坏社会关系并损害表现， 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 现有的治疗没有反应。催产素是一种众所周知的社会行为调节剂， 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，鼻内催产素可以增强社交能力 接近相关行为。然而，其他研究（特别是女性）报告说，鼻内催产素 增加社交焦虑。为什么同样的神经肽会对行为产生如此不同的影响呢？我们的中央 假设催产素在中脑边缘多巴胺系统中起作用，以促进社会接近，而 催产素作用于终纹床核（BNST）以增强社交焦虑。这种假设是 概念上的创新，因为它可以调和在人类和动物身上明显矛盾的发现， 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， 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会 失败模式，这诱导了一个更强的社会焦虑表型的女性比男性。 首先，我们将使用反义吗啉代选择性地抑制BNST内的神经元中的催产素合成， 下丘脑（投射到伏隔核，NAc）以确定这些细胞如何调节社交 焦虑和社交方式。接下来，我们将使用病毒载体来可视化BNST中的催产素产生细胞 和下丘脑我们将分离催产素神经元用于单细胞RNAseq分析，我们还将进行 电生理分析。我们将确定社会压力在多大程度上诱导分子和 增加兴奋性的生理反应。最后，我们将研究催产素的行为效应 使用选择性诱导Gq或BNST的OTR偶联的偏向性激动剂， 或Gi通路。我们的研究团队非常适合执行这些研究。特雷纳博士的实验室开发了 加州小鼠社会挫败模型并收集了大部分的初步数据。罗宾逊医生是一个行为 神经科学家，具有强大的分子和电生理学技能。Settles博士是生物信息学专家， 进行了单细胞RNAseq数据的分析。Chini博士是OTR G蛋白偶联方面的权威， 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机制的分析 来自男性和女性的催产素神经元的不同群体的表型是前所未有的， 从而对如何选择性地靶向这些细胞产生了新的见解。

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.