Role of brain Avpr1a-expressing neurons in modulation of social behavior

项目摘要 理解社会行为的神经生物学的重要性是由以下事实强调的： 互动几乎渗透到人类生活的方方面面。我们是如何成长的，我们与同龄人的互动， 恋爱关系，养育自己的孩子所有这些关系都影响着我们的生活质量， 社会互动对个人和他们的社交网络都有毁灭性的后果。的 破坏社会行为的负面影响可能导致和加剧健康问题，而积极的影响可能导致健康问题。 社会互动和支持性环境可以改善健康结果。更好地理解神经 社会行为背后的机制，国家研究所制定的战略目标的一个关键目标， 心理健康，将有助于确定目标的根本原因，扰乱行为和激励治疗 使用社会互动本身作为治疗干预的新方法，以改善健康结果。几十年 的研究已经明确表明，神经肽精氨酸加压素（Avp）的影响， 社交（例如，父母照顾、青少年游戏、配对结合和社会记忆）和反社会（例如，侵略和 领土侧翼标记）的行为在许多哺乳动物物种，但机制， 社会行为没有得到充分理解，造成了严重的知识差距。前腹前突神经元的解剖学研究 投射提示，在终纹床核（BNST）和内侧核中产生Avp的神经元 杏仁核可能参与调节亲社会行为，因为它们的目标包括大脑 与动机行为、情绪状态和奖励相关联的区域（例如，内侧背丘脑， 研究目标）。一个中心假设是Avp-应答的激活（即，Avp 1A受体 在控制动机和情绪的大脑区域中表达Avpr 1a）神经元促进亲社会行为 (i.e.,增加对社会刺激的兴趣和参与非攻击性行为），并减少反社会 行为（即，社交回避和攻击性行为的表现）。为了验证这个假设， 基本机制，提出了3个目标。拟议的实验利用一个新的特点， 小鼠模型，允许遗传访问Avpr 1a表达细胞，从而实现选择性靶向， Avpr 1a和非Avpr 1a神经元之间的差异。在目标1中，电生理学、转录组学和 病毒追踪策略将用于识别基本的电行为，基因表达模式， 和连接的中间背丘脑Avpr 1a神经元，以前未开发的神经元亚型。的 背内侧丘脑是多巴胺奖赏系统的下游靶点，由BNST Avp支配 系统，并通过其投射到内侧前额叶皮质影响记忆，认知灵活性， 决策，都是社会行为表达的关键。然后是化学遗传性功能丧失 策略将被用来直接评估中背丘脑Avpr 1a神经元亚型的作用， 社会互动（目标2）和认知行为测试（目标3）。

Project Summary The importance of understanding the neurobiology of social behavior is underscored by the fact that social interactions permeate nearly every aspect of human life. How we are raised, our interactions with peers, romantic relationships, parenting our own children. All these relationships impact our quality of life, and atypical social interactions can have devastating consequences both for individuals and their social networks. The negative impact of disrupted social behavior can lead to and exacerbate health problems, whereas positive social interactions and supportive environments can improve health outcomes. Better understanding of neural mechanisms underlying social behavior, a key objective of strategic goals laid out by the National Institute of Mental Health, will help identify targets for treatment of underlying causes that disrupt behavior and motivate new ways of using social interaction itself as a therapeutic intervention to improve health outcomes. Decades of research have shown unequivocally that the neuropeptide arginine vasopressin (Avp) impacts both pro- social (e.g., parental care, juvenile play, pair-bonding, and social memory) and anti-social (e.g., aggression and territorial flank-marking) behaviors in numerous mammalian species, but mechanisms by which Avp impacts social behavior are not fully understood creating a critical gap in knowledge. Anatomical studies of Avp neuron projections suggest that Avp producing neurons in the bed nucleus of the stria terminalis (BNST) and medial amygdala are likely to be involved in the regulation of prosocial behavior given that their targets include brain regions associated with motivated behavior, emotional state, and reward (e.g., the mediodorsal thalamus, the target of proposed studies). A central hypothesis is that activation of Avp-responsive (i.e., Avp 1A receptor- expressing, Avpr1a) neurons in brain regions controlling motivation and emotion promote pro-social behavior (i.e., increase interest in social stimuli and engagement in non-aggressive behaviors) and decrease anti-social behavior (i.e., social avoidance and display of aggressive behaviors). To test this hypothesis and discover underlying mechanisms, 3 Aims are proposed. Proposed experiments make use of a newly characterized mouse model that allows genetic access to Avpr1a-expressing cells enabling selective targeting and differentiation between Avpr1a and non-Avpr1a neurons. In Aim 1, electrophysiological, transcriptomic, and viral tracing strategies will be used to identify the fundamental electrical behavior, gene expression patterns, and connectivity of mediodorsal thalamus Avpr1a neurons, a previously unexplored neuronal subtype. The mediodorsal thalamus is a down stream target of the dopamine reward system, is innervated by the BNST Avp system, and through its projections to the medial prefrontal cortex influences memory, cognitive flexibility, and decision-making, all critical to the expression of social behaviors. Then, a chemogenetic loss-of-function strategy will be used to directly assess the role of the mediodorsal thalamus Avpr1a neuron subtype during social interactions (Aim 2) and tests of cognitive behavior (Aim 3).