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

大脑表达 Avpr1a 的神经元在调节社会行为中的作用

基本信息

批准号：
10737195
负责人：
Benjamin David Rood
金额：
$ 40.25万
依托单位：
ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737195
关键词：
Adolescent Affect Aggressive behavior Agonist Amygdaloid structure Anatomy Argipressin Behavior Behavior Therapy Behavioral Biology Brain Brain region Caring Cell physiology Cells Child Child Rearing Cognition Cognitive Decision Making Disease Dopamine Dorsal Electrophysiology (science)Emotional Emotions Female Gene Expression Gene Expression Profile Genetic Goals Health Heterogeneity Human Individual Investigation Knowledge Life Link Literature Measures Medial Medical Memory Mental Depression Modeling Modernization Molecular Genetics Motivation Mus National Institute of Mental Health Neuroanatomy Neurobiology Neurons Neuropeptides Neurosciences Outcome Pair Bond Partner in relationship Pathway interactions Pattern Personality Disorders Phenotype Physiological Play Prefrontal Cortex Psychoses Psychosocial Stress Quality of life Rattus Regulation Reporter Research Rewards Rodent Role Sampling Serotonin Short-Term Memory Signal Transduction Social Behavior Social Interaction Social Network Stimulus Stream Stress Structure of terminal stria nuclei of preoptic region System Territoriality Testing Thalamic structure Therapeutic Intervention Transgenic Mice V1a vasopressin receptor Vasopressin Receptor Vasopressins Viral Viral Vector antagonist anti social antisocial behavior autism spectrum disorder behavior test behavioral study cell type cognitive testing delivery vehicle electrical property experience experimental study flexibility genetic approach improved improved outcome in vivo insight interest loss of function male motivated behavior mouse model nerve supply neural neural circuit neuromechanism patch clamp peer pharmacologic receptor response sex single-cell RNA sequencing social social anxiety social influence social stress supportive environment targeted treatment tool transcriptomics

项目摘要

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).

项目摘要了解社会行为的神经生物学的重要性是由社会的事实强调的互动几乎渗透到人类生活的各个方面。我们如何培养，与同龄人的互动，浪漫的关系，养育我们自己的孩子。所有这些关系影响我们的生活质量和非典型的生活质量社交互动可能对个人及其社交网络产生毁灭性的后果。这破坏社会行为的负面影响会导致并加剧健康问题，而积极社交互动和支持环境可以改善健康成果。更好地理解神经社会行为的基础机制，这是美国国家研究所（National Institute）制定的战略目标的关键目标心理健康，将有助于确定治疗基本原因的目标，这些原因破坏行为并激励使用社交互动本身作为一种治疗干预措施来改善健康结果的新方法。几十年研究明确表明，神经肽精氨酸加压素（AVP）影响两者社交（例如，父母护理，少年戏剧，成对的束缚和社交记忆）和反社会（例如侵略和在许多哺乳动物物种中的领土侧面标记）行为，但AVP会影响的机制社会行为尚未完全理解，从而在知识上造成了关键的差距。 AVP神经元解剖学研究预测表明，AVP在Stria末端（BNST）和内侧的床核中产生神经元杏仁核可能参与亲社会行为的调节，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的地区拟议研究的目标）。一个中心假设是AVP响应的激活（即AVP 1A受体 - 在控制动机和情绪的大脑区域中表达AVPR1A）神经元促进亲社会行为（即，增加对社会刺激和参与非攻击行为的兴趣）并减少反社会行为（即社会回避和表现出侵略性行为）。检验这个假设并发现潜在的机制，提出了3个目标。提议的实验利用了新的特征允许遗传访问AVPR1A表达AVPR1A的单元的鼠标模型，从而实现选择性靶向和 AVPR1A和非AVPR1A神经元之间的区分。在AIM 1中，电生理，转录组和病毒追踪策略将用于确定基本电气行为，基因表达模式，以及中腹丘脑Avpr1a神经元的连通性，这是一种以前未开发的神经元亚型。这中等多形丘脑是多巴胺奖励系统的下流目标，由BNST AVP支配系统及其对内侧前额叶皮层的预测会影响记忆，认知灵活性和决策，都是社会行为表达至关重要的。然后，功能丧失策略将用于直接评估中腹丘脑Avpr1a神经元亚型的作用社会互动（AIM 2）和认知行为的测试（AIM 3）。