Oxytocin neural circuitry involvement in juvenile social play

催产素神经回路参与青少年社交游戏

• 批准号: 10590706
• 负责人: Alexandra H. Veenema
• 金额: $ 37.69万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590706
• 关键词: ASD patient; Adolescent; Behavior; Brain; Brain region; Cells; Child; Data; Dose; Drug Targeting; Electrophysiology (science); Etiology; Exhibits; Female; Genetic; Globus Pallidus; Goals; Human; Incidence; Knowledge; Life; Mediating; Mental disorders; Methods; Mission; National Institute of Mental Health; Neural Pathways; Neurons; Nucleus Accumbens; Outcome; Oxytocin; Oxytocin Receptor; Pathway interactions; Phenotype; Play; Population; Property; Public Health; Rattus; Receptor Signaling; Regulation; Research; Rewards; Role; Severities; Sex Bias; Sex Differences; Signal Transduction; Social Functioning; Social skills development; Symptoms; Synapses; System; Testing; Therapeutic; Therapeutic Uses; Time; antagonist; autism spectrum disorder; autistic children; extracellular; gamma-Aminobutyric Acid; high reward; improved; individuals with autism spectrum disorder; innovation; insight; male; neural; neural circuit; novel; paraventricular nucleus; rabies viral tracing; recruit; response; sex; social; social deficits; targeted treatment; tool; treatment response; virtual

PROJECT SUMMARY Social play is a highly rewarding behavior and important for social skill development as has been demonstrated for human children and juvenile rats. Children with autism spectrum disorder (ASD) exhibit social play deficits, which contributes to their lifelong social dysfunction. ASD is more prevalent in males than in females, suggest- ing sex differences in the etiology of ASD. Developing effective means to restore social play in children with ASD will improve their lifelong social functioning, but this requires better understanding of the neural basis of social play and potential sex differences herein. Social deficits in ASD are associated with changes in the oxy- tocin (OXT) system and in the brain reward system, with both systems being critical for normal social function- ing. Furthermore, the OXT system is a potential drug target to improve social functioning in ASD patients. However, virtually nothing is known about OXT's role in social play. Our proposed research in rats aims to ad- vance understanding of the neural pathways by which OXT regulates social play in males and females. This is a first essential step to help inform sex-specific therapeutic strategies to effectively improve social play in chil- dren with ASD. Our central hypothesis is that OXT modulates the activity of reward-associated brain regions to regulate social play behavior in sex-specific ways. Specifically, we propose a role for paraventricular nucleus (PVN)-derived OXT in regulating social play by modulating the activity of OXT receptor (OXTR)-expressing neurons in the nucleus accumbens (NAc) that project to the ventral pallidum (VP). We further propose that this pathway is recruited sex-specifically. Based on strong preliminary data, we will test our novel concept that the PVNOXT→NAcOXTR→VP pathway mediates the sex-specific regulation of social play: In Aim 1, we will test the hypothesis that the PVNOXT→NAc pathway regulates social play and does so sex-specifically; In Aim 2, we will test the hypothesis that the NAcOXTR→VP pathway regulates social play and does so sex-specifically; In Aim 3, we will test the hypothesis that the same NAcOXTR neuron population that receives PVNOXT input projects to the VP and is sex-specifically activated during social play. These proposed studies will reveal a new neural circuit spanning 3 brain regions (PVN→NAc→VP) that sex-specifically modulates social play. Using newly developed genetic tools, namely an Oxtr-iCre rat line, we will be the first to examine the neural pathways by which OXT signaling regulates any behavior in rats. Our findings will significantly advance the field by providing the first evidence for the sex-specific involvement of the OXT system in regulating social play. Outcomes will help in- form the role of OXT in typical and atypical social play in human children, and will provide mechanistic insights into why ASD is more prevalent in males than in females.

项目总结 正如已经证明的那样，社交游戏是一种非常有回报的行为，对社交技能的发展很重要 适用于人类儿童和幼年大鼠。患有自闭症谱系障碍(ASD)的儿童表现出社交游戏缺陷， 这导致了他们终生的社交功能障碍。自闭症在男性中比在女性中更常见，这表明- 房间隔缺损病因的性别差异。开发有效手段，恢复儿童的社会游戏 自闭症将改善他们终生的社会功能，但这需要更好地理解自闭症的神经基础 社交游戏和潜在的性别差异。自闭症患者的社会缺陷与氧合作用的变化有关。 催产素(Oxt)系统和大脑奖励系统，这两个系统都对正常的社会功能至关重要- 英。此外，OXT系统是改善ASD患者社会功能的潜在药物靶点。 然而，关于oxt在社交游戏中扮演的角色，人们几乎一无所知。我们计划对老鼠进行的研究旨在-- 万斯对OXT调节男性和女性社交游戏的神经通路的理解。这是 帮助提供针对性别的治疗策略以有效改善儿童的社会游戏的第一个基本步骤-- 患有自闭症的儿童。我们的中心假设是，OXT调节与奖励相关的大脑区域的活动，以 以特定性别的方式规范社交游戏行为。具体地说，我们提出了室旁核的作用 (PVN)来源的OXT通过调节OXT受体(OXTR)表达的活性来调节社交游戏 伏核(NAC)中投射到腹侧苍白球(VP)的神经元。我们进一步建议这一点 PATH是针对性别招募的。基于强大的初步数据，我们将测试我们的新概念，即 PVNOXT→→VP通路介导社会游戏的性别特异性调节：在目标1中，我们将测试 假设PVNOXT→NAC途径调节社会游戏并做到性别特异性；在目标2中，我们将 测试NAcOXtr→VP通路调节社交游戏并且性别特异性地这样做的假设；在目标3中， 我们将检验这样的假设，即接受PVNOXT输入的相同NAcOXTR神经元群体投射到 是副总统，在社交游戏中被性行为激活。这些拟议的研究将揭示一种新的神经回路 跨越3个大脑区域(室旁核、→、NAc、→、VP)，性别特有地调节社交游戏。使用新开发的 遗传工具，即Oxtr-iCre大鼠系，我们将第一个检查OXT通过的神经通路 信号调节老鼠的任何行为。我们的发现将极大地推动该领域的发展，因为它提供了第一个 OXT系统在调节社会游戏中涉及特定性别的证据。结果将有助于- 形成了OXT在人类儿童典型和非典型社交游戏中的作用，并将提供机械性的见解 为什么自闭症在男性中比在女性中更普遍。