Oxytocin neural circuitry involvement in juvenile social play

项目摘要 社会游戏是一种高度有益的行为，对社会技能的发展非常重要，这一点已经得到证实 对人类儿童和幼年大鼠的影响。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。ASD在男性中比女性更普遍，这表明- ASD病因的性别差异。开发有效的方法来恢复儿童的社会游戏， ASD将改善他们的终身社会功能，但这需要更好地理解自闭症的神经基础。 社会游戏和潜在的性别差异。ASD的社会缺陷与氧合酶的变化有关。 催产素（OXT）系统和大脑奖励系统，这两个系统对正常的社会功能至关重要- ing.此外，OXT系统是改善ASD患者社会功能的潜在药物靶点。 然而，几乎没有人知道OXT在社交游戏中的作用。我们计划在老鼠身上进行的研究旨在- 万斯理解的神经通路，其中OXT调节社会发挥在男性和女性。这是 第一个重要的步骤，以帮助通知性别特异性治疗策略，以有效地改善社会发挥在儿童， 与ASD。我们的中心假设是，OXT调节与奖励相关的大脑区域的活动， 以性别特有的方式调节社交游戏行为。具体来说，我们提出室旁核的作用 （PVN）衍生的OXT通过调节OXT受体（OXTR）表达的活性来调节社交游戏 投射到腹侧苍白球（VP）的丘脑核（NAc）中的神经元。我们进一步建议， 该途径是性别特异性地募集的。基于强有力的初步数据，我们将测试我们的新概念， PVNOXT→NAcOXTR→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通路调节社交游戏，并且是性别特异性的;在目标2中，我们将 检验NAcOXTR→VP通路调节社交游戏并且性别特异性地调节社交游戏的假设;在目标3中， 我们将测试以下假设：接收PVNOXT输入的相同NAcOXTR神经元群体投射到 在社交游戏中，VP和性特异性激活。这些拟议中的研究将揭示一种新的神经回路 跨越3个大脑区域（PVN→NAc→VP），性别特异性地调节社交游戏。使用新开发 遗传工具，即Oxtr-iCre大鼠系，我们将是第一个检查OXT通过的神经通路的人。 信号调节老鼠的任何行为。我们的发现将通过提供第一个 OXT系统参与调节社会游戏的性别特异性证据。结果将有助于- 形成OXT在人类儿童典型和非典型社会游戏中的作用，并将提供机械的见解 为什么ASD在男性中比在女性中更普遍

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.