Sex-specific regulation of social play

描述(由申请人提供)：儿童和青春期的社交游戏活动对发展一生所需的社交技能很重要。社交游戏是一种回报很高的活动，并受中脑皮质边缘多巴胺系统的调节。社交游戏缺陷是自闭症谱系障碍(ASD)等神经发育障碍的核心症状。ASD和其他神经发育障碍在发病率、症状严重程度和治疗反应方面进一步显示出明显的性别差异。加压素(VP)系统对社会行为的调节很重要，是性二态的(男性的VP多于女性)，在ASD中表现出异常，并成为治疗社交功能障碍的潜在药物靶点。因此，了解VP如何在发育过程中和两性中调节社会行为是至关重要的。这项研究的长期目标是揭示VP调节两性社交游戏的神经回路。我们使用大鼠作为模型生物，因为社会游戏在大鼠身上得到了很好的定义，而性二态VP系统在哺乳动物中高度保守。总体假设是，LS-VP系统通过与Brai奖赏系统的相互作用，参与了对社会游戏的性别特定调节。在Support中，我们发现，阻断外侧隔(LS)中的VpV1a受体(V1aR；大脑中的主要Vp受体)增强了男性的社交游戏，但降低了女性的社交游戏。这表明，在LS中释放的VP抑制了男性的社交游戏，但刺激了女性的社交游戏。本研究的目的是确定幼年大鼠社会游戏调节中的性别特异性神经元机制以及VP与大脑奖赏回路的相互作用。我们将在这些发现的基础上，确定LS中VP以性别特异性方式调节社会游戏的机制(目标1)，并确定VP是否通过LS-VTA途径以性别特异性的方式调节社会游戏(目标2)。这两个独立的特定目标将共同揭示LS-VP系统如何调节LS和腹侧被盖区(VTA，中皮质边缘多巴胺系统的起源地)的主要神经递质系统，以性别特有的方式调节社会游戏。目的1检验VP在社会游戏中调节LS神经元活动性别差异的假设。目的2检验VP在社会游戏中调节LS-VTA通路性别差异的假设。这项建议是创新的，因为它将识别行为调节的性别特异性神经机制，它将揭示LS-VTA通路参与社会奖励行为，它将使用综合的多学科方法以独特和综合的方式研究LS-VP系统及其与VTA系统的相互作用。这项拟议的研究具有重要意义，因为研究结果将有助于理解VP在儿童典型和非典型社交游戏的性别特定调控中的潜在作用。

DESCRIPTION (provided by applicant): Social play activities during childhood and adolescence are important for the development of social skills needed throughout life. Social play is a highly rewarding activity and is modulated by the mesocorticolimbic dopamine system. Social play deficits are a core symptom of neurodevelopmental disorders such as autism spectrum disorders (ASD). ASD and other neurodevelopmental disorders further show robust sex differences in incidence, symptom severity, and treatment responses. The vasopressin (VP) system is important for the regulation of social behaviors, is sexually dimorphic (males have more VP than females), shows abnormalities in ASD, and emerges as potential drug target in the treatment of social dysfunction. Understanding how VP regulates social behaviors during development and in both sexes is therefore essential. The long-term goal of this research is to reveal the neural circuitry by which VP regulates social play in both sexes. We use rats as model organism because social play is well defined in rats and the sexually dimorphic VP system is highly conserved across mammalian species. The overall hypothesis is that the LS-VP system is involved in sex- specific regulation of social play via its interactions with the brai reward system. In support, we showed that blockade of the VP V1a receptor (V1aR; main VP receptor in the brain) in the lateral septum (LS) enhances social play in males, but decreases it in females. This suggests that VP released in the LS inhibits social play in males, but stimulates social play in females. The objective is to identify the sex-specific neuronal mechanisms and the interaction of VP with the brain reward circuitry in the regulation of social play in juvenile rats We will build on these findings and aim to identify the mechanisms in the LS by which VP modulates social play in sex-specific ways (Aim 1) and determine whether VP acts through the LS-VTA pathway to modulate social play in sex-specific ways (Aim 2). The two independent specific aims will collectively reveal how the LS- VP system modulates major neurotransmitter systems in the LS and in the ventral tegmental area (VTA, site of origin of the mesocorticolimbic dopamine system) to regulate social play in sex-specific ways. Aim 1 will test the hypothesis that VP mediates sex differences in LS neuronal activity during social play. Aim 2 will test the hypothesis that VP mediates sex differences in the LS-VTA pathway during social play. This proposal is innovative because it will identify sex-specific neural mechanisms underlying the regulation of behavior, and it will reveal the involvement of the LS-VTA pathway in social reward behavior, and it will use a comprehensive multidisciplinary approach to examine the LS-VP system and its interactions with the VTA system in a unique and integrated way. The proposed research is significant because outcomes will be informative for understanding the potential role of VP in sex-specific regulation of typical and atypical social play in children.