Sex-dependent regulation of social reward by oxytocin in the mesolimbic reward circuitry

项目总结 社会互动的有益属性对于表达适应性社会行为和 社会关系的发展和维持。然而，人们对这些因素知之甚少。 确定社会互动的奖励价值，或确定社会基础的基本神经机制 奖励，特别是在女性身上。我们知道，中脑边缘多巴胺系统(MDS)是 控制许多其他刺激的奖赏属性的神经回路，如滥用药物。一个主要的 MDS的组成部分是腹侧被盖区(VTA)中投射的含有多巴胺(DA)的神经元 至伏隔核(NAC)以及其他部位，如内侧前额叶皮质。关键投入 包括下丘脑的含有催产素(OT)的投射。我们和其他人有 在雄性啮齿动物中，尾侧VTA和NAC中OT受体的激活是 对于社会互动的有益特性来说是必不可少的。值得注意的是，尽管有相当大的 OT在调节社会行为中的性别差异、OT在调节社会报酬中的作用 女性还没有被调查过。该项目将提供有关以下因素的大量新信息 确定社会互动的奖赏价值以及调节社会奖赏的神经机制 通过在雄性和雌性叙利亚仓鼠身上测试这一系列整合的假设。基于已发布的 以及来自我们实验室和其他实验室的初步数据，我们假设：1)存在倒置的U 社会互动的“剂量”与社会回报的关系，2)这种剂量-反应 女性以比男性更低的剂量启动关系，3)这种性别差异是中介的 通过不同的OT诱导的MDS中DA的释放。这个项目有很大的潜力可以翻译成 与临床相关的问题：1)关于社会刺激如何从 奖励较少的奖励，甚至是厌恶，2)理解众所周知的潜在机制 神经精神障碍和神经发育障碍发病率的性别差异 社会关系失调是一个重要的症状，以及3)性别发展的潜力- 对这些疾病的具体治疗。

PROJECT SUMMARY The rewarding properties of social interactions are critical to the expression of adaptive social behavior and to the development and maintenance of social relationships. Little is known, however, about the factors that determine the reward value of social interactions or about the basic neural mechanisms that underlie social reward, particularly in females. We do know that the mesolimbic dopamine system (MDS) is central to the neural circuitry controlling the rewarding properties of many other stimuli such as drugs of abuse. A primary component of the MDS is dopamine (DA)-containing neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens (NAc) as well as to other sites such as the medial prefrontal cortex. Critical inputs to the MDS include oxytocin (OT)-containing projections from the hypothalamus. We and others have demonstrated that, in male rodents, activation of OT receptors in the caudal VTA and in the NAc is essential for the rewarding properties of social interaction. Remarkably, despite the considerable evidence for sex differences in OT regulation of social behaviors, the role of OT in regulating social reward in females has not been investigated. This project will provide substantial new information on the factors that determine the reward value of social interactions and on the neural mechanisms that mediate social reward by testing this series of integrated hypotheses in male and female Syrian hamsters. Based on published and preliminary data from our lab and others, we have hypothesized that: 1) there is an inverted U relationship between the “dose” of social interactions and social reward, 2) this dose-response relationship is initiated at lower doses in females than in males, and 3) this sex difference is mediated by differential OT-induced DA release in the MDS. This project has substantial potential for translation to clinically-related problems by providing: 1) new information on how social stimuli can transition from being rewarding to being less rewarding or even aversive, 2) potential mechanisms for understanding well-known sex differences in the incidence of neuropsychiatric and neurodevelopmental disorders for which dysfunctional social relationships are an important symptom, and 3) the potential for development of gender- specific treatments for these disorders.