Novel Approaches to Enhancing Social Cognition by Stimulating Oxytocin Release

描述（由申请人提供）：催产素（OT）在哺乳动物和人类的社会行为中都起作用。OT广泛增强社会认知的能力使其成为改善以社会缺陷为特征的精神疾病（包括自闭症谱系障碍）的社会功能的可行候选者。事实上，鼻内OT已被证明可以增强健康人群和患者的社会认知的某些方面。不幸的是，鼻内OT穿透血脑屏障以广泛激活中枢OT受体的程度可能是这种治疗方法有效性的限制因素。黑素皮质激素激动剂被认为是刺激OT中枢释放以增强社会认知的替代方法。黑素皮质激素激动剂，作用于脑特异性黑素皮质激素4受体（MC4R），已经被证明可以刺激OT的体外释放。社会一夫一妻制草原田鼠（Microtus ochrogaster）是研究社会认知和社会依恋的一个著名模型。草原田鼠伴侣偏好的形成是一个复杂的社会认知过程，涉及社会信息加工和社会强化，并在OT的作用下得到促进。我们最近的研究表明，外周给药Melanotan II (MTII)，一种高选择性激活MC4R的化合物，可以增强雄性和雌性草原田鼠的伴侣偏好形成。目前尚不清楚的是MTII增强伴侣偏好形成的确切中心机制，这是一个知识缺口，妨碍了对该方法潜在临床适用性的准确评估。该提议的总体假设是，位于前脑OT的主要来源，下丘脑室旁核的MC4Rs的激活，刺激OT系统以增强草原田鼠的社会认知。在目的1中，我们将通过药理学操作结合行为评估来确定MTII是否在MC4R中起中心作用，以促进伴侣偏好的形成。在Aim 2中，我们将确定MC4R激活在下丘脑室旁核中的作用，以及OT系统在MTII行为效应中的具体贡献。目标2将使用药理学和分子遗传操作与行为评估相结合。拟议的实验将推进我们对功能性社会认知的认识，并促进对如何在治疗上操纵OT系统的更好理解。这是一个独特的研究路线，在寻找新的治疗人类精神疾病的社会缺陷。

DESCRIPTION (provided by applicant): Oxytocin (OT) plays a role in mammalian social behavior in both model animals and humans. The ability of OT to broadly enhance social cognition makes it a viable candidate for improving social function in psychiatric disorders characterized by social deficits, including Autism Spectrum Disorder. Indeed, intranasal OT has been shown to enhance some facets of social cognition in both healthy and patient populations. Unfortunately, the extent to which intranasal OT penetrates the blood-brain barrier to broadly activate central OT receptors is likely a limiting factor in the efficacy of this therapeutic approach. Melanocortin agonists are proposed as an alternative approach to stimulate central release of OT to enhance social cognition. Melanocortin agonists, acting at the brain-specific melanocortin 4 receptor (MC4R), have been previously shown to stimulate OT release in vitro. The socially monogamous prairie vole (Microtus ochrogaster) is a well-known model for the study of social cognition and social attachment. Formation of a partner preference in the prairie vole is a complex social cognitive process involving social information processing and social reinforcement that is facilitated by OT. We have recently shown that peripheral administration of Melanotan II (MTII), a compound with high selectivity for activating MC4R, enhances partner preference formation in male and female prairie voles. What remains unknown is the precise central mechanism by which MTII enhances partner preference formation, a knowledge gap that prevents accurate assessment of the potential clinical applicability of this approach. The overarching hypothesis of this proposal is that activation of MC4Rs located in the primary source of forebrain OT, the paraventricular nucleus of the hypothalamus, stimulates the OT system to enhance social cognition in the prairie vole. In Aim 1, we will determine whether MTII acts centrally at MC4R to facilitate partner preference formation using pharmacological manipulations combined with behavioral assessments. In Aim 2, we will determine the role of MC4R activation in the paraventricular nucleus of the hypothalamus, and the specific contribution of the OT system, in the behavioral effects of MTII. Aim 2 will use both pharmacological and molecular genetic manipulations in combination with behavioral assessment. The proposed experiments will advance our knowledge of functional social cognition as well as facilitate a greater understanding of how the OT system can potentially be manipulated therapeutically. This is a unique route of investigation in the search for novel treatments of social deficits in human psychiatric disorders.