Novel Approaches to Enhancing Social Cognition by Stimulating Oxytocin Release

描述（由申请人提供）：催产素（OT）在模型动物和人类的哺乳动物社会行为中发挥作用。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障碍（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人群中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功效的限制因素。黑皮质素激动剂被提出作为刺激OT的中枢释放以增强社会认知的替代方法。作用于脑特异性黑皮质素4受体（MC4R）的黑皮质素激动剂先前已显示在体外刺激OT释放。社会性一夫一妻制的草原田鼠（Microtus ochrogaster）是研究社会认知和社会依恋的著名模型。草原田鼠伴侣偏好的形成是一个复杂的社会认知过程，涉及到社会信息加工和社会强化，并受到OT的促进。我们最近发现，外周给药的Melanotan II（MTII），具有高选择性激活MC4R的化合物，增强了男性和女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央机制，这是一个知识缺口，阻碍了对这种方法潜在临床适用性的准确评估。该提议的首要假设是，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。在目标1中，我们将确定MTII是否集中在MC4R，以促进合作伙伴的偏好形成，使用药理学操作结合行为评估。在目的2中，我们将确定MC4R激活下丘脑室旁核的作用，以及OT系统的具体贡献，在MTII的行为效应。目标2将使用药理学和分子遗传学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，并有助于更好地理解OT系统如何在治疗上被操纵。这是一个独特的调查路线，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.