Novel Approaches to Enhancing Social Cognition by Stimulating Oxytocin Release

通过刺激催产素释放来增强社会认知的新方法

• 批准号: 8837869
• 负责人: Kara Ann Kittelberger
• 金额: $ 4.27万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2017-09-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837869
• 关键词: Affect; Agonist; Animal Model; Behavior assessment; Behavioral; Behavioral Paradigm; Blood - brain barrier anatomy; Brain; Clinical Research; Cognitive; Complex; Data; Development; Dopamine; Face; Female; Future; Human; Hypothalamic structure; In Vitro; Infusion procedures; Injection of therapeutic agent; Investigation; Knowledge; Learning; Mediating; Melanocortin 4 Receptor; Mental disorders; Microtus; Modeling; Molecular Genetics; Neurons; Opiates; Oxytocin; Oxytocin Receptor; Partner in relationship; Patients; Peripheral; Persons; Pharmacologic Substance; Play; Process; Prosencephalon; Psychological reinforcement; Quality of life; Rattus; Receptor Activation; Regulation; Rewards; Rodent Model; Role; Route; Schizophrenia; Signal Transduction; Site; Social Behavior; Social Development; Social Functioning; Social Reinforcement; Source; Study models; System; Testing; Therapeutic; Treatment Efficacy; Viral Vector; autism spectrum disorder; behavior test; cell type; clinical application; genetic manipulation; improved; information processing; innovation; insight; knock-down; male; melanotan-II; neurobiological mechanism; neurotransmission; novel; novel strategies; paraventricular nucleus; patient population; prairie vole; preference; prevent; promoter; public health relevance; receptor expression; research study; screening; small hairpin RNA; social; social attachment; social cognition

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.

描述(申请人提供)：催产素(OT)在模式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，鼻腔催产素已被证明在健康人群和患者群体中都能增强社会认知的某些方面。不幸的是，鼻腔OT穿透血脑屏障以广泛激活中枢OT受体的程度可能是该治疗方法疗效的限制因素。黑素皮质素激动剂被认为是刺激催产素中枢释放以增强社会认知的一种替代方法。黑素皮质素激动剂作用于大脑特定的黑素皮质素4受体(MC4R)，已被证明在体外可以刺激OT的释放。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，这是由OT促进的。我们最近已经证明，外周给药黑素二号(MTII)，一种具有高选择性激活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MTII增强伴侣偏好形成的确切核心机制，这是一个知识缺口，阻碍了对该方法潜在临床适用性的准确评估。这一假设的主要假设是，位于前脑OT的初级来源，即下丘脑室旁核的MC4Rs的激活，刺激OT系统来增强草原田鼠的社会认知。在目标1中，我们将确定MTII是否在MC4R发挥中央作用，通过结合药理学操作和行为评估来促进伴侣偏好的形成。在目标2中，我们将确定下丘脑室旁核MC4R激活的作用，以及OT系统在MTII行为效应中的具体贡献。AIM 2将同时使用药理学和分子遗传操作，并结合行为评估。拟议的实验将促进我们对功能性社会认知的了解，并有助于更好地理解OT系统如何潜在地被操纵为治疗性的。这是寻找人类精神疾病社会缺陷的新疗法的一条独特的调查路线。