Neural Circuits That Regulate Social Motivation in Autism

调节自闭症社交动机的神经回路

• 批准号: 9296174
• 负责人: GABRIEL S DICHTER
• 金额: $ 14.8万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9296174
• 关键词: Animal Model; Autistic Disorder; Brain; Center for Translational Science Activities; Clinical; Dopamine; Evaluation; Human; Impairment; Individual; Motivation; Neurodevelopmental Disorder; Neurons; Neuropeptides; Nucleus Accumbens; Output; Oxytocin; Pathologic; Rewards; Social Behavior; Social Development; Social Functioning; Social support; System; Ventral Tegmental Area; autism spectrum disorder; interest; mesolimbic system; motivated behavior; mouse model; neural circuit; neuroimaging; optogenetics; relating to nervous system; response; social; social attention; social cognition; social engagement

Autism spectrum disorder (ASD) is characterized by social impairments, including impaired social cognition, social percepfion, and social attention. Recently, there has been increased interest in examining the impact of motivational systems on social functioning in ASD. The frarinework of the so-called "social motivation hypothesis" of ASD is that functional disruption in brain circuits that support social motivational may constitute a primary deficit in ASD that may have downstream effects on the development of social cognition. The mesolimbic dopamine system arising in the ventral tegmental area (VTA) and projecfing to the nucleus accumbens (NAc) is an essential substrate for the expression of many forms of motivated behaviors. Human neuroimaging studies have demonstrated reduced mesolimbic activation in ASD to social rewards, suggesting that reduced function of the mesolimbic dopaminergic system may underlie decreased sociial motivation in ASD. Whereas social deficits in ASD may be related to pathological mesolimbic dopamine system activity, it is unknown if precise neural circuit manipulations that can directly control dopamine output in the NAc to promote pro-social behaviors in animal models of ASD. In addition, the neuropeptide oxytocin (OT) is a promising therapeufic to promote social engagement in ASD and is known to regulate VTA activity in response to social rewards specifically. However the functional neural circuitry by which OT neurons regulate VTA dopaminergic activity has not been identified. These are critical gaps in our understanding of the neural cii-cuitry that controls motivated social engagement. We propose a translational project integrating optogenetic circuit manipulafions in a mouse model of ASD with a clinical functional neuroimaging evaluation of the effects of OT on reward circuits in individuals with ASD.

自闭症谱系障碍（ASD）的特征在于社会障碍，包括受损的社会认知， 社会感知和社会关注。最近，人们越来越有兴趣研究 ASD社会功能的激励系统。所谓的“社会动机" ASD的“假说”是支持社会动机的脑回路的功能中断可能构成 ASD的主要缺陷可能对社会认知的发展产生下游影响。的 中脑边缘多巴胺系统起源于腹侧被盖区（VTA）并投射到核团 大脑皮层（NAc）是表达多种形式动机行为的重要基质。人类 神经影像学研究表明，ASD患者的中脑边缘系统对社会奖励的激活减少， 中脑边缘多巴胺能系统功能的降低可能是社交动机降低的基础， 自闭症虽然ASD的社会缺陷可能与病理性中脑边缘多巴胺系统活动有关，但它是 未知是否精确的神经回路操作，可以直接控制NAc中的多巴胺输出， ASD动物模型中的亲社会行为。此外，神经肽催产素（OT）是一种很有前途的 治疗促进ASD中的社会参与，并且已知响应于社会参与调节VTA活性。 具体奖励。然而，OT神经元调节VTA的功能神经回路 多巴胺能活性尚未被鉴定。这些是我们对神经系统的理解中的关键空白， 控制积极社会参与的文化。我们提出了一个整合光遗传学的翻译项目， 在ASD小鼠模型中进行电路操作的临床功能神经影像学评价 OT对ASD患者奖励回路的影响