Effect of adolescent social isolation on adult decision making and corticostriatal circuitry

项目摘要/摘要 青春期是社会和认知发展的一个特别重要的时期，具有 这在一定程度上是由于探索、社会互动和神经连接的快速增长。社交 青春期的孤独对一系列的行为和行为都有明显而深远的影响 生理终点一直延伸到成年期。这项研究的总体目标是 一项提案是阐明青春期雄性和雌性小鼠的社交隔离如何改变基于价值观的 成年期的决策，以及驱动这些决策的潜在皮质纹状体回路 复杂的目标导向行为。这项工作是及时和至关重要的，就像新冠肺炎一样 使越来越多的青少年因学校关闭而受到社会孤立 呆在家里的订单。 这项建议的第一个目标是使用操作性任务来系统地调查青少年 社交隔离会影响老鼠后来如何评估奖励收益和整合预期成本 做决定。初步数据表明，青少年的社交隔离会放大奖励价值， 但决策行为的具体方面将与计算建模分开 基于价值的选择。第二个目标建立在这一行为工作的基础上，以检验以下假设 青春期社交隔离对成年时皮质纹状体回路和纹状体输出的影响 基于价值的决策。在决策过程中使用分布式神经网络- 背内侧纹状体(DMS)是该网络的关键节点。前额叶的输入 内侧前额叶皮质(MPFC)和眶前叶皮质(OFC)的DMS受到严重影响 分别在行动选择和结果评估方面。所有这三个节点 经历青春期的成熟和完善，以及青少年的社交孤立 扰乱了这一发展。然而，这对成人皮质纹状体功能的影响仍然存在。 未知。使用活体电生理学、局部场电位(LFP)和单单位记录 将被用来测试青少年社交隔离如何影响突触强度和连接性 在基于价值的决策行为中从这些皮质区域到DMS。 这项在指导研究科学家发展奖中提出的工作将为伊丽莎白博士提供 霍莉在决策行为和活体计算建模方面的培训 电生理学，这将是她独立研究基础的重要部分 职业生涯。完成这一奖项后，霍莉博士的目标是过渡到终身教职 教师职位，并申请R01。霍莉博士组建的指导团队将确保她 成功地培训了这些技巧，并为她过渡到自己的独立做好了准备 研究实验室。

PROJECT SUMMARY/ABSTRACT Adolescence is a particularly important period in social and cognitive development, characterized in part by rapid increases in exploration, social interaction, and neural connectivity. Social isolation in adolescence has a clear, profound impact on a wide range of behavioral and physiological endpoints extending into adulthood. The overarching research goal of this proposal is to elucidate how adolescent social isolation in male and female mice alters value-based decision making in adulthood, as well as the underlying corticostriatal circuitry driving these complex goal-directed behaviors. This work is timely and vitally important as COVID-19 has subjected an increasing number of adolescents to social isolation through school closures and stay-at-home orders. A first aim of this proposal is to use operant tasks to systematically investigate how adolescent social isolation impacts how mice later value reward benefits and integrate expected costs during decision making. Preliminary data suggests that adolescent social isolation amplifies reward value, but specific aspects of decision-making behavior will be disentangled with computational modeling of value-based choice. The second aim builds on this behavioral work to test the hypothesis that adolescent social isolation disrupts corticostriatal circuitry and striatal output during adult value-based decision-making. A distributed neural network is engaged during decision- making, and the dorsomedial striatum (DMS) is a key node in this network. Prefrontal inputs to the DMS from the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) are critically involved in action selection and outcome valuation, respectively. All three of these nodes undergo maturation and refinement during adolescence, and adolescent social isolation disrupts this development. However, how this impacts adult corticostriatal function remains unknown. Using in vivo electrophysiology, local field potential (LFP) and single- unit recordings will be used to test how adolescent social isolation affects synaptic strength and connectivity from these cortical regions to the DMS during value-based decision-making behavior. This work proposed in the Mentored Research Scientist Development Award will provide Dr. Elizabeth Holly with training in computational modeling of decision-making behavior and in vivo electrophysiology, which will be an important part of the foundation of her independent research career. By completion of this Award, the goal is for Dr. Holly to transition to a tenure-track faculty position and apply for an R01. The mentorship team Dr. Holly has assembled will ensure her successful training in these techniques, and prepare her to transition to her own independent research laboratory.