Behavioral and neural mechanisms mediating social motivation in a rat model for ASD

自闭症大鼠模型中调节社会动机的行为和神经机制

• 批准号: 10553444
• 负责人: Marco Venniro
• 金额: $ 43.3万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-16 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553444
• 关键词: Adoption; Amygdaloid structure; Animal Model; Animals; Behavior; Behavioral; Behavioral Mechanisms; Brain region; Classification; Complex; Cues; Drug Interactions; Electrophysiology (science); Emotional; Ethology; Event; Future; Genes; Goals; Human; Impairment; Intuition; Machine Learning; Medial; Mediating; Modeling; Motivation; Mutation; Neurosciences; Pharmaceutical Preparations; Pre-Clinical Model; Procedures; Punishment; Pythons; Rattus; Reciprocal Social Interaction; Reporting; Research; Rewards; Rodent; Rodent Model; Role; Self Administration; Social Behavior; Social Interaction; Stimulus; Study models; System; Testing; Time; addiction; autism spectrum disorder; autistic children; awake; craving; drug relapse; genetic manipulation; graphical user interface; individuals with autism spectrum disorder; insight; interest; neural; neurobiological mechanism; neuroethology; neuromechanism; neuropsychiatric disorder; novel; open source; optogenetics; pharmacologic; pre-clinical; preclinical study; prevent; social; social communication impairment; social deficits; social deprivation; social engagement; social factors; social model; supervised learning; temporal measurement; tool; unsupervised learning

Project Summary Autism spectrum disorder (ASD) is characterized by impaired social communication, often attributed to misreading of emotional cues. Despite progress toward understanding ASD, treatment options remain limited. This is partly due to limitations of animal models of ASD that fail to capture an essential aspect of the ASD condition – people with ASD have impairments in the motivation to engage in social interactions. We recently developed an operant model of choice between addictive drugs and social interaction, showing that operant social reward prevents drug self-administration and drug relapse. Our model highlights the importance of incorporating social factors into addiction neuroscience to mimic the human condition more closely. Our model allows us to directly assess both social reward and motivation to engage socially and the ethology of consequent naturalistic volitional social interactions using machine learning approaches for complex social behavior. The combination of a novel operant social model and advanced computational neuroethological analytical pipelines provides a unique toolkit to study the neurobiological mechanisms underlying social reward and potential disruption of social motivation in rodent model for ASD. The overarching aim of this proposal is to study the neural mechanisms mediating social motivation and the impact of Shank3 mutation (a rat model for ASD). In Aim 1, we will use open-source Python packages with graphical interface and intuitive workflow that uses pose-estimation, to create supervised and unsupervised machine learning-based predictive classifiers of social behavior. We hypothesize that Shank3-deficient rat model, but not wild-type rats will show aberrant social behaviors. In Aim 2, we will investigate the potential autism-like-induced shifts in social motivation using different behavioral approaches: social seeking, social progressive ratio, and social self-administration despite negative consequences. By combining our social self-administration model with a rat model of ASD, we will test the hypothesis that Shank3-deficient rats will show a disruption in social motivation behaviors, relative to wild-type rats. In Aim 3, we will use single-unit electrophysiological recording into the Medial Amygdala (MeA – a brain region critical for social behaviors) to identify units encoding rats’ social motivation or potential deficit in social motivation using a translational relevant social choice procedure. Additionally, we will use optogenetic approaches to reverse potential Shank3-dependent social motivation deficit in awake-behaving rats. These approaches will provide new frameworks on our understanding of the role of MeA for predicting aspects of future social-related events and for using these predictions to guide behavior within a rat model for ASD. Our proposal will provide new insights into behavioral and neural mechanisms mediating the motivation for social interaction in rat model for ASD.

项目摘要 自闭症谱系障碍（ASD）的特点是社会沟通受损，通常归因于 对情绪线索的误读尽管对ASD的了解有所进展，但治疗选择仍然有限。 这部分是由于ASD动物模型的局限性，其未能捕获ASD的基本方面 条件-患有ASD的人在参与社会互动的动机方面有障碍。我们最近 开发了一个成瘾性药物和社会互动之间的选择操作模型，表明操作性 社会奖励可防止自我吸毒和复吸。我们的模型强调了 将社会因素纳入成瘾神经科学，以更接近地模拟人类状况。我们的模型 使我们能够直接评估社会回报和参与社会的动机以及 使用机器学习方法进行复杂的社会互动， 行为一种新颖的操作性社会模型和先进的计算神经行为学的结合 分析管道提供了一个独特的工具包来研究社会奖励背后的神经生物学机制 以及ASD啮齿动物模型中社会动机的潜在破坏。本提案的总体目标是 研究介导社会动机的神经机制以及Shank 3突变的影响（大鼠模型 ASD）。在Aim 1中，我们将使用具有图形界面和直观工作流程的开源Python包， 使用姿势估计，创建基于监督和无监督机器学习的预测分类器， 社会行为我们假设Shank 3缺陷大鼠模型，而不是野生型大鼠，将显示异常的 社会行为在目标2中，我们将研究潜在的自闭症样诱导的社会动机的变化，使用 不同的行为方法：社会寻求，社会进步率，社会自我管理，尽管 负面后果。通过将我们的社会自我管理模型与ASD大鼠模型相结合， 测试Shank 3缺陷大鼠将显示社会动机行为中断的假设，相对于 野生型大鼠。在目标3中，我们将使用单单位电生理记录进入内侧杏仁核（MeA -） 一个对社会行为至关重要的大脑区域），以识别编码大鼠社会动机或潜在缺陷的单位。 社会动机使用翻译相关的社会选择程序。此外，我们将使用光遗传学 方法来扭转潜在的Shank 3依赖的社会动机赤字清醒行为的大鼠。这些 这些方法将为我们理解MeA在预测疾病方面的作用提供新的框架。 未来的社会相关事件，并使用这些预测来指导ASD大鼠模型的行为。我们 该提案将为调节社交动机的行为和神经机制提供新的见解。 在ASD大鼠模型中相互作用。