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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要自闭症谱系障碍 (ASD) 的特点是社交沟通受损，通常归因于尽管在理解自闭症谱系障碍方面取得了进展，但治疗选择仍然有限。这部分是由于 ASD 动物模型的局限性，未能捕捉到 ASD 的一个重要方面状况——患有自闭症谱系障碍的人参与社交互动的动机受到损害。开发了一种在成瘾药物和社交互动之间进行选择的操作模型，表明操作模型社会奖励可以防止药物自我给药和药物复发。将社会因素纳入成瘾神经科学中，以更接近地模拟人类状况。使我们能够直接评估社会奖励和参与社会的动机以及道德使用机器学习方法进行复杂社交的自然意志社交互动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自闭症谱系障碍啮齿动物模型中社会动机的潜在破坏该提案的首要目标是研究介导社会动机的神经机制以及 Shank3 突变的影响（大鼠模型）在目标 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。使用姿势估计来创建基于监督和无监督机器学习的预测分类器我们追求Shank3缺陷的大鼠模型，但野生型大鼠不会表现出异常。在目标 2 中，我们将使用以下方法来研究潜在的自闭症样诱发的社会动机转变。不同的行为方法：社会寻求、社会进步比率和社会自我管理，尽管通过将我们的社会自我管理模型与 ASD 大鼠模型相结合，我们将检验以下假设：相对于 Shank3 缺陷的大鼠，其社交动机行为会受到干扰在目标 3 中，我们将使用单单元电生理记录记录内侧杏仁核 (MeA – 对社交行为至关重要的大脑区域）来识别编码大鼠社交动机或潜在缺陷的单位使用翻译相关社会选择程序的社会动机此外，我们将使用光遗传学。逆转清醒行为大鼠中潜在的 Shank3 依赖性社会动机缺陷的方法。这些方法将为我们理解 MeA 在预测各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 大鼠模型中的行为。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 ASD 大鼠模型中的相互作用。