Unstable nucleus accumbens social representations in models of social behavioral dysfunction.

摘要： 自闭症谱系障碍(ASD)的社会动机/回报理论概述了自闭症患者倾向于不追求、参与或维持社交活动，因为他们发现社交活动不如没有ASD的人那么有回报。一个重要的假说是，传统的奖赏回路在社会动机和奖赏中发挥着重要作用，在自闭症中可能功能失调；然而，对这一有趣的假说的机械证据一直很少。我们最近发现，伏隔核(NAC)D1R神经元是奖励回路中的一个关键节点，在社交互动过程中有相当大比例的神经元被激活，并且这些神经元的一个子集在几天内维持着社交互动的神经群表征。我们还发现，在具有社会行为功能障碍的cntnap2/-突变动物中，社会互动的短期和长期NAC群体表征都变得不稳定。此外，我们还开发了一个社会奖励任务，即通过社会接触来奖励动物的特定行为。在这项社会奖励任务的执行过程中，VTA向NAC的多巴胺能投射被激活，多巴胺被释放，再次强调了NAC对社会奖励的重要性。此外，利用自由行为动物的神经像素记录，我们显示了社会互动过程中前额叶皮质和NAC的相互协调，表明多区域同步可能在调节社会奖励方面发挥关键作用。戈尔沙尼和洪实验室有着卓有成效的合作历史。我们将一起测试最重要的假设，即不稳定的长期NAC D1R社会表征，由于对NAC的输入改变而导致的，在具有社会行为功能障碍的模型中驱动异常的社会行为。在目标1中，使用无线微型显微镜的钙成像和选择性地标记NAC中的D1R-MSN和D2R-MSN，然后进行解码分析，我们将检验这一假设，即在cntnap2和Shank3b突变的社会行为障碍动物中，D1R-MSN的社会互动和社会奖励的神经表征随着时间的推移而退化和不稳定。在目标2中，利用逆转录病毒介导的特异性VTA和mPFC传入NAC的标记、微型显微镜和多纤维光度法，我们将检验mPFC和多巴胺能VTA向NAC的投射在两个具有异常社会行为的突变动物中表现出退化、不稳定和不协调的社会表征的假设。我们还将使用自由行为动物的神经像素记录来探索mPFC和NAC之间的精细同步。在目标3中，我们将使用社会相互作用激活的NAC神经元的活动依赖的ChR2标记和这些神经元的闭环重新激活来测试在社会相互作用期间活动的稳定是否可以延长和增加具有异常社会行为的突变动物的社会相互作用的概率。这些实验将验证未来神经调节的目标，并通过不同的带有社会行为障碍的遗传模型找到导致社会功能障碍的趋同原因。

Abstract: The social motivation/reward theory of autism spectrum disorder (ASD) outlines that individuals with autism tend not to pursue, engage or maintain social interactions because they find social interactions less rewarding than individuals without ASD. A major hypothesis is that traditional reward circuits play an important role in social motivation and reward and may be dysfunctional in autism; yet, mechanistic proof for this intriguing hypothesis has been sparse. We have recently discovered that a significant proportion of nucleus accumbens (NAc) D1R neurons, a key node in the reward circuit, are activated during social interaction and that a subset of these neurons maintains a neural population representation of social interaction across days. We have also found that both short- and long-term NAc population representations of social interaction become destabilized in the Cntnap2 -/- mutant animals with social behavioral dysfunction. In addition, we have developed a social reward task where animals are rewarded for specific actions with social contact. VTA dopaminergic projections to NAc are activated and dopamine is released during the performance of this social reward task, again highlighting the importance of NAc for social reward. Furthermore, using Neuropixels recordings in freely behaving animals, we show reciprocal coordination of the prefrontal cortex and NAc during social interaction, suggesting that multiregional synchronization may play a key role in modulating social reward. The Golshani and Hong labs have a strong history of productive collaboration. Together, we will test the overarching hypothesis that unstable long-term NAc D1R social representations, resulting from altered inputs to NAc, drive abnormal social behaviors in models with social behavioral dysfunction. In Aim 1, using calcium imaging with wire-free miniaturized microscopes and selective labeling of D1R-MSN and D2R-MSNs in NAc, followed by decoding analysis, we will test the hypothesis that D1R-MSN neural representations of social interaction and social reward are degraded and less stable across days in the Cntnap2 and Shank3b mutant animals with social behavioral dysfunction. In Aim 2, using retroAAV-mediated labeling of specific VTA and mPFC inputs to NAc, miniaturized microscopy and multi-fiber photometry, we will test the hypothesis that the mPFC and dopaminergic VTA projections to NAc show degraded, unstable and uncoordinated social representations in the two mutant animals with abnormal social behavior. We will also probe fine-scale synchrony between mPFC and NAc using Neuropixels recordings in freely behaving animals. In Aim 3, we will use activity-dependent ChR2 labeling of NAc neurons activated by social interaction and closed-loop reactivation of these neurons to test whether stabilization of activity during social interaction can prolong and increase the probability of social interactions in both mutant animals with abnormal social behavior. These experiments will validate targets for future neuromodulation and find convergent causes for social dysfunction across different genetic models with social behavioral dysfunction.