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

不稳定的伏核在社会行为功能障碍模型中具有社会表征。

• 批准号: 10735723
• 负责人: Peyman Golshani
• 金额: $ 76.89万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735723
• 关键词: Animals; Automobile Driving; Behavior; Behavioral; Biological Assay; Brain region; Calcium; Collaborations; Complement; Custom; Data; Development; Disease model; Dopamine; Dopamine D2 Receptor; Fiber; Frequencies; Functional disorder; Future; Genetic Models; Image; Imaging Device; Immediate-Early Genes; Individual; Knowledge; Label; Learning; Medial; Mediating; Microscope; Microscopy; Modeling; Motivation; Neurons; Nucleus Accumbens; Pattern; Performance; Photometry; Play; Population; Population Analysis; Prefrontal Cortex; Probability; Productivity; Recording of previous events; Rewards; Role; Signal Transduction; Social Behavior; Social Interaction; Task Performances; Testing; Time; Ventral Tegmental Area; autism spectrum disorder; cell type; dopaminergic neuron; experimental study; improved; individuals with autism spectrum disorder; miniaturize; mutant; neural; neural circuit; neuroregulation; optogenetics; social; social contact; social deficits; theories

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.

摘要： 自闭症谱系障碍（ASD）的社会动机/奖励理论概述了自闭症患者倾向于不追求，参与或保持社会互动，因为他们发现社会互动比没有ASD的人更少奖励。一个主要的假设是，传统的奖励回路在社会动机和奖励中发挥着重要作用，并且可能在自闭症中功能失调;然而，这个有趣的假设的机械证据很少。我们最近发现，在社会互动过程中，很大一部分的神经核（NAc）D1 R神经元（奖励回路中的关键节点）被激活，并且这些神经元的一个子集在几天内保持着社会互动的神经群体代表。我们还发现，在具有社会行为功能障碍的Cntnap 2-/-突变动物中，短期和长期NAc群体对社会互动的表征变得不稳定。此外，我们还开发了一个社会奖励任务，动物通过社会接触的特定行为得到奖励。腹侧被盖区多巴胺能投射到NAc被激活，多巴胺在执行这种社会奖励任务期间被释放，再次强调了NAc对社会奖励的重要性。此外，在自由行为的动物使用Neuropixels记录，我们显示在社会互动过程中的前额叶皮层和NAc的相互协调，这表明多区域同步可能在调节社会奖励中发挥关键作用。Golshani和Hong实验室有着良好的合作历史。总之，我们将测试总体假设，即不稳定的长期NAc D1 R社会表征，导致改变输入NAc，驱动异常的社会行为与社会行为功能障碍的模型。在目标1中，使用无线微型显微镜的钙成像和选择性标记NAc中的D1 R-MSN和D2 R-MSN，然后进行解码分析，我们将测试以下假设：在具有社会行为功能障碍的Cntnap 2和Shank 3b突变动物中，社会互动和社会奖励的D1 R-MSN神经表征在几天内退化且不太稳定。在目标2中，使用retroAAV介导的特异性VTA和mPFC输入NAc的标记，小型化显微镜和多纤维光度法，我们将测试以下假设：在具有异常社会行为的两种突变动物中，mPFC和多巴胺能VTA向NAc的投射显示退化、不稳定和不协调的社会表征。我们还将使用Neuropixels记录自由行为的动物，探索mPFC和NAc之间的精细同步性。在目标3中，我们将使用活动依赖性ChR 2标记的NAc神经元激活的社会互动和闭环再激活这些神经元，以测试是否稳定的活动在社会互动可以延长和增加社会互动的概率在这两个突变动物异常的社会行为。这些实验将验证未来神经调节的目标，并在具有社会行为功能障碍的不同遗传模型中找到社会功能障碍的趋同原因。