Impaired social interaction is one of the core symptoms of the autism spectrum disorder (ASD)1. However, the etiology and neural circuit mechanisms underlying these behavioral impairments are not well understood2. Currently, behavioral therapies are the most effective interventions for ASD, although the benefits from such treatments are minimal3,4. Here, we demonstrate that the autistic-like social deficits of Shank3 knockout mice5 can be durably rescued by social training coupled with optogenetic activation of neurons in the midbrain dorsal raphe nucleus (DRN) — a region encoding reward through 5-HT and glutamate6. A single training session resulted in a significant rescue effect on social preference, and such rescue effect was retained for several days with increased neuronal activation in the DRN when facing social stimuli. Multiple training sessions resulted in much longer-lasting rescue effects. Intriguingly, the durable rescue effect was generated by stimulating Pet-1 neurons in the DRN, but not by stimulating dopamine neurons in the ventral tegmental area (VTA) — the classical reward center. Our results suggest that the DRN should be viewed as an attractive target for future ASD interventions.

中文翻译：

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背缝神经元的光遗传学激活挽救了Shank3基因敲除小鼠的自闭症样社会缺陷

社会交往障碍是自闭症谱系障碍（ASD）1的核心症状之一。然而，这些行为障碍的病因和神经回路机制尚不十分清楚2。目前，行为疗法是自闭症最有效的干预措施，尽管这种疗法的收益极少3,4。在这里，我们证明了Shank3基因敲除小鼠5的自闭症样社会缺陷可以通过社交训练以及中脑背脊神经核（DRN）的神经元的光遗传激活（通过编码5-HT和谷氨酸6的区域来持久地挽救）来挽救。一次培训会对社交偏好产生重大的挽救效果，并且当面对社交刺激时，DRN中神经元激活的增加会导致挽救效果持续数天。多次培训导致了更长久的营救效果。有趣的是，持久刺激作用是通过刺激DRN中的Pet-1神经元产生的，而不是通过刺激腹侧被盖区（VTA）（经典奖励中心）中的多巴胺神经元产生的。我们的结果表明，DRN应该被视为未来ASD干预的有吸引力的目标。