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.

The social motivation hypothesis proposes that social impairments result from attributing decreased level of reward to social interaction, a process that has been putatively associated with abnormal brain functions in individuals with ASD4. Functional neuroimaging studies have indicated that social deficits in ASD are related to dysfunction of the reward circuitry in the brain7. Optogenetic approaches have been widely used to study the neural circuits underlying social behaviors8,9,10. Based on recent findings that optogenetic activation of Pet1 neurons in the DRN6 or dopamine neurons in the VTA10,11,12 can produce strong reward signals and reinforce mouse behaviors, we tested whether such activation may be effective in rescuing the autistic-like social deficits in Shank3 mutant autism mouse model5. We crossed Shank3−/− mice with the ePet1-Cre mouse line13 or the DAT-Cre mouse line14. A Cre-dependent AAV viral vector was then used to achieve the cell type- and brain region-specific (DRN or VTA) expression of either ChR2-mCherry or mCherry. Optical fibers were subsequently implanted at the virus-injection sites. Only male animals were used across all the behavior tests.

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