Somatosensory input shapes an S1-ACC circuit that impacts social behaviors in mice

Abstract

Autism spectrum disorder (ASD) is diagnosed by changes in social behavior and restricted, repetitive behaviors. Additionally, ~95% of autistic individuals exhibit sensory disruptions, including abnormal responses to touch. Multiple ASD models, including Shank3 mutant mice, exhibit touch over-reactivity that is due to abnormal function of peripheral somatosensory neurons innervating the skin. Peripheral somatosensory neuron dysfunction during development causes disruptions in the region of primary somatosensory cortex that processes touch to the body (S1TR), and social impairments in adult mice. However, the mechanisms through which peripheral somatosensory neuron dysfunction leads to social behavior deficits in mouse models for ASD are unknown. We hypothesized that peripheral somatosensory neuron dysfunction alters S1TR functions, which disrupts S1TR long-range connections with circuits that modulate social behaviors. S1 integrates somatosensory information and can influence complex behaviors via long-range projections. Yet, most studies of S1 in mice have focused on the subregion of S1 that receives whisker inputs (S1barrel), while little is known about S1TR long-range connectivity and how it may differ from that of S1barrel. We found that S1TR and S1barrel long-range connectivity throughout the brain differ dramatically, including a unique S1TR projection that targets the rostral part of ACC (rACC), which does not receive inputs from S1barrel. Using in vivo multiunit electrode recordings, we observed robust and heterogeneous responses to touch stimuli in rACC neurons and found that the S1TR projection to rACC is required for these responses. As ACC is known to be important for shaping social behaviors, we hypothesized that peripheral somatosensory neuron dysfunction alters S1TR-rACC circuitry, which alters touch stimulus encoding in rACC and disrupts social behaviors. We found that S1TR-ACC anatomical connectivity is decreased in Shank3 mutant mice. We also found that S1TR-rACC neurons may be dysfunctional in Shank3 mutants and that rACC neuron responses to light touch stimuli are decreased and less reliable in mice with germline or selective loss of Shank3 in peripheral somatosensory neurons. Lastly, we found that optogenetic activation of S1TR-ACC neurons promotes social behavior in control mice, but S1TR-ACC modulation of social behaviors is attenuated in Shank3 mutants, likely due to altered anatomical and functional properties of this S1TR-rACC circuit. Thus, our results identify how altered tactile inputs, beginning with peripheral somatosensory neuron dysfunction, disrupt the anatomy and function of an S1TR-rACC circuit that then contributes to social behavior abnormalities in mouse models for ASD.