Autism spectrum disorders (ASD) are heterogeneous in clinical presentation and in their genetic and pathophysiological etiology. Although common core symptom domains including communication deficits, social impairment and restricted and repetitive behaviors unify this disorder, impairments in motor function, sensory integration, pain perception and intelligence are also frequently observed. Although there have been significant advances in our understanding of the genetic, molecular and synaptic contributions to ASD pathophysiology, causal roles for specific brain circuit-level disruptions in the expression of ASD symptom domains has been relatively under-investigated.

Alterations in insular cortical (INS) function have been strongly implicated in ASD. This is not surprising given the role of the insula in interoception, social emotion modulation, pain perception and multisensory integration. Despite these intriguing data, how alterations in INS function disrupt ASD-related behavioral processes at the circuit level is not well understood. Preliminary data from Sachin Patel’s laboratory indicates that a strong excitatory projection from the INS to the central amygdala (CeA) — a striatal-like subcortical nucleus at the limbic-motor interface — impairs social function and pain perception in mice. The behavioral effects of INS-CeA circuit activation in vivo recapitulate many behavioral phenotypes of monogenetic ASD mouse models.

Based on these findings, Patel proposes a series of studies in mice aimed at providing causal evidence that the INS-CeA glutamatergic circuit modulates social and nociceptive behavior. His laboratory also aims to determine whether increased INS-CeA signaling is a conserved feature across two distinct ASD genetic mouse models (Shank3b knock-out and Mecp2 duplication). They also aim to determine if inhibition of INS-CeA activity improves deficits in social function present in these models. Patel’s group will utilize optogenetic approaches, combined with ex vivo electrophysiology and mouse behavior to rigorously test these hypotheses.

The successful completion of these studies will provide the first evidence that INS-CeA circuit activity regulates social function and nociceptive processing. These studies could also provide support for the hypothesis that increased INS-CeA signaling contributes to social deficits in two monogenetic ASD models and determine the degree to which increased INS-CeA activity is a conserved circuit-based pathophysiological signature of social and sensory deficits in ASD models. Lastly, these studies could also provide proof-of-concept support for the notion that targeting increased INS-CeA activity could represent a potential therapeutic approach for the treatment of ASD.