Excitatory synaptogenesis in the anterior cingulate cortex is required for effort/reward evaluation

Synaptogenesis is essential for circuit development; however, whether it is critical in adulthood for learning and performance of voluntary behaviors is unknown. Here we show that reward-based training in mice induces excitatory synapse formation onto Anterior Cingulate Cortex (ACC) neurons projecting to the dorsomedial striatum (DMS). We used germline and conditional knockout mice for Gabapentin/Thrombospondin receptor α2δ-1, which is required for excitatory synaptogenesis in the cortex, and found that loss of α2δ-1 in the adult ACC-DMS circuit is sufficient to abolish training-induced excitatory synaptogenesis. Surprisingly, this manipulation did not affect learning, instead caused a profound increase in effort exertion. Optogenetic activation of ACC-DMS neurons was sufficient to diminish effort exertion in wildtype mice and rescued the effort/reward evaluation deficit of the conditional α2δ-1 mutants. These results highlight the importance of synaptogenic signaling in the adult and pinpoint the ACC-DMS neuronal circuit as the controller of effort exertion during voluntary behaviors. ### Competing Interest Statement The authors have declared no competing interest.