Training-Induced Circuit-Specific Excitatory Synaptogenesis is Required for Effort Control

Synaptogenesis is essential for circuit development; however, it is unknown whether it is critical for the establishment and performance of goal-directed voluntary behaviors. Here, we show that operant-conditioning via lever-press for food reward-training in mice induces excitatory synapse formation onto a subset of Anterior Cingulate Cortex neurons projecting to the dorsomedial striatum (ACC->DMS). Training-induced synaptogenesis is controlled by the Gabapentin/Thrombospondin receptor α2δ-1, which is an essential neuronal protein for proper intracortical excitatory synaptogenesis. Using germline and conditional knockout mice, we found that deletion of α2δ-1 in the adult ACC->DMS circuit diminishes training-induced excitatory synaptogenesis. Surprisingly, this manipulation did not impact learning but instead resulted in a profound increase in effort exertion without affecting sensitivity to reward value or changing contingencies. Bidirectional optogenetic manipulation of ACC->DMS neurons rescued or phenocopied the behaviors of the α2δ-1 cKO mice highlighting the importance of synaptogenesis within this cortico-striatal circuit in regulating effort exertion.