Training-induced circuit-specific excitatory synaptogenesis in mice is required for effort control
Francesco Paolo Ulloa Severino, Oluwadamilola O. Lawal, Kristina Sakers, Shiyi Wang, Namsoo Kim, Alexander Friedman, Sarah A. Johnson, Chaichontat Sriworarat, Ryan H. Hughes, Scott H. Soderling, Il Hwan Kim, Henry H. Yin, Çağla Eroğlu
Abstract
Abstract 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 does not impact learning but results in a significant increase in effort exertion without affecting sensitivity to reward value or changing contingencies. Bidirectional optogenetic manipulation of ACC →DMS neurons rescues or phenocopies the behaviors of the α2δ−1 cKO mice, highlighting the importance of synaptogenesis within this cortico-striatal circuit in regulating effort exertion.