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 David Friedman, Sarah Anne Johnson, Chaichontat Sriworarat, Ryan H. Hughes, Scott H. Soderling, Il Hwan Kim, Henry H. Yin () and Cagla Eroglu ()
Additional contact information
Francesco Paolo Ulloa Severino: Duke University Medical Center
Oluwadamilola O. Lawal: Duke University Medical Center
Kristina Sakers: Duke University Medical Center
Shiyi Wang: Duke University Medical Center
Namsoo Kim: Duke University
Alexander David Friedman: Duke University
Sarah Anne Johnson: Duke University Medical Center
Chaichontat Sriworarat: Duke University Medical Center
Ryan H. Hughes: Duke University
Scott H. Soderling: Duke University Medical Center
Il Hwan Kim: University of Tennessee Health and Science Center
Henry H. Yin: Duke University
Cagla Eroglu: Duke University Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-22

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.

Date: 2023
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DOI: 10.1038/s41467-023-41078-z

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