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

Abstract

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.

Astrocytic thrombospondins 1 and 2 are required for cortical synapse development controlling instrumental performance

“…In agreement with this, similar to our previous finding for trained WT ACC [54], training in TSP1/2-KO mice upregulated immediate early genes such as Arc, Egr2, and To implicate which cell types may be impacted in the trained versus untrained TSP1/2-KO ACC, we compared our DEGs to previously published cortical single cell dataset [87]. To do so we used the single-cell mapper package in R [88] to generate cell-type specificity scores using the downregulated DEGs in trained TSP1/2-KO ACC compared to untrained.…”

“…Training increased excitatory synapse density in WT and TSP1/2-KO ACC layers 1 and 2/3 (Fig 4B and 4C). In ACC L5, like our previous findings [54], training did not significantly increase excitatory synapse density in WT mice (Fig 4D ), whereas training also significantly increased excitatory synapse density in the ACC L5 of TSP1/2-KO mice (Fig 4D). These findings indicate that unlike in mice lacking α2δ-1, the loss of TSP1/2 does not fully impair training-induced synapse formation in the ACC.…”

“…This activation was found to be due to an increase in the number and activity of excitatory synapses in the trained compared to untrained mice [54]. The loss of the thrombospondin receptor, α2δ-1, ablated training-induced excitatory synapse formation in the ACC but did not impair the learning of the operant task [54]. Instead, α2δ-1 KO mice exhibited a significant increase in effort exertion during high-effort tasks, revealing that they were less sensitive to behavioral cost.…”

“…We next investigated whether the constitutive loss of TSP1/2 prevents traininginduced synapse formation, which was the case in α2δ-1 KO mice [54]. To do so, we quantified intracortical (VGluT1/PSD95 positive) synapses in the ACC of trained WT and TSP1/2-KO mice and compared them to their untrained controls (Fig 4A).…”

“…Instead, α2δ-1 KO mice exhibited a significant increase in effort exertion during high-effort tasks, revealing that they were less sensitive to behavioral cost. Ablation of α2δ-1 specifically in the adult ACC neurons projecting to the dorsomedial striatum, a critical circuit for goaldirected actions (GDAs), was sufficient to impair training-induced synapse formation and increase effort exertion [54].…”