Brain circuits undergo substantial structural changes during development, driven by the formation, stabilization, and elimination of synapses. Synaptic connections continue to undergo experience‐dependent structural rearrangements throughout life, which are postulated to underlie learning and memory. Astrocytes, a major glial cell type in the brain, are physically in contact with synaptic circuits through their structural ensheathment of synapses. Astrocytes strongly contribute to the remodeling of synaptic structures in healthy and diseased central nervous systems by regulating synaptic connectivity and behaviors. However, whether structural plasticity of astrocytes is involved in their critical functions at the synapse is unknown. This review will discuss the emerging evidence linking astrocytic structural plasticity to synaptic circuit remodeling and regulation of behaviors. Moreover, we will survey possible molecular and cellular mechanisms regulating the structural plasticity of astrocytes and their non‐cell‐autonomous effects on neuronal plasticity. Finally, we will discuss how astrocyte morphological changes in different physiological states and disease conditions contribute to neuronal circuit function and dysfunction.
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.
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