GABAergic signaling by VIP interneurons gates running-dependent visual recovery in the adult brain

Experience-dependent plasticity in the adult visual cortex is enhanced by locomotion, a process mediated by vasoactive intestinal peptide (VIP)-expressing interneurons. While VIP interneurons are known to signal through both Gamma-aminobutyric acid (GABA) and VIP peptide, the specific contributions of these pathways during different forms of plasticity remain unclear. Monocular deprivation (MD) in adult mice alters cortical responses, though more slowly and differently than during a critical period in early life. Here, we used two-photon calcium imaging in awake adult mice to dissect the roles of VIP and GABA release from VIP interneurons during adult MD and subsequent binocular recovery. We found comparable level of ocular dominance shifts after MD in mice deficient in either peptidergic or GABA signaling, but disrupting GABA signaling impaired recovery of binocular responses. We also showed that running preferentially enhances contralateral eye responses in binocular primary visual cortex. However, this eye-specific modulation of visual responses by running was altered during recovery from MD and was dependent on VIP signaling pathways. These findings highlight the GABA-mediated inhibition by VIP interneurons as a critical pathway for promoting visual restoration in the adult brain. Significance StatementUsing longitudinal two-photon imaging in awake adult mice with genetically altered signaling path-ways in VIP interneurons, we demonstrate that GABAergic, but not peptidergic, signaling from VIP interneurons is essential for the recovery of binocular vision following monocular deprivation. We further reveal that locomotion modulates cortical responses in an eye-specific manner, a property dynamically reshaped by plasticity and dependent on VIP interneuron function. These findings identify a discrete inhibitory circuit element that links behavioral state to sensory recovery and highlight GABA release from VIP cells as a potential therapeutic target for restoring visual function in adulthood.