CHOLINERGIC MODULATION PRESERVES PERINEURONAL NET ORGANIZATION IN THE ADULT MOUSE VISUAL CORTEX AFTER RETINAL INJURY

Cholinergic potentiation through the acetylcholinesterase inhibitor donepezil (DPZ) enhances cortical plasticity and perceptual learning during visual training, possibly involving parvalbumin (PV+) interneurons and their associated perineuronal nets (PNNs). This study therefore investigated whether DPZ modulates inhibitory circuit integrity following visual impairment through structural changes of PV+ and PNNs. Choroidal neovascularization (CNV) was induced unilaterally by photocoagulation in adult C57BL/6 mice. Effects at two and seven days post-lesion were examined in the visual cortex of animals receiving daily DPZ treatment (0.3 mg/kg) or no treatment. Visual recovery was assessed using the visual cliff test. Changes in PNN and PV+ interneuron density were analyzed by immunohistochemistry and quantified using deep learning-based detection models. Two days after CNV, a significant reduction in PNN density and double-labeled PV+/PNN+ cells was observed in untreated mice, an effect prevented by DPZ administration. These changes were most pronounced in cortical layers 2/3 and 5, whereas layer 4, the primary thalamorecipient layer, was unaffected. At seven days post-lesion, similar effects persisted but were restricted to layer 2/3. In addition, PV+ interneuron density was reduced at seven days post-CNV, possibly reflecting adaptive regulation of parvalbumin expression. Treated mice also showed better visual recovery and performance during the visual cliff test. Together, these findings suggest that reduced retinal input disrupts interlaminar functional connectivity in the visual cortex and that cholinergic potentiation with DPZ may preserve this connectivity by stabilizing inhibitory circuit organization, thereby influencing the excitation–inhibition balance in supragranular layers and cortical integration.