Abstract Body: Stroke, the leading cause of adult disability, necessitates new therapeutic strategies informed by a deeper understanding of brain repair mechanisms. This pilot study investigates the role of parvalbumin inhibitory interneurons (PV-INs) in post-stroke recovery using wide-field optical imaging (WFOI) and optogenetics. PV-INs, the largest subclass of GABAergic interneurons, are crucial in regulating cortical excitability and mediating activity-dependent plasticity. However, their specific function in stroke recovery remains unclear.

Here we use 5 aged mice expressing Channelrhodopsin (ChR2) in PV-INs and the red-shifted genetically encoded calcium indicator, jRGECO1a, driven by the Thy1 promoter to allow for simultaneous optogenetic targeting of PV-INs and mesoscopic imaging of excitatory activity. Photothrombosis was induced in the left primary somatosensory forepaw cortex and subsequent optogenetic photostimulation of PV-INs, calcium, and hemodynamic imaging was conducted pre- and post-stroke to map PV-IN circuitry and assess changes in cortical activity.

Preliminary results revealed significant disruptions in homotopic resting-state functional connectivity and cortical activity one-week post-stroke. Power maps indicated reduced activity in the somatosensory, hindpaw, and parietal cortices, with electrical forepaw stimulation showing decreased activity in both left and right primary somatosensory forepaw regions. Contralesional excitation increased in the retrosplenial and parietal cortices during forepaw stimulation. Further, optogenetic stimulation of PV-INs pre-stroke showed increased inhibition, while post-stroke stimulation resulted in less ipsilesional inhibition and more global excitation. Behavioral assessments using the cylinder rearing test indicated a 26% decrease in right forepaw use post-stroke, aligning with imaging findings.

Ongoing studies aim to extend these observations by including a larger cohort of aged mice and a cohort of young mice at 1-, 4-, and 8- weeks post-stroke to examine age-related differences in PV-IN-mediated plasticity during stroke recovery. These studies will elucidate the critical contributions of PV-INs to post-stroke plasticity and recovery, potentially guiding new therapeutic approaches for stroke rehabilitation.