Specific parvalbumin-positive optogenetic stimulations in specific brain regions restore navigational flexibility in an acute MK801 mouse model of schizophrenia.

Abstract

Impairments in decision-making and behavioral flexibility in patients with schizophrenia (SCZ) are currently among the most investigated aspects of SCZ. Increased GLUergic excitatory activity and decreased GABAergic inhibitory activity induce mPFC-vHPC γ/θ band desynchronization in many tasks where behavioral flexibility is tested. However, these tasks used "perceptual" decision-making/flexibility but not navigational decision-making/flexibility. Our study investigated the role of frequency-specific optogenetic stimulation of GABAergic parvalbumin-positive (PV+) interneurons in two pivotal brain structures used in flexibility (mPFC) and navigation (vHPC), at frequencies resembling the γ/θ band (50 Hz, γ-like; and 10 Hz, θ-like) in an acute MK801 mouse model of navigational inflexibility. We used a modified version of the active place avoidance task on a rotating arena. The behavioral results revealed that frequency-specific optogenetic stimulation of the mPFC or vHPC had different effects on restoring navigational flexibility. Moreover, immunohistochemical assays confirmed that optogenetic stimulations activated PV+ interneurons that were transfected with the optogenetic actuators, advancing our understanding of the pivotal role of PV+ activity in SCZ-like navigational decision-making/flexibility.