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.

Institute of Physiology of the Czech Academy of Sciences Videnska 1830 14200 Prague 4 Czech Republic

Institute of Physiology of the Czech Academy of Sciences Videnska 1830 14200 Prague 4 Czech Republic; 3rd Faculty of Medicine Charles University Ruska 87 100 00 Prague 10 Czech Republic

Institute of Physiology of the Czech Academy of Sciences Videnska 1830 14200 Prague 4 Czech Republic; Center for Advanced Behavioral Research Londynska 41 12000 Prague 2 Czech Republic

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The role of prefrontal-hippocampal functional connectivity in schizophrenia-related cognitive dysfunction and the thalamic ventral midline involvement: in vivo and silico evidence