UCSF

Adapting goal-directed behavior to changing environments (cognitive flexibility) depends on the mammalian prefrontal cortex. In mice, Parvalbumin-positive inhibitory interneurons (PVINs) in the medial prefrontal cortex (mPFC) support efficient behavioral adaption in a rule-shifting task (Cho et al., 2015, 2020). How PVINs modulate single-cell activity dynamics and information encoding in mPFC during cognitive flexibility is unclear. Heterozygous knockout of the Dlx5/6+/- transcription factor in mice (Dlx5/6+/- mice) disrupts rule-shifting performance and PVINs electrophysiology— administering a low-dose benzodiazepine (CLNZ) pre-task lastingly rescues these dysfunctions (Cho et al, 2015). We used one-photon calcium imaging in Dlx5/6+/-mice to study mPFC single-cell calcium activity before, during, and after pharmacological rescue. We found single-cell and population abnormalities in mPFC task-associated activity of Dlx5/6+/-mice, predominantly during initial rule learning. CLNZ treatment reversed these abnormalities. During initial rule learning, pre-treatment Dlx5/6+/-mice mPFC cells had abnormally greater activity following error trials. Cells significantly active during error trials in the initial rule also abnormally re-activated in all other task stages in Dlx5/6+/-mice. Machine learning classification found increased similarity in the structure of activity during error trials, within different rules, for pre-treatment Dlx5/6+/-mice. CLNZ treatment lastingly reduced abnormally high initial rule error activity, and decreased reactivation of initial rule error cells in other task stages. CLNZ increases the linear separability of mPFC population activity between errors in different rule blocks. These results demonstrate a novel role of PV+ cells in differentiating mPFC neuron activity from previous network states during behavior adaptation.