Cocaine Hijacks the Npas4-dependent Somatostatin Ensembles in the mPFC to Mediate Attention.

Cocaine disrupts the physiological function of the prefrontal cortex and impairs attention, short-term memory, and other cognitive functions. However, the specific cellular basis of maladaptation remains poorly understood. Here, using neuronal activity-dependent tagging, rabies retrograde tracing, electrophysiological recording, and behavioral analyses in mice, we show that a single injection of cocaine increases the recruitment of both the Npas4 transcription-dependent ensemble (N-RAM) and the N-RAM+ somatostatin-expressing interneuron (N-RAM+ SST-IN) ensemble in the medial prefrontal cortex (mPFC). Npas4 induction in mPFC SST-INs upregulates plasticity and excitatory synaptic input from the mediodorsal thalamus (MD). Chemogenetic inhibition of either the N-RAM+ or N-RAM+ SST-IN ensemble in the mPFC impaired attention in the 5‑choice serial reaction time task (5-CSRTT). Our study identifies a unique role of the mPFC N-RAM+ SST-IN ensemble in regulating attention following acute cocaine injection, providing a potential therapeutic target for attention deficits.