Impact of NPAS2 on mPFC dopamine synthesis and nap behavior

The biological basis of the afternoon nap, a widespread yet poorly understood phenomenon, has remained elusive. Here we identify NPAS2, among core circadian regulators, as a sex-independent determinant of the nap behavior in mice. Specifically, medial prefrontal cortex (mPFC)-expressed NPAS2 orchestrates nap regulation through circadian modulation of local dopaminergic activity. We demonstrate that tyrosine hydroxylase-positive (TH+) neurons in mPFC exhibit time-of-day dependent wake-promoting activity, showing minimal excitation precisely during nap hours. Mechanistically, NPAS2 achieves this circadian suppression through a POU2F2-TH regulatory pathway: 1) transcriptional activation of the transcription repressor POU2F2, and 2) consequent downregulation of TH expression (a rate-limiting enzyme for dopamine synthesis) and dopamine production in mPFC TH+ neurons. These findings establish an endogenous circadian mechanism where mPFC NPAS2 periodically inhibits wake-promoting dopaminergic activity to drive nap behavior, providing fundamental insights into the neural and molecular regulation of nap biology. The biological basis of afternoon nap remains unclear. Here, authors show that NPAS2 in mPFC TH-positive neurons activates POU2F2 to suppress TH level and dopamine production, thereby reducing wake-promoting neural activity and driving nap behavior.