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<p>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<sup>+</sup>) 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<sup>+</sup> 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.</p>

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Impact of NPAS2 on mPFC dopamine synthesis and nap behavior

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月16日

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  • Lianxia Guo,
  • Haobin Cen,
  • Yuwei Huang,
  • Zanjin Li,
  • Kengran Zeng,
  • Zicong Wu,
  • Jiaxian Weng,
  • Xiaocao Guo,
  • Di He,
  • Xinyu Liu,
  • Zhehan Yang,
  • Haiman Xu,
  • Tingying Hao,
  • Binbin Wei,
  • Xingxing Diao,
  • Baojian Wu

摘要

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.