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<p>The locus coeruleus (LC), a norepinephrine nucleus governing arousal states through tonic activity, requires precise regulatory mechanisms to maintain its dynamic activation levels. However, the neural circuitry underlying LC activity maintenance remains unclear. Here, we identify a glutamatergic projection from the ventrolateral periaqueductal gray (vlPAG) to the LC in mice as a critical regulator of arousal dynamics. Fiber photometry recordings revealed stress-induced Ca<sup>2+</sup> dynamics in vlPAG<sup>CaMKIIα</sup>-LC axon terminals across diverse threat paradigms. Slice electrophysiology demonstrated that this pathway mediates LC-norepinephrine (LC-NE) neuronal activity <i>via</i> glutamatergic transmission. Low-frequency pathway activation (1 Hz) mainly induced anxiety-like behaviors, whereas high-frequency stimulation (10 Hz) evoked more panic-like hyperlocomotion, establishing a frequency-dependent continuum of arousal states. Conversely, pathway inhibition reduced pupil size, a reliable biomarker for arousal, concurrently suppressing threat avoidance behaviors and alleviating anxiety-related behaviors without altering environmental preference. These findings reveal that the vlPAG<sup>CaMKIIα</sup>-LC pathway maintains baseline arousal while dynamically scaling threat-induced hyperarousal.</p>

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Glutamatergic Periaqueductal Gray Projections to the Locus Coeruleus Orchestrate Adaptive Arousal States in Threatening Contexts

  • 期刊论文

  • 发表日期：

    2025年8月25日

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  • Siyu Wang,
  • Yiwen Yang,
  • Sijia Hao,
  • Yanhui Sun,
  • Hao Wang

摘要

The locus coeruleus (LC), a norepinephrine nucleus governing arousal states through tonic activity, requires precise regulatory mechanisms to maintain its dynamic activation levels. However, the neural circuitry underlying LC activity maintenance remains unclear. Here, we identify a glutamatergic projection from the ventrolateral periaqueductal gray (vlPAG) to the LC in mice as a critical regulator of arousal dynamics. Fiber photometry recordings revealed stress-induced Ca2+ dynamics in vlPAGCaMKIIα-LC axon terminals across diverse threat paradigms. Slice electrophysiology demonstrated that this pathway mediates LC-norepinephrine (LC-NE) neuronal activity via glutamatergic transmission. Low-frequency pathway activation (1 Hz) mainly induced anxiety-like behaviors, whereas high-frequency stimulation (10 Hz) evoked more panic-like hyperlocomotion, establishing a frequency-dependent continuum of arousal states. Conversely, pathway inhibition reduced pupil size, a reliable biomarker for arousal, concurrently suppressing threat avoidance behaviors and alleviating anxiety-related behaviors without altering environmental preference. These findings reveal that the vlPAGCaMKIIα-LC pathway maintains baseline arousal while dynamically scaling threat-induced hyperarousal.