Glutamatergic Periaqueductal Gray Projections to the Locus Coeruleus Orchestrate Adaptive Arousal States in Threatening Contexts
Siyu Wang1,2,3,4 · Yiwen Yang1,3 · Sijia Hao5 · Yanhui Sun3 · Hao Wang1,2,3,4
1 Department of Neurosurgery of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Key Laboratory for Biomedical Engineering of the Ministry of Education, Zhejiang University School of Medicine, Hangzhou 310058, China
2 Nanhu Brain-computer Interface Institute, Hangzhou 311100, China
3 NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain Machine Integration, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China
4 Lingang Laboratory, Shanghai 200031, China 5 Institute of Brain Science and Department of Physiology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China
Abstract
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.
Keywords
Arousal; Ventrolateral periaqueductal gray; Locus coeruleus; Panic; Anxiety
