Wang Siyu, Yang Yiwen, Hao Sijia, Sun Yanhui, Wang Hao
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.
Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China.
Neurosci Bull. 2025 Aug 25. doi: 10.1007/s12264-025-01491-4.
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 dynamics in vlPAG-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 vlPAG-LC pathway maintains baseline arousal while dynamically scaling threat-induced hyperarousal.
蓝斑（LC）是一个通过紧张性活动调节觉醒状态的去甲肾上腺素能核团，需要精确的调节机制来维持其动态激活水平。然而，维持LC活动的神经回路仍不清楚。在这里，我们确定了小鼠中从腹外侧导水管周围灰质（vlPAG）到LC的谷氨酸能投射是觉醒动态的关键调节因子。纤维光度记录揭示了在不同威胁范式下，应激诱导的vlPAG-LC轴突终末中的钙动态变化。脑片电生理学表明，该通路通过谷氨酸能传递介导LC-去甲肾上腺素（LC-NE）神经元活动。低频通路激活（1Hz）主要诱导焦虑样行为，而高频刺激（10Hz）则诱发更多惊恐样的过度运动，建立了一个频率依赖性的觉醒状态连续体。相反，通路抑制会减小瞳孔大小，这是觉醒的一个可靠生物标志物，同时抑制威胁回避行为并减轻焦虑相关行为，而不改变对环境的偏好。这些发现表明，vlPAG-LC通路维持基线觉醒，同时动态调节威胁诱导的过度觉醒。
