Cai Ping, Chen Hui-Yun, Tang Wei-Tao, Hu Yu-Duan, Chen Shang-Yi, Lu Jing-Shan, Lin Zhi-Hui, Huang Sheng-Nan, Hu Li-Huan, Su Wei-Kun, Li Qi-Xuan, Lin Zhi-Jie, Kang Tian-Rui, Yan Xiong-Bin, Liu Pei-Chang, Chen Li, Yin Dou, Wu Si-Ying, Li Huang-Yuan, Yu Changxi
Fujian Province Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, 350108, Fujian, China.
Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, 350108, Fujian, China.
Neuropharmacology. 2022 May 1;208:108979. doi: 10.1016/j.neuropharm.2022.108979. Epub 2022 Feb 4.
Defensive behavior, a group of responses that evolved due to threatening stimuli, is crucial for animal survival in the natural environment. For defensive measures to be timely and successful, a high arousal state and immediate sleep-to-wakefulness transition are required. Recently, the glutamatergic basal forebrain (BF) has been implicated in sleep-wake regulation; however, the associated physiological functions and underlying neural circuits remain unknown. Here, using in vivo fiber photometry, we found that BF glutamatergic neuron is activated by various threatening stimuli, including predator odor, looming threat, sound, and tail suspension. Optogenetic activation of BF glutamatergic neurons induced a series of context-dependent defensive behaviors in mice, including escape, fleeing, avoidance, and hiding. Similar to the effects of activated BF glutamatergic cell body, photoactivation of BF glutamatergic terminals in the ventral tegmental area (VTA) strongly drove defensive behaviors in mice. Using synchronous electroencephalogram (EEG)/electromyogram (EMG) recording, we showed that photoactivation of the glutamatergic BF-VTA pathway produced an immediate transition from sleep to wakefulness and significantly increased wakefulness. Collectively, our results clearly demonstrated that the glutamatergic BF is a key neural substrate involved in wakefulness and defensive behaviors, and encodes these behaviors through glutamatergic BF-VTA pathway. Overexcitation of the glutamatergic BF-VTA pathway may be implicated in clinical psychiatric diseases characterized by exaggerated defensive responses, such as autism spectrum disorders.
防御行为是一组因威胁性刺激而进化出的反应，对于动物在自然环境中的生存至关重要。为了使防御措施及时且成功，需要高唤醒状态以及从睡眠到觉醒的即时转变。最近，谷氨酸能基底前脑（BF）被认为与睡眠-觉醒调节有关；然而，相关的生理功能和潜在神经回路仍不清楚。在这里，我们使用体内光纤光度法发现，BF谷氨酸能神经元会被各种威胁性刺激激活，包括捕食者气味、逼近的威胁、声音和尾部悬吊。对BF谷氨酸能神经元进行光遗传学激活会在小鼠中诱发一系列依赖于情境的防御行为，包括逃跑、躲避、回避和躲藏。与激活BF谷氨酸能细胞体的效果类似，对腹侧被盖区（VTA）中的BF谷氨酸能终末进行光激活也强烈驱使小鼠产生防御行为。通过同步脑电图（EEG）/肌电图（EMG）记录，我们表明谷氨酸能BF-VTA通路的光激活会使小鼠立即从睡眠转变为觉醒，并显著增加觉醒时间。总的来说，我们的结果清楚地表明，谷氨酸能BF是参与觉醒和防御行为的关键神经基质，并通过谷氨酸能BF-VTA通路对这些行为进行编码。谷氨酸能BF-VTA通路的过度兴奋可能与以防御反应过度为特征的临床精神疾病有关，如自闭症谱系障碍。
