Endocannabinoid signaling in hypothalamic circuits regulates arousal from general anesthesia in mice
Haixing Zhong, … , Lize Xiong, Xia Zhang
Haixing Zhong, … , Lize Xiong, Xia Zhang
Published May 2, 2017
Citation Information: J Clin Invest. 2017;127(6):2295-2309. https://doi.org/10.1172/JCI91038.
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Research Article Neuroscience

Endocannabinoid signaling in hypothalamic circuits regulates arousal from general anesthesia in mice

Abstract

Consciousness can be defined by two major attributes: awareness of environment and self, and arousal, which reflects the level of awareness. The return of arousal after general anesthesia presents an experimental tool for probing the neural mechanisms that control consciousness. Here we have identified that systemic or intracerebral injection of the cannabinoid CB1 receptor (CB1R) antagonist AM281 into the dorsomedial nucleus of the hypothalamus (DMH) — but not the adjacent perifornical area (Pef) or the ventrolateral preoptic nucleus of the hypothalamus (VLPO) — accelerates arousal in mice recovering from general anesthesia. Anesthetics selectively activated endocannabinoid (eCB) signaling at DMH glutamatergic but not GABAergic synapses, leading to suppression of both glutamatergic DMH-Pef and GABAergic DMH-VLPO projections. Deletion of CB1R from widespread cerebral cortical or prefrontal cortical (PFC) glutamatergic neurons, including those innervating the DMH, mimicked the arousal-accelerating effects of AM281. In contrast, CB1R deletion from brain GABAergic neurons or hypothalamic glutamatergic neurons did not affect recovery time from anesthesia. Inactivation of PFC-DMH, DMH-VLPO, or DMH-Pef projections blocked AM281-accelerated arousal, whereas activation of these projections mimicked the effects of AM281. We propose that decreased eCB signaling at glutamatergic terminals of the PFC-DMH projection accelerates arousal from general anesthesia through enhancement of the excitatory DMH-Pef projection, the inhibitory DMH-VLPO projection, or both.

Authors

Haixing Zhong, Li Tong, Ning Gu, Fang Gao, Yacheng Lu, Rou-gang Xie, Jingjing Liu, Xin Li, Richard Bergeron, Lisa E. Pomeranz, Ken Mackie, Feng Wang, Chun-Xia Luo, Yan Ren, Sheng-Xi Wu, Zhongcong Xie, Lin Xu, Jinlian Li, Hailong Dong, Lize Xiong, Xia Zhang

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Figure 8

Proposed model for eCB modulation of brain circuitry participating in arousal from anesthesia.

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Proposed model for eCB modulation of brain circuitry participating in ar...
Glutamatergic neurons in the prelimbic and infralimbic areas of the PFC directly innervate both glutamatergic and GABAergic neurons in the DMH, which then send glutamatergic axons into the Pef and GABAergic axons into the VLPO, respectively. Glutamatergic DMH-Pef projection innervates excitatory orexin-containing neurons in the Pef, activation of which accelerates arousal. In contrast, GABAergic DMH-VLPO projection innervates inhibitory GABA-containing neurons in the VLPO, activation of which suppresses arousal. Thus, reduced eCB activation of CB1R in axon terminals of glutamatergic PFC-DMH projection increases presynaptic release of glutamate, which activates inhibitory DMH-VLPO projection, excitatory DMH-Pef projection, or both. Then suppression of the inhibitory VLPO neurons, enhancement of the excitatory Pef neurons, or both accelerate arousal after anesthesia.