Endocannabinoid signaling in hypothalamic circuits regulates arousal from general anesthesia in mice
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
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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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 3

Isoflurane-mediated increase of eCB signaling in DMH glutamatergic but not GABAergic synapses.

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Isoflurane-mediated increase of eCB signaling in DMH glutamatergic but n...
(A–E) Plots of normalized IPSC (A and B) or EPSC amplitude (C and D) and summary histograms (E) show that the DSI magnitude of DMH LTS+ and LTS– neurons does not significantly change following bath application of isoflurane (Iso) as compared with baseline (Con) (E: A, P = 0.1333; B, P = 0.8729), which, however, significantly increases DSE magnitude of both LTS+ and LTS– neurons. Representative IPSC and EPSC traces are shown above each plot. The summarized data in E represent the first time point after depolarization of the cell, which is marked with “2” in A–D. (F) The representative traces (left) and summary histograms (right) show that relative to baseline (Con), bath application of isoflurane induces rapid hyperpolarization of the membrane potential and significantly decreases of the firing rate of both LTS+ and LTS– neurons in the DMH, which return to the baseline levels after washout (Wash). All summary graphs show mean ± SEM; n, number of rats recorded in each group. *P < 0.05 and **P < 0.01 vs. Con, Student’s t test (E) or Tukey’s post-hoc test after 1-way ANOVA (F: LTS+, F2,12 = 5.669, P < 0.05; LTS–, F2,3212 = 8.517, P < 0.01).