Distinct glutamatergic projections of the posteroventral medial amygdala play different roles in arousal and anxiety
Ying Li, Yuchen Deng, Yifei Zhang, Dan Xu, Xuefen Zhang, Yue Li, Yidan Li, Ming Chen, Yuxin Wang, Jiyan Zhang, Like Wang, Yufeng Cang, Peng Cao, Linlin Bi, Haibo Xu
Ying Li, Yuchen Deng, Yifei Zhang, Dan Xu, Xuefen Zhang, Yue Li, Yidan Li, Ming Chen, Yuxin Wang, Jiyan Zhang, Like Wang, Yufeng Cang, Peng Cao, Linlin Bi, Haibo Xu
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Research Article Neuroscience

Distinct glutamatergic projections of the posteroventral medial amygdala play different roles in arousal and anxiety

Abstract

Sleep disturbance usually accompanies anxiety disorders and exacerbates their incidence rates. The precise circuit mechanisms remain poorly understood. Here, we found that glutamatergic neurons in the posteroventral medial amygdala (MePVGlu neurons) are involved in arousal and anxiety-like behaviors. Excitation of MePVGlu neurons not only promoted wakefulness but also increased anxiety-like behaviors. Different projections of MePVGlu neurons played various roles in regulating anxiety-like behaviors and sleep-wakefulness. MePVGlu neurons promoted wakefulness through the MePVGlu/posteromedial cortical amygdaloid area (PMCo) pathway and the MePVGlu/bed nucleus of the stria terminals (BNST) pathway. In contrast, MePVGlu neurons increased anxiety-like behaviors through the MePVGlu/ventromedial hypothalamus (VMH) pathway. Chronic sleep disturbance increased anxiety levels and reduced reparative sleep, accompanied by the enhanced excitability of MePVGlu/PMCo and MePVGlu/VMH circuits but suppressed responses of glutamatergic neurons in the BNST. Inhibition of the MePVGlu neurons could rescue chronic sleep deprivation–induced phenotypes. Our findings provide important circuit mechanisms for chronic sleep disturbance–induced hyperarousal response and obsessive anxiety-like behavior and are expected to provide a promising strategy for treating sleep-related psychiatric disorders and insomnia.

Authors

Ying Li, Yuchen Deng, Yifei Zhang, Dan Xu, Xuefen Zhang, Yue Li, Yidan Li, Ming Chen, Yuxin Wang, Jiyan Zhang, Like Wang, Yufeng Cang, Peng Cao, Linlin Bi, Haibo Xu

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Figure 6

The role of the MePVGlu/VMH pathway on wakefulness and anxiety-like behaviors.

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The role of the MePVGlu/VMH pathway on wakefulness and anxiety-like beha...
(A) An optical fiber was implanted into the VMH region of MePVGlu-ChR2 mice to investigate the function of MePVGlu→VMH projection (left). The VMH picture depicted the distribution of ChR2-expressing MePV glutamatergic terminals as well as the placement of optical fiber (right). Scale bar = 200 μm. (B) Patch-clamp electrophysiology diagram (left). The EPSC was generated by 2 Hz laser stimulation in the VMH as seen by voltage-clamp traces (right). (C) An EEG spectrogram and EEG-EMG trace showed that 10 Hz stimulation was administered during NREM sleep. The arrowheads represent 4 (red) and 8 Hz (blue). The color scale represents the raw power spectral density. Fre., frequency. (D) Latencies to awaken from sleep following varied frequencies of optical stimulation (The stimulation was performed once per animal; GFP: 8 mice; ChR2: 8 mice). (E) Two-hour optogenetic stimulation hypnograms during the light phase. (F) Time spent in each state throughout 2 hours of light stimulation. (G) MePVGlu-VMH-ChR2 mice were subjected to 2 hours of opto-stimulation (10 Hz for 4 seconds with a 56-second interval): the proportion of waking, NREM, and REM sleep duration. (H) Representative open field test track plots (left). The open field test involved time spent in the center zone and distance traveled (right). The red frame represents the middle zone. (I) Heatmaps of the EPM test (left) and time spent on the open/closed arms (right). Mann-Whitney rank sum test for D. Two-way RM ANOVA with Holm-Šídák post hoc comparison for F–I. All error bars represent SEM. D, F, and G: n = 7 per group, H and I: n = 8 per group. *P < 0.05, **P < 0.01, ***P < 0.001.