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Ventral subiculum promotes wakefulness through several pathways in male mice

Neuropsychopharmacology (2024)Cite this article

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Abstract

The ventral subiculum (vSUB), the major output structure of the hippocampal formation, regulates motivation, stress integration, and anxiety-like behaviors that rely on heightened arousal. However, the roles and underlying neural circuits of the vSUB in wakefulness are poorly known. Using in vivo fiber photometry and multichannel electrophysiological recordings in mice, we found that the vSUB glutamatergic neurons exhibited high activities during wakefulness. Moreover, activation of vSUB glutamatergic neurons caused an increase in wakefulness and anxiety-like behaviors and induced a rapid transition from sleep to wakefulness. In addition, optogenetic stimulation of vSUB glutamatergic terminals and retrograde-targeted chemogenetic activation of vSUB glutamatergic neurons revealed that vSUB promoted arousal by innervating the lateral hypothalamus (LH), nucleus accumbens (NAc) shell, and prefrontal cortex (PFC). Nevertheless, local microinjection of dopamine D1 or D2/D3 receptor antagonist blocked the wake-promoting effect induced by chemogenetic activation of vSUB pathways. Finally, chemogenetic inhibition of vSUB glutamatergic neurons decreased arousal. Altogether, our findings reveal a prominent contribution of vSUB glutamatergic neurons to the control of wakefulness through several pathways.

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Fig. 1: Neural activity of vSUB glutamatergic neurons across spontaneous sleep–wake cycle.
Fig. 2: Chemogenetic activation of vSUB glutamatergic neurons increases wakefulness and anxiety-like behaviors.
Fig. 3: The vSUB glutamatergic neurons control arousal through the NAc, LH, and PFC pathways.
Fig. 4: Local blockade of dopamine receptors abolishes wake-promoting effects induced by activation of vSUB pathways.
Fig. 5: Chemogenetic inhibition of vSUB glutamatergic neurons decreases wakefulness.

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Data availability

The raw data generated in this study have been deposited in the Figshare database under accession code: https://doi.org/10.6084/m9.figshare.25658037.

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Acknowledgements

We thank the following individuals for technical assistance to this work: Xiao Tan, Yuyang Ni, Meifang Ma, Zhenzhen Tian, Caijun Dong, Shuping Fang, Wenting Yang, Hongjun Liu, Feiyang Zhang, Yun Wang, Wei Jing.

Funding

This study was supported by National Natural Science Foundation of China (grants: 81771819 and 32071140), the Scientific Research Project of Hubei Provincial Health Commission (grant: WJ2019H058), the Scientific Research Project of Traditional Chinese Medicine of Hubei Province (ZY2023Q032) and Research Grant of Guangdong Province Key Laboratory of Psychiatric Disorders (N202301).

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  1. These authors contributed equally: Xue-Fen Zhang, Yi-Dan Li.

Authors and Affiliations

  1. Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China

    Xue-Fen Zhang, Yi-Dan Li, Yue Li, Ying Li & Hai-Bo Xu

  2. Department of Nuclear Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China

    Dan Xu

  3. Department of Pathology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, 430071, China

    Lin-Lin Bi

  4. Center for Pathology and Molecular Diagnostics, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China

    Lin-Lin Bi

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X-.FZ, H-.BX and L-LB designed the experiments. X-FZ, Y-DL, Yue Li, Ying Li and DX collected and analysed the data. X-FZ, and Y-DL discussed the results and wrote the paper.

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Correspondence to Lin-Lin Bi or Hai-Bo Xu.

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Zhang, XF., Li, YD., Li, Y. et al. Ventral subiculum promotes wakefulness through several pathways in male mice. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01875-6

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