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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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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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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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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DOI: https://doi.org/10.1038/s41386-024-01875-6