A whole-brain male mouse atlas of long-range inputs to histaminergic neurons

Wenkai Lin, Xinyan Zhu, Xuemin Yu, Zhuowen Fang, Qinyan Xia, Li Cheng, Menghan Li, Xiaoyun Qiu, Lingyu Xu, Sile An, Chuhao Dou, Yanrong Zheng, Weiwei Hu, Pertti Panula, Anan Li, Yi Wang, Qingming Luo () and Zhong Chen ()
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Wenkai Lin: Zhejiang Chinese Medical University
Xinyan Zhu: Zhejiang Chinese Medical University
Xuemin Yu: Zhejiang Chinese Medical University
Zhuowen Fang: Zhejiang University School of Medicine
Qinyan Xia: Zhejiang Chinese Medical University
Li Cheng: Zhejiang Chinese Medical University
Menghan Li: Zhejiang Chinese Medical University
Xiaoyun Qiu: Zhejiang Chinese Medical University
Lingyu Xu: Zhejiang Chinese Medical University
Sile An: JITRI Institute for Brainsmatics
Chuhao Dou: JITRI Institute for Brainsmatics
Yanrong Zheng: Zhejiang Chinese Medical University
Weiwei Hu: Zhejiang University School of Medicine
Pertti Panula: University of Helsinki
Anan Li: JITRI Institute for Brainsmatics
Yi Wang: Zhejiang Chinese Medical University
Qingming Luo: Hainan University
Zhong Chen: Zhejiang Chinese Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The precise structural and functional characteristics of input circuits targeting histaminergic neurons remain poorly understood. Here, using a rabies virus retrograde tracing system combined with fluorescence micro-optical sectioning tomography, we construct a 3D monosynaptic long-range input atlas of male mouse histaminergic neurons. We identify that the hypothalamus, thalamus, pallidum, and hippocampus constitute major input sources, exhibiting diverse spatial distribution patterns and neuronal type ratios. Notably, a specific layer distribution pattern and co-projection structures of upstream cortical neurons are well reconstructed at single-cell resolution. As histaminergic system is classically involved in sleep-wake regulation, we demonstrate that the lateral septum (predominantly supplying inhibitory inputs) and the paraventricular nucleus of the thalamus (predominantly supplying excitatory inputs) establish monosynaptic connections, exhibiting distinct functional dynamics and regulatory roles in rapid-eye-movement sleep. Collectively, our study provides a precise long-range input map of mouse histaminergic neurons at mesoscopic scale, laying a solid foundation for future systematic study of histaminergic neural circuits.

Date: 2025
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DOI: 10.1038/s41467-025-63394-2

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