Activation of hypothalamic-pontine-spinal pathway promotes locomotor initiation and functional recovery after spinal cord injury in mice

The hypothalamus is critical for regulating behaviors essential for survival and locomotion, but how it integrates internal needs and transmits locomotion commands to the spinal cord (SC) remains unclear. We found that glutamatergic neurons in lateral hypothalamic area (LHA) are essential for regulating motivated locomotor activity. Using single-neuron projectome analysis, trans-synaptic tracing, and optogenetic manipulation, we showed that LHA facilitates motivated locomotion during food seeking via pontine reticular nucleus, oral part (PnO) projection neurons, rather than direct SC projections or indirect stress signaling via medial septum and diagonal band. Activating PnO-SC projection neurons also initiated locomotion. Importantly, LHA-PnO projection neurons were crucial for regulating locomotor recovery following mouse spinal cord injury (SCI). Motor cortex signals gated LHA deep brain stimulation treatment markedly promoted long-term restoration of hindlimb motor functions after severe SCI. Thus, we have identified a hypothalamic-pontine-spinal pathway and the stimulation paradigm for potential therapeutic intervention after SCI.

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Publication Details

Journal
Nature Communications
Published
2025-12-06
DOI
https://doi.org/10.1038/s41467-025-67133-5
Primary Topic
Zebrafish Biomedical Research Applications
Type
article
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article

Activation of hypothalamic-pontine-spinal pathway promotes locomotor initiation and functional recovery after spinal cord injury in mice

Yi Li, Xiaohong Xu, Xiaoxue Shi, Bowen Zheng et al.
Nature Communications
Zebrafish Biomedical Research Applications
article

Activation of hypothalamic-pontine-spinal pathway promotes locomotor initiation and functional recovery after spinal cord injury in mice

Yi Li, Xiaohong Xu, Xiaoxue Shi, Bowen Zheng, Weihua Cai, Yaxuan Wei, Hanyu Shi, Xiao Yu, Qifang Wang, Zhuolei Jiao, Taorong Xie, Y. Zhang, Ziqi Zhao, Ziyu Li, Zhiyuan Zheng, Zeyu Lin, Xiaofei Wang, Juxiang Chen, Rui Tan, Jin Fan, Yu Shuisheng, Yun Qu, Chengyue Ji
article en

Abstract

The hypothalamus is critical for regulating behaviors essential for survival and locomotion, but how it integrates internal needs and transmits locomotion commands to the spinal cord (SC) remains unclear. We found that glutamatergic neurons in lateral hypothalamic area (LHA) are essential for regulating motivated locomotor activity. Using single-neuron projectome analysis, trans-synaptic tracing, and optogenetic manipulation, we showed that LHA facilitates motivated locomotion during food seeking via pontine reticular nucleus, oral part (PnO) projection neurons, rather than direct SC projections or indirect stress signaling via medial septum and diagonal band. Activating PnO-SC projection neurons also initiated locomotion. Importantly, LHA-PnO projection neurons were crucial for regulating locomotor recovery following mouse spinal cord injury (SCI). Motor cortex signals gated LHA deep brain stimulation treatment markedly promoted long-term restoration of hindlimb motor functions after severe SCI. Thus, we have identified a hypothalamic-pontine-spinal pathway and the stimulation paradigm for potential therapeutic intervention after SCI.

Nature CommunicationsVol. 17(1)
Second Military Medical University (CN), Anhui Medical University (CN), Chinese Academy of Sciences (CN), Center for Excellence in Brain Science and Intelligence Technology (CN), Changhai Hospital (CN), Second Affiliated Hospital of Anhui Medical University (CN), Jiangsu Province Hospital (CN), Shanghai Center for Brain Science and Brain-Inspired Technology (CN), University of Chinese Academy of Sciences (CN), Nanjing Medical University (CN)
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Zebrafish Biomedical Research Applications
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