Excitatory Spinal Lhx9-Derived Interneurons Modulate Locomotor Frequency in Mice

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Locomotion allows us to move and interact with our surroundings. Spinal networks that control locomotion produce rhythm and left–right and flexor–extensor coordination. Several glutamatergic populations, Shox2 non-V2a, Hb9-derived interneurons, and, recently, spinocerebellar neurons have been proposed to be involved in the mouse rhythm generating networks. These cells make up only a smaller fraction of the excitatory cells in the ventral spinal cord. Here, we set out to identify additional populations of excitatory spinal neurons that may be involved in rhythm generation or other functions in the locomotor network. We use RNA sequencing from glutamatergic, non-glutamatergic, and Shox2 cells in the neonatal mice from both sexes followed by differential gene expression analyses. These analyses identified transcription factors that are highly expressed by glutamatergic spinal neurons and differentially expressed between Shox2 neurons and glutamatergic neurons. From this latter category, we identified the Lhx9-derived neurons as having a restricted spinal expression pattern with no Shox2 neuron overlap. They are purely glutamatergic and ipsilaterally projecting. Ablation of the glutamatergic transmission or acute inactivation of the neuronal activity of Lhx9-derived neurons leads to a decrease in the frequency of locomotor-like activity without change in coordination pattern. Optogenetic activation of Lhx9-derived neurons promotes locomotor-like activity and modulates the frequency of the locomotor activity. Calcium activities of Lhx9-derived neurons show strong left–right out-of-phase rhythmicity during locomotor-like activity. Our study identifies a distinct population of spinal excitatory neurons that regulates the frequency of locomotor output with a suggested role in rhythm-generation in the mouse alongside other spinal populations.
OriginalsprogEngelsk
Artikelnummere1607232024
TidsskriftJournal of Neuroscience
Vol/bind44
Udgave nummer18
Antal sider25
ISSN0270-6474
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
This work was supported by the Karolinska Institute (PhD fellowship to M.B.), the Novo Nordisk Foundation Laureate Program (NNF15OC0014186), the Lundbeck Foundation (R345-2020-1769), Hj\u00E4rnfonden and the Swedish Research Council (all to O.K.). We also acknowledge the Biomedicum Imaging Core (BIC) at the Biomedicum (Karolinska Institutet) and the Core Facility for Integrated Microscopy (CFIM) at the Faculty of Health and Medical Sciences (University of Copenhagen). We thank Dr. Aharon Lev-Tov and Dr. Yoav Mor for providing the SpinalCore software and Dr. Ilary Allodi, Roser Monta\u00F1ana-Rosell and Dr. Stefan Dietrich for assistance with the RNAscope in situ hybridization experiments. We are grateful to Estelle Proux-W\u00E9ra, Mikael Huss and to SciLifeLab Bioinformatics Long-term Support (WABI) for their invaluable biostatistical assistance. We would also like to acknowledge support from Science for Life Laboratory, the National Genomics Infrastructure, NGI, and Uppmax for providing assistance in massive parallel sequencing and computational infrastructure.

Funding Information:
This work was supported by the Karolinska Institute (PhD fellowship to M.B.), the Novo Nordisk Foundation Laureate Program (NNF15OC0014186), the Lundbeck Foundation (R345-2020-1769), Hj\u00E4rnfonden and the Swedish Research Council (all to O.K.). We also acknowledge the Biomedicum Imaging Core (BIC) at the Biomedicum (Karolinska Institutet) and the Core Facility for Integrated Microscopy (CFIM) at the Faculty of Health and Medical Sciences (University of Copenhagen). We thank Dr. Aharon Lev-Tov and Dr. Yoav Mor for providing the SpinalCore software and Dr. Ilary Allodi, Roser Monta\u00F1ana-Rosell and Dr. Stefan Dietrich for assistance with the RNAscope in situ hybridization experiments. We are grateful to Estelle Proux-W\u00E9ra, Mikael Huss

Publisher Copyright:
Copyright © 2024 Bertho et al.

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