Molecular and functional organization of the locomotor networks : from brainstem to spinal cord

Locomotion is a complex behavior that allows us to move and interact with the surroundings. In mammals, descending locomotor commands from the brainstem act directly onto spinal locomotor circuits to initiate or halt locomotor activity. However, it is the spinal locomotor networks themself that activate and modulate rhythm and pattern generation underlying locomotor activity. The development of genetic tools for manipulating specific neuron populations has significantly advanced our understanding of locomotor circuits extending from the brainstem to the spinal cord.

Yet the knowledge of which spinal circuits are targeted by the descending commands and how they transform this supraspinal drive into rhythmicity is not well understood in mammals. Moreover, while pattern-generating circuits are starting to be well characterized in the spinal cord, less is known about the rhythm-generating networks which involve several excitatory spinal populations. However, these populations only comprise a fraction of the excitatory neurons found in the spinal cord. Thus, there is a need to find new molecular markers for excitatory spinal neurons that could depict new excitatory populations involved in rhythm generation or other functions of the spinal locomotor networks.

The work of this thesis addresses these questions by using mice genetics to either activate, inhibit, or record the activity of specific neuronal populations.

In Paper I of this thesis, we examined the transition node between the descending commands and the spinal locomotor networks. We found that the LPGi/CVL neurons send the final descending commands to the spinal cord and activate different spinal clusters in a spatiotemporal manner. In Paper II, we investigated the transcriptomic profiles of spinal glutamatergic neurons which led us to characterize a new spinal glutamatergic population expressing the transcription factor Lhx9. We showed that this population is involved in the modulation of the locomotor frequency and, therefore, is suggested to be part of the rhythm-generating networks.

Overall, the work presented in this thesis widens our understanding of the initiation and modulation of locomotor activity from the brainstem to the spinal cord in mice which may further aid in unraveling the functional organization of locomotor circuits.

List of scientific papers

I. Hsu, LJ., Bertho, M. & Kiehn, O. (2023). Deconstructing the modular organization and real-time dynamics of mammalian spinal locomotor networks. Nature Communications. 14, 873.
https://doi.org/10.1038/s41467-023-36587-w

II. Bertho, M., Caldeira, V., Hsu, LJ., Löw, P., Borgius, L., Kiehn, O. (2024). Excitatory spinal Lhx9-derived interneurons modulate locomotor frequency in mice. Journal of Neuroscience.
https://doi.org/10.1523/JNEUROSCI.1607-23.2024