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  1. eLife

    eLife assessment

    The authors provide a new method to target mouse CSF-cNs via intracerebroventricular injection of adeno-associated virus (AAV) with a neuron-specific promoter, which enabled them to introduce any genes into CSF-cNs. By doing so, they established the structure, connectivity, and function of mouse CSF-cNs in locomotion, recapitulating the findings obtained in zebrafish and lamprey, and extending the recent observations in mice. This study is very conclusive and important for the sensorimotor field.

  2. eLife

    Reviewer #1 (Public Review):

    The group of Ueno also describes that the pkd2l1:cre line previously used to study CSF-cNs was not specific in the adult mouse as it labels olig2+ glial cells in the gray matter. Ueno's group in this study has discovered a method to target mouse CSF-cNs via intracerebroventricular injection of adeno-associated virus (AAV) with a neuron-specific promoter, which enabled them to introduce any genes into CSF-cNs. By doing so, the authors established the structure, connectivity, and function of mouse CSF-cNs in locomotion, recapitulating the findings obtained in zebrafish and lamprey, and extending the recent observations in mice. This study is very conclusive and important for the sensorimotor field in vertebrates.

    Ueno's group showed using a set of sophisticated and versatile approaches that :

    1. Most CSF-cNs conserve in mouse the ipsilateral and ventral ascending morphology and are inhibitory neurons;
    2. CSF-cNs project onto axial motor neurons of the neck and back and premotor excitatory neurons in addition to themselves via recurrent connections;
    3. CSF-cNs contribute to enhancing speed during movement on a treadmill, similarly to what has been observed in zebrafish. Chemogenetic inhibition of CSF-cNs reduce speed and increase stride length, indicating that CSF-cNs control body-limb coordination. This exciting finding had been missed in previous investigation.
  3. eLife

    Reviewer #2 (Public Review):

    The present study proposes a novel methodology for genetic labeling and manipulation of cerebrospinal fluid-contacting neurons (CSF-cNs). This is based on an impressive quantity of nice images of very high quality, results being obtained both in classical confocal microscopy and electronic microscopy and an advanced images analysis procedure. Anatomical findings are put in a more functional aspect with investigations of neuronal properties and motor function using in vitro and in vivo approaches examining functional consequences of perturbation of CSF-cNs' activity. Conclusions are strongly supported by the data. Nevertheless, it could be important to describe a bit more how the quantity of virus injected can be controlled, to increase the size of the sample for the collection of in vivo data (n=4 presently) and eventually discuss these new anatomical data with the presence of locomotor central pattern generators known to be located in restricted regions of the spinal cord (is there any relation or not). Overall this new method should be of great interest for researchers investigating the anatomy and the role of these still enigmatic cells.

  4. eLife

    Reviewer #3 (Public Review):

    The work by Nakamura and Colleagues describes a new method that allows, for the first time in mammals, to specifically target cerebrospinal fluid-contacting neurons (CSF-cNs) in the spinal cord with an adeno-associated virus. The role of these neurons still remains largely unknown. The new method allows to introduce a gene into these neurons in order to label them for anatomical investigations, to activate them to decipher the microcircuitry they form with other cells, or to silence them to investigate their function during behavior. The authors were successful to specifically target cerebrospinal fluid-contacting neurons located in the ventral part of the central canal leading to an exceptional amount of anatomical data (including at the ultrastructural level). The material provided (figures and videos) is qualitatively and quantitatively tremendously valuable. The observation of synaptic contacts allows the authors to make assumptions on the microcircuitry they form with other neurons. Importantly, optogenetic stimulation combined with electrophysiological recording allows the authors to fully demonstrate that each CSF-cN establishes functional inhibitory connections with other CSF-cN located more rostrally. However, the connectivity with axial motor neurons, V0c and V2a interneurons only relies on the anatomical study. We may wonder whether a more solid and full demonstration could be provided using again optogenetics tools and electrophysiological recordings in complement to the anatomical data? Finally, the authors report the interesting observation that mice with inactivated CSF-cNs cannot run on a treadmill at a speed faster than 15 m/s in sharp contrast with mice with functional CSF-cNs.

  5. Version 1 published on bioRxiv