The cerebrospinal fluid (CSF) is a complex solution that circulates around the CNS, and whose composition changes as a function of an animal’s physiological state. Ciliated neurons that are bathed in the CSF — and thus referred to as CSF-contacting neurons (CSF-cNs) — are unusual polymodal interoceptive neurons. As chemoreceptors, CSF-cNs respond to variations in pH and osmolarity and to bacterial metabolites in the CSF. Their activation during infections of the CNS results in secretion of compounds to enhance host survival. As mechanosensory neurons, CSF-cNs operate together with an extracellular proteinaceous polymer known as the Reissner fibre to detect compression during spinal curvature. Once activated, CSF-cNs inhibit motor neurons, premotor excitatory neurons and command neurons to enhance movement speed and stabilize posture. At longer timescales, CSF-cNs instruct morphogenesis throughout life via the release of neuropeptides that act over long distances on skeletal muscle. Finally, recent evidence suggests that mouse CSF-cNs may act as neural stem cells in the spinal cord, inspiring new paths of investigation for repair after injury.
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This work received support from the European Research Council (ERC), the New York Stem Cell Foundation (NYSCF), the Human Frontier Science Program (HFSP), the Fondation pour la Recherche Médicale (FRM), the Fondation Bettencourt-Schueller (FBS), the Fondation Schlumberger pour l’Education et la Recherche (FSER) and the Marie Skłodowska-Curie European Training Network initiative. The authors thank Headquarter for conceiving illustrations, J. Guedes, manager of the Zenith programme, for feedback and all members of the Wyart laboratory, past and present, at the Paris Brain Institute (Institut du Cerveau).
The authors declare no competing interests.
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Supplementary Video 1 | Sagittal time series showing the cilium of a ventral cerebrospinal fluid-contacting neuron (CSF-cN) in vivo beating in the central canal. Video was obtained in a 4-day-old larval zebrafish and has a 30 Hz acquisition rate. The cilium was beating at 7 Hz. Reprinted from ref. 4, Springer Nature Ltd.
Supplementary Video 10 | Rostral cerebrospinal fluid-contacting neurons (CSF-cNs) form axo-axonic connections onto Vsx2+ reticulospinal neurons in the hindbrain. The video shows a dorsal view of the zebrafish hindbrain. CSF-cNs appear green and Vsx2-positive reticulospinal neurons appear in pink. Synapses are highlighted with arrows. Reprinted with permission from ref. 46, Elsevier).
Supplementary Video 2 | Time series showing active beating by the cilium of a cerebrospinal fluid-contacting neuron (CSF-cN) from a primary zebrafish culture. The cilium is labelled by an arrow. Adapted from ref. 4, Springer Nature Ltd.
Supplementary Video 3 | 3D serial electron microscopy sections reveal the proximity of cerebrospinal fluid-contacting neuron (CSF-cN) cilium to the Reissner fibre. The blue arrow highlights the CSF-cN and the white arrow indicates the cilium, whereas the red arrow highlights the Reissner fibre. Adapted with permission from ref. 7, Elsevier).
Supplementary Video 4 | Cerebrospinal fluid-contacting neuron (CSF-cN) calcium activity and cell position during single tail bends corresponding to acousto-vestibular escape responses in larval zebrafish. In order to quantify the activation of CSF-cNs reflected in the increase in intracellular calcium, a correction of the motion artefact is necessary. This was accomplished by calculating the ratio of the signal of the fluorescent sensor GCaMP, used as a reporter of neuronal activity, over the signal of tagRFP, used as a reporter of cell position relative to the focal plane of the two photon microscope. One can appreciate that CSF-cNs respond only to compression on the side of negative curvature during a tail bend. Adapted from ref. 4, Springer Nature Ltd.
Supplementary Video 5 | Artistic animation showing how the Reissner fibre can interact with cerebrospinal fluid-contacting neurons (CSF-cNs) to detect bending of the spinal cord on the side of compression. The video was created based on the results from refs. 4,7. Animation created with the help of Headquarter (https://headquarter.paris).
Supplementary Video 6 | Cerebrospinal fluid-contacting neurons (CSF-cNs) show reduced basal activity and sustained massive calcium transients upon injection of Streptococcus pneumoniae into the brain ventricles. We can appreciate on this video how the basal activity of CSF-cNs is reduced while a subset of CSF-cNs shows unusually large and long-lasting calcium transients. Reprinted from ref. 19 CC BY 4.0 (https://creativecommons.org/licences/by/4.0/).
Supplementary Video 7 | Cerebrospinal fluid-contacting neurons (CSF-cNs) in primary cultures respond to cytolysin and bacterial metabolites secreted by Streptococcus pneumoniae. From left to right: negative control showing no response to a pressure application of aCSF; response to pneumolysin 0.05 mg/mL; response to mixture of bitter compounds at 50 mM; response to the bitter compound DMDS tested alone at 50 mM; response to the other bitter compound 2 pentanone tested alone at 50 mM. Reprinted from ref. 19 CC BY 4.0 (https://creativecommons.org/licences/by/4.0/).
Supplementary Video 8 | Deep learning can be used to estimate the probability of rolling probability over time during acousto-vestibular responses of larval zebrafish. By focusing on the head, analysis revealed that, after ablation of cerebrospinal fluid-contacting neurons (CSF-cNs), larval zebrafish roll more often and do so by losing balance after the initial large bend called the C-bend. When rolling is happening, a red dot appears at the top left of the image. The probability for rolling is indicated in the bottom left corner. Reprinted with permission from ref. 46, Elsevier.
Supplementary Video 9 | Rostral cerebrospinal fluid-contacting neurons (CSF-cNs) project onto the soma of occipital motor neurons in the hindbrain. The video shows a dorsal view of the zebrafish hindbrain. CSF-cNs appear in green and motor neurons appear in pink. Synapses are highlighted with arrows. Reprinted with permission from ref. 46, Elsevier).
- Axo-axonic synapses
Synapses formed from one axon onto another.
- Central pattern generators
Self-organizing biological neural circuits that produce rhythmic outputs in the absence of rhythmic input.
- Choroid plexuses
A network of blood vessels and epithelial cells in the ventricles of the brain that make the cerebrospinal fluid (CSF).
- Corollary discharge
In motor systems, a copy of the movement command that is broadcast to other regions of the brain to warn them of the impending movement.
- Dense core secretory vesicles
Vesicles that mediate the regulated release of neuropeptides and peptide hormones.
- Escape responses
Mechanisms by which animals avoid potential predation in response to an aversive stimulus.
An excessive curvature of the thoracic spine, commonly referred to as hunchback.
A method that uses antibodies linked to an enzyme or a fluorescent dye to reveal certain antigens in a sample of tissue.
- Innate immunity
The initial response of the body to detect invaders such as viruses, bacteria, parasites and toxins, or to sense wounds or trauma.
Relating to sensory functions arising within the body, in the viscera or within the CNS itself.
A short microscopic hair-like vibrating structure found on the surfaces of certain cells, which either causes currents in the surrounding fluid or generates active movements of a ciliated apical extension in hair cells and cerebrospinal fluid-contacting neurons (CSF-cNs).
Components of the cell skeleton that determine the shape of a cell and are involved in different functions including the assembly of mitotic spindle (in dividing cells) and axon extension (in neurons).
Microscopic actin-based cellular membrane protrusions that are involved in a wide variety of functions, including absorption, secretion, cellular adhesion and mechanotransduction.
- Progenitor domains
Territories in which cascades of transcription factors are expressed during development.
Relative to proprioception, the sense of body position.
Abnormal lateral curvature of the spine showing 3D torsion.
- Taste receptors
Cellular receptors that facilitate the sensation of taste.
- Transcriptomic analyses
Methods involving the quantification of transcriptional activity to reveal a global picture of cell function.
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Wyart, C., Carbo-Tano, M., Cantaut-Belarif, Y. et al. Cerebrospinal fluid-contacting neurons: multimodal cells with diverse roles in the CNS. Nat. Rev. Neurosci. 24, 540–556 (2023). https://doi.org/10.1038/s41583-023-00723-8