Final Report Summary - OPTOLOCO (Dynamic sensory-motor integration in spinal circuits)
While researchers previously believed that sensory neurons were restrained to the periphery and excluded from the spinal cord, we discovered a novel sensory-motor loop in the vertebrate spinal cord itself (Bohm, Prendergast et al., Nature Communications 2016). We showed that neurons in contact with the cerebrospinal fluid (CSF) were sensory and provided a GABAergic feedback to interneurons and motor neurons controlling locomotion and posture (Fidelin et al., Current Biology 2015; Hubbard et al., Current Biology 2016).
We showed that these neurons in contact with the cerebrospinal fluid are conserved in vertebrates (Djenoune et al., Frontiers 2014; Djenoune et al., Scientific Reports 2017). We proved that CSF-cNs were mechanosensory cells in vivo (Bohm, Prendergast et al., Nature Communications 2016) and in vitro (Sternberg et al., in revision). We showed the role of the channel Pkd2l1 in mediating these sensory function in these cells (Bohm, Prendergast et al., Nature Communications 2016; Sternberg et al., in revision). We identified the neuronal targets of CSF-cNs in the spinal cord (Fidelin et al., Current Biology 2015; Hubbard et al., Current Biology 2016; Wu et al., in prep.). In addition, we dissected the role of the Reissner Fiber, a component of the CSF conserved in vertebrates, by using CRISPR/Cas9 mediated genome editing to mutate the principal component of the Reissner Fiber, scospondin (Cantaut-Belarif et al., submitted). Remarkably, we found that animals deprived of the Reissner Fiber cannot grow a straight body axis, raising multiple questions on how the Reissner Fiber interact with instructive molecules to control morphogenesis of the body axis. Furthermore, our team described for the first time the flow of CSF in the central canal and investigated the role of CSF-contacting neurons for detecting flow generated by cilia (Sternberg et al., in revision). Our work inspired multiple groups working in mammals to test whether CSF contacting neurons are sensory neurons modulating locomotion and posture as well in mouse and rats.
Furthermore, we investigated the role of peripheral mechanosensory feedback to locomotion and showed a specific speed-dependent effect leading to an increase of speed during locomotion (Knafo, Fidelin et al., eLife 2017). Optogenetic-mediated mapping enabled to identify a pathways underlying this effect in the spinal cord. Our most recent work maps circuits in the hindbrain (Severi et al., in preparation).
Altogether, our work revealed general rules of operation for the modulation of spinal circuits by mechanosensory feedback during locomotion. Interestingly, circuits and molecular mechanisms we found seam to be relevant for development of the spine in the juvenile stages as well. This work offers new avenues of investigation for the contribution of mechanoception to locomotion and development in mammals.
We showed that these neurons in contact with the cerebrospinal fluid are conserved in vertebrates (Djenoune et al., Frontiers 2014; Djenoune et al., Scientific Reports 2017). We proved that CSF-cNs were mechanosensory cells in vivo (Bohm, Prendergast et al., Nature Communications 2016) and in vitro (Sternberg et al., in revision). We showed the role of the channel Pkd2l1 in mediating these sensory function in these cells (Bohm, Prendergast et al., Nature Communications 2016; Sternberg et al., in revision). We identified the neuronal targets of CSF-cNs in the spinal cord (Fidelin et al., Current Biology 2015; Hubbard et al., Current Biology 2016; Wu et al., in prep.). In addition, we dissected the role of the Reissner Fiber, a component of the CSF conserved in vertebrates, by using CRISPR/Cas9 mediated genome editing to mutate the principal component of the Reissner Fiber, scospondin (Cantaut-Belarif et al., submitted). Remarkably, we found that animals deprived of the Reissner Fiber cannot grow a straight body axis, raising multiple questions on how the Reissner Fiber interact with instructive molecules to control morphogenesis of the body axis. Furthermore, our team described for the first time the flow of CSF in the central canal and investigated the role of CSF-contacting neurons for detecting flow generated by cilia (Sternberg et al., in revision). Our work inspired multiple groups working in mammals to test whether CSF contacting neurons are sensory neurons modulating locomotion and posture as well in mouse and rats.
Furthermore, we investigated the role of peripheral mechanosensory feedback to locomotion and showed a specific speed-dependent effect leading to an increase of speed during locomotion (Knafo, Fidelin et al., eLife 2017). Optogenetic-mediated mapping enabled to identify a pathways underlying this effect in the spinal cord. Our most recent work maps circuits in the hindbrain (Severi et al., in preparation).
Altogether, our work revealed general rules of operation for the modulation of spinal circuits by mechanosensory feedback during locomotion. Interestingly, circuits and molecular mechanisms we found seam to be relevant for development of the spine in the juvenile stages as well. This work offers new avenues of investigation for the contribution of mechanoception to locomotion and development in mammals.