Spinal ascending projection neuron repertoire and sex specific neurons

We are excited to share our latest preprint characterizing the ascending projection neuron repertoire as well as the first sex-specific neuron types in the mammalian spinal cord. This was a major effort in the lab led by Liliana Cano-Gomez, Helen Poldsam and Satoshi Ishishita. Combining single-nucleus multiomic profiling, single-molecule spatial transcriptomics and multiplexed retrograde viral tracing across more than 750k neurons, we report two findings we find particularly exciting. First, we identified seventy-eight classes of ascending spinal projection neurons spanning the full rostro-caudal axis of the cord, linking it to hindbrain, midbrain and forebrain centers for pain, itch, touch and proprioception. We believe this represents most of the mammalian spinal projection neuron repertoire, a more than fivefold increase over previous efforts that were restricted to individual spinal regions or developmental lineages. Second, we describe what are, to our knowledge, the first sex-specific neuron types in the mammalian spinal cord: seven transcriptomically distinct types concentrated in thoracic and sacral segments, which are strong candidates for the cellular control of sexually dimorphic autonomic and reproductive functions.

The key to both findings was analytical granularity. Conventional group-level clustering of spinal transcriptomes, the resolution at which most published atlases operate, detected no sexual dimorphism whatsoever and could not separate projection neurons from interneurons. Only when we resolved the data into more than five hundred transcriptomically and anatomically distinct neuron types did sex-specific classes emerge and the molecular identity of the ascending output become tractable. We think this argues strongly that spinal circuits need to be analyzed at finer resolution than has been standard, and that transcriptomic and anatomical data must be interpreted together. To make these results usable by the community, we built an interactive online atlas for browsing the molecular, anatomical and rojectional properties of spinal cord neuronal diversity, available at https://spinal-cord-explorer.shinyapps.io/explorer/. This work was made possible by the generous support from the BRAIN Initiative BICAN project, the McKnight Foundation’s Neurobiology of Disease Award, the Rita Allen Foundation and the McDermott Endowed Scholars Funds. We are grateful to all of them.