Structure of long-range direct and indirect spinocerebellar pathways as well as local spinal circuits mediating proprioception

Abstract

Proprioception, the sense of limb and body position, generates a map of the body that is essential for proper motor control, yet we know little about precisely how neurons in proprioceptive pathways develop and are wired. Proprioceptive and cutaneous information from the periphery is sent to secondary neurons in the spinal cord that integrate and relay this information to the cerebellum either directly or indirectly through the medulla. Defining the anatomy of these direct and indirect pathways is fundamental to understanding how proprioceptive circuits function. Here, we use genetic tools in mice to define the developmental origins and unique anatomical trajectories of these pathways. Developmentally, we find that Clarke's column (CC) neurons, a major contributor to the direct spinocerebellar pathway, derive from the Neurog1 progenitor domain. By contrast, we find that two of the indirect pathways, the spino-lateral reticular nucleus (spino-LRt) and spino-olivary pathways, are derived from the Atoh1 progenitor domain, despite previous evidence that Atoh1-lineage neurons form the direct pathway. Anatomically, we also find that the mossy fiber terminals of CC neurons diversify extensively with some axons terminating bilaterally in the cerebellar cortex. Intriguingly, we find that CC axons do not send axon collaterals to the medulla or cerebellar nuclei like other mossy fiber sources. Altogether, we conclude that the direct and indirect spinocerebellar pathways derive from distinct progenitor domains in the developing spinal cord and that the proprioceptive information from CC neurons is processed only at the level of granule cells in the cerebellum.

An Atoh1 CRE Knock-In Mouse Labels Motor Neurons Involved in Fine Motor Control

“…1 A , B , arrows). Note that the TOM + cell bodies in the intermediate spinal cord are from other Atoh1 -lineage interneurons involved in the proprioceptive system ( Yuengert et al, 2015 ; Pop et al, 2020 ).…”

“…Developing a genetic tool that labels IH and IF MNs would have significant utility in interrogating the function and circuitry of fine motor control. To this end, we found that digit-innervating MNs were labeled using CRE-loxP recombination driven by the bHLH transcription factor atonal homolog 1, Atoh1 , a transiently expressed gene in the dorsal-most part of the developing neural tube that is also known to specify excitatory ( Vglut2 + ) spinal cord neurons that project rostrally to the hindbrain ( Bermingham et al, 2001 ; Gowan et al, 2001 ; Sakai et al, 2012 ; Yuengert et al, 2015 ; Pop et al, 2020 ).…”

Electrophysiological properties of neurons in the intermediate thoracolumbar spinal cord mediating proprioception

“…We also found that CC neurons make 43-47% of all spinocerebellar neurons (Pop et al, 2022). Therefore, it is important to understand how this major cell type responds to electrical activity.…”

“…These experiments found cells of the DSCT that responded either to cutaneous touch stimuli, proprioceptive stimuli, or both from the hindlimb. However, CC neurons make up a subset of the DSCT and recordings with sharp and metal electrodes were limited in their ability to assess the cellular response properties of CC neurons (Matsushita and Hosoya, 1979; Baek et al, 2019; Pop et al, 2022). With the advent of patch clamp technology in the 1980s (Hamill et al, 1981), together with current genetic and molecular biology tools, we can precisely identify CC neurons to understand their physiological currents.…”

“…In addition to CC neurons, our group discovered that a subset of neurons derived from progenitor cells defined by expression of the basic helix-loop-helix transcription factor, Atonal homolog 1 ( Atoh1 ) also receive proprioceptive information (Yuengert et al, 2015; Pop et al, 2022). CC and Atoh1 -lineage neurons all reside in laminae V-VII of the thoracolumbar spinal cord.…”