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Anatomical diversity of the adult corticospinal tract revealed by single cell transcriptional profiling.

ABSTRACT: The corticospinal tract (CST) forms a central part of the voluntary motor apparatus in all mammals. Thus, injury, disease, and subsequent degeneration within this pathway result in chronic irreversible functional deficits. Current strategies to repair the damaged CST are sub-optimal in part due to underexplored molecular heterogeneity within the adult tract. Here we combine spinal retrograde CST tracing with single-cell RNA sequencing in adult male and female mice to index corticospinal neuron (CSN) subtypes that differentially innervate the forelimb and hindlimb. We exploit publicly available datasets to confer anatomical specialization among CSNs and show that CSNs segregate not only along the forelimb and hindlimb axis but also by supraspinal axon collateralization. These anatomically defined transcriptional data allow us to use machine learning tools to build classifiers that discriminate between CSNs and cortical layer 2/3 and non-spinally terminating layer 5 neurons in M1, and separately identify limb specific CSNs. Utilizing these tools, CSN subtypes can be differentially identified to study postnatal patterning of the CST in vivo, leveraged to screen for novel limb-specific axon growth survival and growth activators in vitro, and ultimately exploited to repair the damaged CST after injury and disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE293184 | GEO | 2026/03/25

REPOSITORIES: GEO

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Project description:While the central nervous system is perpetually reshaped by evolution, the principles governing how such changes promote ecologically relevant behaviors without breaking established functions are poorly understood. The expansion of neuron number is a potential mechanism by which the nervous system evolves to support changes in behavior without disrupting existing circuit function. Corticospinal neurons (CSNs) are a classic example: an expansion in the corticospinal system in the primate lineage has been hypothesized to underlie their exceptional dexterity. However, the role of CSN number in behavior has been difficult to assess due to the lack of a tractable model system. We compared two closely related subspecies of deer mice (Peromyscus maniculatus): forest mice, which evolved the ability to adeptly climb, presumably to support a semi-arboreal lifestyle, and prairie mice, which are less proficient climbers. We find that forest mice have about two-fold larger corticospinal tracts (CSTs) driven by an increase in CSN number in secondary motor and sensory cortical areas (M2 and S2). Furthermore, forest mice display greater manual dexterity than their prairie counterparts in a reach-to-grasp task, consistent with the idea that an increase in CSN number supports more dexterous behavior. High-throughput neural recordings during this task revealed a difference in the timing of neural activity between forest and prairie mice, specifically in M2: in forest mice, the peak of activity was shifted towards the grasping phase of the behavior. Forest mice also outperform their prairie counterparts on an ecologically relevant climbing task, where they spend more time upright crossing a thin rod, move faster, and right themselves more quickly when they fall, suggesting a general difference in motor dexterity not restricted to hand use. Finally, we use F2 hybrid animals to show that CST size is correlated with climbing dexterity, providing support for the long-standing hypothesis that corticospinal system expansion supports the evolution of dexterity. Together, our work establishes the forest-prairie deer mouse system as a model to investigate the role of neuron number expansion, and CSNs in particular, in dexterous movement.

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Anatomical diversity of the adult corticospinal tract revealed by single cell transcriptional profiling.

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