Circular continuum of alpha motoneuron types

ABSTRACT Alpha-motoneurons (α-MNs) are traditionally classified into slow (S), fast fatigue-resistant (FR), and fast-fatigable (FF), which exist along a continuum of properties between slow and fast, enabling the generation of graded force and seamless movement. Using combinations of markers, we developed novel immunohistochemistry protocols that enabled co-labeling of six major and transitional α-MN types throughout the mouse lumbar spinal cord with unprecedented detail. Intriguingly, our protocols labeled for the first time: α-MNs of the fast fatigue intermediate (FI) type; a previously undescribed transitional α-MN subtype (FR/FI); and a novel subtype of α-MNs exhibiting hybrid characteristics of both S and FF types – termed S/FF – which resist ALS degeneration. Electrophysiological recordings confirmed FR/FI and S/FF subtypes, both exhibiting mixed traits. The discovery of S/FF subtype reveals that α-MNs exist along a circular continuum between slow and fast types, challenging the traditional linear model and reshaping our understanding of their role in motor control. New & Noteworthy This study introduces a novel immunohistochemistry protocol to co-label six distinct types of adult spinal cord motor neurons. This technical innovation led to a conceptual paradigm shift, revealing a circular continuum of motor neuron subtypes rather than a linear one. This new framework provides unprecedented precision for studying their varying susceptibility to degeneration in diseases like ALS, with broad implications for understanding motor control in health and disease. Competing Interest Statement The authors have declared no competing interest. Footnotes Figures 2 was updated to include clear images for support of the data. Figure 4 was separated into 2 figures in order to include clearer images for the reader. Subsequent text was updated to reflect the changes in the figures and their IDs. The supplemental figure 1 was removed as the images are now presented in the altered figures in the text.