Pathan, J. | bioRxiv Science

bioRxiv2025

Activity Protects Spinal Premotor Interneurons from Microglial Phagocytosis and Transneuronal Degeneration After Corticospinal Injury

Spinal premotor circuits play a fundamental role in motor control. The corticospinal tract (CST) provides control signals to premotor circuits in the spinal cord, guiding voluntary skilled movements. Unilateral selective lesion of the CST in the medullary pyramidal tract (PTX) produces transneuronal degeneration, whereby Choline Acetyltransferase-positive (ChAT) premotor interneurons contralesionally undergo non-apoptotic degeneration by microglial phagocytosis. Evidence shows that transneuronal degeneration has an activity dependence: MCX inactivation produces transneuronal degeneration and spinal DC neuromodulation after PTX ameliorates it. This study expands our understanding of transneuronal degeneration mechanisms by examining the activity-dependence of degeneration vulnerability and the implications for motor recovery in a mouse model of a complete CST lesion model (bilateral PTX). We address four key unanswered questions: Are Chx10 (VGlut2) interneurons, the largest spinal interneuron class to receive direct synaptic connections from the CST vulnerable to transneuronal degeneration after CST loss; using DREADD neuromodulation, what are effective sources of presynaptic activation for protecting spinal premotor interneurons after CST loss; how are ameliorating transneuronal interneuron degeneration and reducing microglial activation associated; and does effective rescue of interneuron degeneration rescue grip strength after injury? Transneuronal degeneration is a pervasive pathophysiological change injury; CST lesion produces significant Chx10 interneuron loss. Multiple sources of neuronal DREADD activation--motor cortex, reticular formation, and spinal interneurons--are effective in ameliorating transneuronal degeneration. Interneuron rescue is strongly associated with ameliorating inflammation, showing potential causality between interneuron degeneration and inflammation after CST lesion. Finally, rescuing spinal interneurons was associated with restoring function. Our findings demonstrate the interplay between neuronal activity, microglia actions mediating transneuronal degeneration, and motor recovery following CNS injury.

neuroscience↗

bioRxiv2018

Electron microscopy 3-dimensional segmentation and quantification of axonal dispersion and diameter distribution in mouse brain corpus callosum

To model the diffusion MRI signal in brain white matter, general assumptions have been made about the microstructural properties of axonal fiber bundles, such as the axonal shape and the fiber orientation dispersion. In particular, axons are modeled by perfectly circular cylinders with no diameter variation within each axon, and their directions obey a specific orientation distribution. However, these assumptions have not been validated by histology in 3-dimensional high-resolution neural tissue. Here, we reconstructed sequential scanning electron microscopy images in mouse brain corpus callosum, and introduced a semi-automatic random-walker (RaW) based algorithm to rapidly segment individual intra-axonal spaces and myelin sheaths of myelinated axons. Confirmed with a conventional machine-learning-based interactive segmentation method, our semi-automatic algorithm is reliable and less time-consuming. Based on the segmentation, we calculated histological estimates of size-related (e.g., inner axonal diameter, g-ratio) and orientation-related (e.g., Fiber orientation distribution and its rotational invariants, dispersion angle) quantities, and simulated how these quantities would be observed in actual diffusion MRI experiments by considering diffusion time-dependence. The reported dispersion angle is consistent with previous 2-dimensional histology studies and diffusion MRI measurements, though the reported diameter is larger than those in other mouse brain studies. Our results show that the orientation-related metrics have negligible diffusion time-dependence; however, inner axonal diameters demonstrate a non-trivial time-dependence at diffusion times typical for clinical and preclinical use. In other words, the fiber dispersion estimated by diffusion MRI modeling is relatively independent, while the \"apparent\" axonal size estimated by axonal diameter mapping potentially depends on experimental MRI settings.

neuroscience↗