McDaniel, D. P. | bioRxiv Science

bioRxiv2023

Sustained Generation of Neurons Destined for Neocortex with Oxidative Metabolic Upregulation upon Filamin Abrogation

Neurons in the neocortex are generated during embryonic development. While the adult ventricular-subventricular zone (V-SVZ) contains cells with neural stem/progenitors characteristics, it remains unclear whether it has the capacity of producing neocortical neurons. Here we show that the generation of neurons exhibiting transcriptomic resemblance to neurons of the upper cortical layers continues in the V-SVZ of mouse models of a human condition known as periventricular heterotopia by abrogating filamin. We found such surplus neurogenesis was associated with V-SVZs transcriptional upregulation of oxidative phosphorylation, mitochondrial biogenesis, and increased vascularization. Our spatial transcriptomics analysis also showed that the neurogenic activation of V-SVZ was coupled with enriched expression of genes in diverse pathways for energetics, signaling, neuronal activities, and metabolic turnovers of nucleic acids and proteins in upper cortical layers. These findings support the potential of generating neocortical neurons in adulthood through enhancing brain-wide vascular circulation, aerobic ATP synthesis, and neuronal vitality.

neuroscience↗

bioRxiv2021

Genetic inactivation of SARM1 axon degeneration pathway improves outcome trajectory after experimental traumatic brain injury based on pathological, radiological, and functional measures

Traumatic brain injury (TBI) causes chronic symptoms and increased risk of neurodegeneration. Axons in white matter tracts, such as the corpus callosum (CC), are critical components of neural circuits and particularly vulnerable to TBI. Treatments are needed to protect axons from traumatic injury and mitigate post-traumatic neurodegeneration. The Sarm1 gene is a central driver of axon degeneration through a conserved molecular pathway. Sarm1-/- mice with knockout (KO) of the Sarm1 gene enable genetic proof-of-concept testing of Sarm1 inactivation as a therapeutic target. We evaluated Sarm1 deletion effects after TBI using a concussive model that causes traumatic axonal injury and progresses to CC atrophy at 10 weeks, indicating post-traumatic neurodegeneration. Sarm1 wild-type (WT) mice developed significant CC atrophy that was reduced in Sarm1 KO mice. Using electron microscopy to quantify individual axons demonstrated that Sarm1 KO preserved more intact axons and reduced damaged or demyelinated axons. MRI in live mice identified significantly reduced CC volume after TBI in Sarm1 WT mice that was attenuated in Sarm1 KO mice. MR diffusion tensor imaging detected reduced fractional anisotropy in both genotypes while axial diffusivity remained higher in Sarm1 KO mice. Immunohistochemistry revealed significant attenuation of CC atrophy, myelin loss, and neuroinflammation in Sarm1 KO mice after TBI. Functionally, TBI resulted in late-stage motor learning and sleep deficits that were ameliorated in Sarm1 KO mice. Based on these findings, Sarm1 inactivation can protect axons and white matter tracts to improve translational outcomes associated with CC atrophy and post-traumatic neurodegeneration.

neuroscience↗