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Mechanisms that drive acute and chronic remyelination after spinal cord injury

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2021, Doctor of Philosophy, Ohio State University, Neuroscience Graduate Studies Program.
Spinal cord injury (SCI) results in life-long motor and sensory impairments caused by primary neuron damage and secondary tissue disruption. Within hours of SCI, extensive oligodendrocyte death and myelin breakdown slows electrical conduction between the brain and spinal cord and diminishes neural signaling. Fortunately, some demyelinated axons are spontaneously remyelinated early after SCI by NG2+ glia that differentiate into new oligodendrocytes. Since remyelination protects axons from damage and improves conduction, enhancing remyelination is often a therapeutic strategy to restore function after SCI. However, no pro-myelinating therapies currently exist for SCI patients. To help design future clinical trials and identify new therapies, we examined the extent, target, function, and underlying mechanisms of acute and chronic remyelination in transgenic mouse models of contusion SCI. Using an inducible reporter mouse that selectively labels new OLs and myelin, we show that new myelin formation peaks from 8-12 weeks post-injury (wpi), and continues for at least 26 wpi. Since axon conduction is sensitive to changes in myelin, the function of this new myelin was assessed by recording motor evoked potentials (MEPs). MEP amplitude decreased immediately after SCI due to axon degeneration and demyelination, but then increased 2-fold between 4-10 wpi, a period of robust remyelination. Improvements in fine locomotor skills were also observed from 4-10 wpi. Oligodendrocyte and myelin genesis are unaffected by tamoxifen administration; therefore, these data indicate that the endogenous repair of demyelinated axons persists chronically after SCI. Since NG2 cells are the primary source of new oligodendrocytes and myelin, understanding the mechanisms that regulate NG2 cell function post-injury is critical. Previous work from demyelination studies show that the mammalian target of rapamycin (mTOR) and glutamate signaling from active axons promotes oligodendrocyte differentiation and remyelination. Here, a time course study revealed that overall mTOR activity and Vglut2 expression increased continuously after SCI, but that mTOR activation peaked in NG2 cells from 1-2 wpi whereas Vglut2/NG2 cell contacts peaked chronically. To examine how mTOR alters NG2 cell function after SCI, we assessed oligodendrocyte lineage cells, myelination, and functional recovery in mice with a genetic deletion of mTOR in NG2 cells at 2, 5, and 12 wpi. At 2 wpi, mice lacking mTOR in NG2 cells had worse hindlimb locomotor recovery, fewer mature oligodendrocytes, and increased demyelination compared to littermate controls. However, chronic oligodendrogenesis equalized these outcomes in mice that survived to 5 or 12 wpi. To assess how NG2 cells are regulated chronically, Vglut2+ axons in the thoracic spinal cord were activated or silenced using designer receptors exclusively activated by designer drugs (DREADDs) from 2-4 wpi. Activated Vglut2+ axons had twice the number of NG2 cell contacts compared to controls, whereas silenced axons had half the number of contacts as controls. Overall, these data highlight that cellular repair mechanisms vary over time after SCI, and that increasing mTOR or glutamatergic axon activity may optimize the function of spared tissue to enhance repair after injury. However, all therapeutic strategies should be cognizant of possible disruptions to endogenous remyelination in the acute and chronic SCI setting.
Dana McTigue, PhD (Advisor)
Andrew Fischer, PhD (Committee Member)
Andrea Tedeschi, PhD (Committee Member)
Min Zhou, PhD (Committee Member)

Recommended Citations

Citations

  • Pukos, N. (2021). Mechanisms that drive acute and chronic remyelination after spinal cord injury [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1625747482421628

    APA Style (7th edition)

  • Pukos, Nicole. Mechanisms that drive acute and chronic remyelination after spinal cord injury. 2021. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1625747482421628.

    MLA Style (8th edition)

  • Pukos, Nicole. "Mechanisms that drive acute and chronic remyelination after spinal cord injury." Doctoral dissertation, Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu1625747482421628

    Chicago Manual of Style (17th edition)