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Chronic Systemic Manipulation of Axonal Inhibitory Perineuronal Net and rPTPσ Promotes Forelimb Recovery and Neuroplasticity

Milton, Adrianna Jerrell
http://orcid.org/0009-0009-9309-1688
http://rave.ohiolink.edu/etdc/view?acc_num=case1693943168972067

Abstract Details

2024, Doctor of Philosophy, Case Western Reserve University, Neurosciences.
Spinal cord injuries, for which there are limited effective treatments, result in enduring paralysis and hypoesthesia due, in part, to the inhibitory microenvironment that develops and limits regeneration/sprouting, especially during chronic stages. Recently, we discovered that targeted enzymatic modulation of the inhibitory chondroitin sulfate proteoglycan (CSPG) component of the extracellular and perineuronal net (PNN) matrix via Chondroitinase ABC (ChABC) rapidly restores robust respiratory function to the previously paralyzed hemi-diaphragm after remarkably long times post-injury (up to 1.5 years) following a cervical level 2 lateral hemi-transection. Importantly, ChABC treatment at cervical level 4 in this chronic model also elicited improvements in gross upper arm function. In the present study, we sought to further optimize and elucidate the capacity for nerve sprouting and/or regeneration to restore crude as well as fine motor control of the forearm and digits at lengthy chronic stages post-injury. However, instead of using ChABC, we utilized a novel and more clinically relevant systemic combinatorial treatment strategy designed to both reduce and overcome inhibitory CSPGs simultaneously and spatially extensively. Following a three- xii month upper cervical spinal hemi-lesion using adult female Sprague Dawley rats, we show that the combined treatment had a profound effect on functional recovery of the chronically paralyzed forelimb and paw, specifically during walking as well as precision movements of the digits. The regenerative and immune system related events that we describe deepen our basic understanding of the crucial role of CSPG mediated inhibition via the PTPσ receptor in constraining functional synaptic plasticity at lengthy time-points following SCI, hopefully leading to clinically relevant translational benefits.
Evan Deneris (Committee Chair)
Yu-Shang Lee (Committee Member)
Jerry Silver (Committee Member)
Heather Broihier (Committee Member)
Behavioral Sciences; Behaviorial Sciences; Neurosciences

Recommended Citations

Citations

  • Milton, A. J. (2024). Chronic Systemic Manipulation of Axonal Inhibitory Perineuronal Net and rPTPσ Promotes Forelimb Recovery and Neuroplasticity [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1693943168972067

    APA Style (7th edition)

  • Milton, Adrianna. Chronic Systemic Manipulation of Axonal Inhibitory Perineuronal Net and rPTPσ Promotes Forelimb Recovery and Neuroplasticity . 2024. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1693943168972067.

    MLA Style (8th edition)

  • Milton, Adrianna. "Chronic Systemic Manipulation of Axonal Inhibitory Perineuronal Net and rPTPσ Promotes Forelimb Recovery and Neuroplasticity ." Doctoral dissertation, Case Western Reserve University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=case1693943168972067

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.