Dissertations, Theses, and Capstone Projects

Date of Degree

9-2025

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy

Program

Biology

Advisor

John Martin

Committee Members

Jonathan Levitt

Andreas Kottmann

Karim Fouad

Monica Perez

Subject Categories

Molecular and Cellular Neuroscience | Systems Neuroscience

Keywords

Corticospinal Tract, Pyramidotomy, Spinal Cord, Bilateral, H-Reflex

Abstract

The corticospinal tract (CST) is the primary descending motor pathway in mammals, essential for precise, dexterous movements, especially in humans and nonhuman primates. Damage to the CST, such as from spinal cord injury (SCI), impairs skilled motor function and triggers maladaptive changes including aberrant proprioceptive afferent sprouting and increased spinal excitability. These changes are closely linked to both muscle weakness and the development of hyperreflexia, compounding the functional deficits. Animal models of SCI are valuable for investigating mechanisms of injury and recovery, though traditional models often limit the ability to isolate circuit-specific contributions. To address this, I employed selective unilateral and bilateral CST lesions (pyramidotomy). I examined mechanisms underlying hyperreflexia, a common consequence of motor cortex stroke and SCI, by assessing 1a afferent-motor neuron connectivity, presynaptic inhibition via GABAergic neurons (GABApre), and expression of the chloride transporter KCC2. My experiments took a comprehensive approach and revealed distinct mechanisms to understand how they collectively contribute to aberrant physiological reflex activity following selective unilateral and bilateral CST injury models. Following selective unilateral CST injury, hyperreflexia was observed exclusively in the contralesional forelimb but not in the hindlimb, suggesting that its occurrence was closely linked to the lack of proper regulation of 1a afferent fiber sprouting by GABApre inhibition. Bilateral CST injury led to widespread hyperreflexia, persistent reductions in motor-evoked potentials, increased 1a afferent terminal density, downregulation of membrane-bound KCC2, and impaired GABApre function. Application of intermittent theta burst stimulation (iTBS) restored muscle recruitment and reduced hyperreflexia by enhancing GABApre regulation and stabilizing KCC2 expression. These findings demonstrate that iTBS promotes corticospinal plasticity and modulates spinal excitability at both the circuit and cellular levels. Scaling this model to more clinically relevant SCI paradigms could deepen understanding of hyperreflexia and inform targeted therapeutic strategies.

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