Dissertations, Theses, and Capstone Projects
Date of Degree
9-2024
Document Type
Dissertation
Degree Name
Ph.D.
Program
Biology
Advisor
John Martin
Committee Members
Andreas Kottmann
Maral Tajerian
Ona Bloom
Yutaka Yoshida
Subject Categories
Neuroscience and Neurobiology
Keywords
Biomedical engineering, neuroimmunology
Abstract
Producing skilled, voluntary movements in humans and many animals requires the corticospinal tract, the direct motor pathway connecting the cerebral cortex with spinal cord interneurons and motor neurons in humans and many non-human primates. Spinal cord injury (SCI) typically results in corticospinal tract damage, leading to transneuronal degeneration of its interneuron targets. Complement protein C1q triggers this degenerative process and induces microglia, the innate immune cells of the central nervous system, to phagocytose non-apoptotic interneurons. We examined two classes of premotor interneurons, cholinergic (ChAT) and glutamatergic (Chx10), essential to the spinal motor circuit as they receive direct corticospinal tract inputs and synapse onto motor neurons to produce muscle contraction. We studied a model corticospinal tract lesion in the mouse and a preclinical SCI model in the rat. We determined the effect of excitatory neuromodulatory strategies on transneuronal interneuron degeneration and changes in the inflammatory responses that underpin neurodegeneration. In the mouse, we used a bilateral corticospinal tract lesion to study the effect of complete loss of the corticospinal tract on interneuron degeneration. We found chemogenetic excitatory neuromodulation selectively in the motor cortex, brain stem reticular formation, or spinal cord 24 hours after complete corticospinal tract ablation mitigates premotor interneuron transneuronal degeneration and improves functional recovery during the acute phase (10 days post-injury). To elucidate the mechanism, we examined phagocytic microglia with chemogenetic neuromodulation. Our findings in the mouse model lesion show that motor cortex, brain stem, and spinal cord excitatory neuromodulation effectively protect spinal interneurons from degeneration, with a reciprocal relation between the number of ChAT and Chx10 interneurons and phagocytic microglia. These results suggest that motor cortex and spinal cord stimulation alone may reduce interneuron degeneration and phagocytosis after SCI. To translate these findings from the mouse lesion model, we used a cervical contusion (fourth cervical segment) SCI rat model to determine if dual electrical neuromodulation of the motor cortex and spinal cord, a preclinical protocol that shows efficacy in improving motor performance after injury, during the subacute phase would provide sustained neuroprotection of ChAT and Chx10 interneurons and abrogation of innate immune responses during the chronic phase of SCI (8 weeks post-injury). Intriguingly, the dual electrical neuromodulation mitigated ChAT and Chx10 transneuronal degeneration but did not reduce microglia number; instead, it induced a 2-fold increase. This increase in microglia numbers was associated with electrical neuromodulation inducing microglia polarization towards an anti-inflammatory phenotype. Further, we showed that SCI upregulated phosphatidylserine (PS) and chemotaxis for microglia contact-based mechanisms, including phagocytosis. Neuromodulation after SCI returned PS to baseline immunopositivity. Our findings in the rat indicate that dual motor cortex-spinal cord electrical neuromodulation can attenuate transneuronal degeneration and modulate the associated innate immune responses post-stimulation in the chronic phase of SCI. By preventing transneuronal degeneration through neuromodulation, spinal circuits will likely be more effective in mediating recovery after SCI than if there is premotor interneuron degeneration. A key finding in our published rat studies using the same contusion model is that the dual neuromodulation protocol improves motor function. Thus, for both rat and mouse, evidence shows an association between transneuronal degeneration after SCI and neuroprotection with neuromodulation. Determining how augmenting neural activity prevents transneuronal degeneration and modulates the innate immune response can lead to better SCI therapeutic targets.
Recommended Citation
Pathan, Jasmine L., "Harnessing Neural Activity to Prevent Non-Apoptotic Spinal Neurons from Microglial Phagocytosis After Motor System Injury" (2024). CUNY Academic Works.
https://academicworks.cuny.edu/gc_etds/5928