Dissertation
Effects of BDNF and epidural stimulation on locomotor outcomes and spinal RORb interneurons after complete SCI in mouse
Doctor of Philosophy (Ph.D.), Drexel University
Dec 2023
DOI:
https://doi.org/10.17918/00002011
Abstract
Spinal cord injury (SCI) disrupts descending control of spinal circuits below the lesion, often resulting in chronic paralysis and/or hyperreflexia. Lumbar spinal circuits can generate locomotor rhythm and pattern in the absence of descending control and, thus, serve as therapeutic targets. Locomotor rehabilitation after complete SCI relies on excitatory and inhibitory sensory and motor pathways and functional recovery will likely require a multifaceted approach. To identify specific changes associated with functional recovery, we utilized a mouse model of SCI to test the effects of virally-delivered brain derived neurotrophic factor (AAV-BDNF) with and without daily sub-motor threshold epidural stimulation (ES), both of which have been associated with locomotor improvements. AAV-BDNF resulted in significant improvements in hindlimb stepping, but also exacerbated hyperreflexia. BDNF-induced hyperreflexia was reduced during ES, but daily stimulation had no lasting effect on locomotor outcomes. Given their role in gating proprioceptive afferents during locomotion, we hypothesized that inhibitory RORb interneurons were a point of convergence of BDNF and ES actions, and that cellular excitability would be related to locomotor improvements. Whole-cell patch clamp recordings from RORb neurons in lumbar spinal slices revealed that the excitability of inhibitory deep dorsal RORb neurons was decreased in mice with poor locomotor function but similar to control in 'good stepping' groups after SCI. Further, chemogenetic excitation of lumbar RORb neurons reduced BDNF-induced hyperreflexia and improved stepping, mimicking the effects of ES. Taken together, our findings identify inhibitory RORb interneurons a target population to restore locomotor function after complete SCI.
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Details
- Title
- Effects of BDNF and epidural stimulation on locomotor outcomes and spinal RORb interneurons after complete SCI in mouse
- Creators
- Nicholas James Stachowski
- Contributors
- Kimberly J. Dougherty (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 121 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; College of Medicine; Drexel University
- Other Identifier
- 991021819215704721