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Dissertation
Sex-dependent mechanisms underlying cognitive deficits following repeated mild TBI in adolescent rats: the role of the cholinergic system and corticotrophin-releasing factor
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2023
DOI:
https://doi.org/10.17918/00001818
Abstract
Sports-related concussions (SRC, a subset of mild TBI) affect approximately 1.5 million adolescents annually and serve as a leading cause of disability in this population. Post-traumatic deficits in hippocampal-dependent learning and memory are frequently reported long-term impairments; however, an absence of FDA-approved pharmacological treatments highlights the need for continued studies examining the mechanisms underlying these deficits. Current literature on moderate TBI and chronic stress in adult animals demonstrates that alterations in the expression of choline acetyltransferase (ChAT) and corticotrophin-releasing factor (CRF) in the medial septum (MS), respectively, contribute to impairments in hippocampal-dependent memory. Bridging these studies, we hypothesized that CRF acts as a neuromodulator of ChAT expression in the MS wherein increased CRF signaling post-injury would reduce ChAT+ staining, leading to hippocampal-dependent cognitive deficits. Therefore, we developed and characterized a model of SRC in adolescent rats using a repeated mild TBI paradigm and found that male brain-injured animals exhibit early and sustained spatial memory deficits whereas female brain-injured animals show a delayed onset of impairment. Further, we examined alterations in the septo-hippocampal pathway which contains cholinergic neuronal projections from the MS to the dorsal hippocampus and revealed decreased ChAT expression and activity of nicotinic acetylcholine receptors that corresponded directly with the sex-dependent temporal pattern observed in behavioral output. While MS CRF expression remained unchanged following injury, we uncovered sex and time-dependent changes in crfr1 mRNA levels. Pharmacological manipulations using a CRFR1 antagonist injected directly into the MS allowed us to identify sex-specific roles of CRF as a mediator of cognitive output through modulation of ChAT expression in the MS post-injury. Collectively, this study is the first to identify a causal relationship between extrahypothalamic CRF and cognition in the context of mild TBI, offering insight into a novel therapeutic target for cognitive dysfunction following SRC in adolescents.
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Details
- Title
- Sex-dependent mechanisms underlying cognitive deficits following repeated mild TBI in adolescent rats
- Creators
- Taylor A. McCorkle
- Contributors
- Ramesh Raghupathi (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiv, 218 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Neurology; Drexel University
- Other Identifier
- 991021229815404721