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Dissertation
Neuroinflammation and circuitry changes in the dorsal raphe nucleus with depressive phenotype after spinal cord injury
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2019
DOI:
https://doi.org/10.17918/38qf-xy81
Abstract
Major Depressive Disorder (MDD) is attributed to an imbalance of the serotonin system that includes neurons of the dorsal raphe nucleus (DRN) involved in modulation of affective features such as attention, working memory and emotional control. In addition to motor, sensory, and autonomic dysfunction, patients with spinal cord injury (SCI) are at three-times the risk for MDD compared to the general population. Inflammation is implicated in MDD pathology as elevated levels of pro-inflammatory cytokines (TNF[alpha] and Il-6) frequently are detected in the serum of MDD patients and intracerebral adminstration of TNF[alpha] can elicit depressive-like behaviors in rodents. In a rat model of thoracic-contusion injury we correlated elevated DRN levels of TNF[alpha] with depressive phenotype at 5 weeks post-SCI. Chronic peripheral inhibition of soluble TNF[alpha] by administration of XPro1595 (a dominant-negative inhibitor) resulted in increase in the incidence of depression, yet central intracerebroventricular (i.c.v.) administration had no effect on incidence. These results suggest that modulation of additional components of neuroinflammation may be necessary to offset depressive phenotype after SCI. Whole cell patch clamp electrophysiology revealed an increase in excitability of DRN serotonergic neurons of post-SCI non-depressed vs. depressed mice, based on intrinsic membrane properties. No significant alterations in excitatory/inhibitory input to GABAergic or serotonergic neurons were found, though both cell types demonstrated an increase in action potential bursting after depolarizing current injection, suggesting a potential role for ion channel dysregulation in multiple neuronal types with post-SCI depression. Our findings suggest that intrinsic neuronal changes in excitability may contribute to decreased serotonergic output and the subsequent development of SCI-depression, providing beneficial insight in identifying future therapeutic targets.
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Details
- Title
- Neuroinflammation and circuitry changes in the dorsal raphe nucleus with depressive phenotype after spinal cord injury
- Creators
- Kaitlin Farrell - DU
- Contributors
- John D. Houle (Advisor) - Drexel University (1970-)Wen-jun Gao (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- ix, 130 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Neurology; Drexel University
- Other Identifier
- 9364; 991014632257104721