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Functional and Transcriptomic Dynamics Governing Serotonergic Dysregulation in Mild Traumatic Brain Injury

O''Connell, Christopher
http://rave.ohiolink.edu/etdc/view?acc_num=ucin171291269500856

Abstract Details

2024, PhD, University of Cincinnati, Pharmacy: Pharmaceutical Sciences.
Traumatic Brain Injury (TBI) is a primary cause of disability and death within the United States of America. In the clinic, TBI presents as extraordinarily heterogenous pathologies given that brain injuries may be induced by a plethora of diverse and deleterious environmental interactions including but not limited to penetrating head injuries, acceleration-deceleration inertial forces acting upon the parenchyma of the brain, and exposure to blast waves. In civilian populations, it is thought that the reporting of TBIs, particularly mild TBIs (mTBI) or concussions, is significantly lower than the true prevalence in the population at large. Although the pathologies associated with each TBI are often distinct between cases and vary between individuals, sustaining a TBI significantly and unilaterally increases the risk for developing chronic emotional, social, and psychological complications regardless of injury modality which represents a critical factor in determining quality of life for those afflicted. The prevalence of psychosocial abnormalities includes an increased risk for developing major depressive disorder (MDD), anxiety disorders like generalized anxiety disorder (GAD) and panic disorders, as well as post-traumatic stress disorder (PTSD) is greatly increased in individuals who have sustained neurotrauma. Decades of research have linked the monoamine neurotransmitter serotonin (5HT) and the central serotonin system to the development and maintenance of mood, memory, and perception and have localized the nexus of serotonergic signaling to a midbrain structure called the raphe nucleus (RN). While the United States Food and Drug Administration (FDA) -approved pharmacotherapies for the treatment of disorders like anxiety and depression, selective serotonin reuptake inhibitors (SSRIs), are moderately efficacious in attenuating non-injury elicited psychopathologies, the application of these drugs in the context of TBI does not significantly improve patient outcomes or minimize injury sequelae The effects of TBI on central nervous system function reported in the clinic have been recapitulated utilizing various preclinical models for TBI in laboratory settings, yet the changes of the molecular substrate underlying disruptions in perception, mood, and social function following neurotrauma have yet to be experimentally resolved. Using a murine model for multimodal mTBI, we demonstrate that neurotrauma significantly alters the processing of serotonin in the dorsal raphe nucleus (DRN) at a chronic timepoint, driving significantly increased serotonin abundance in the midbrain. We also show that mTBI elicits reductions in the serotonin transporter (SERT) protein expression and uptake capacity in a region- and time-specific manner. We report that mTBI induces significant changes in transcriptional regulation of genes required for serotonin synthesis and serotonergic neuron identity in the DRN 10-days following injury induction. Finally, we identify the neuron restrictive silencer factor, Rest, as a novel mechanism-derived target for therapeutic development to attenuate TBI-elicited neuropsychiatric sequelae. Combined these studies identify protracted changes in the central serotonin system following mTBI, experimentally resolve the mechanisms governing the functional and transcriptional disturbance within the DRN and identify a novel target for therapeutic development. We believe the therapeutic target depicted in these studies comprises a novel direction for drug discovery in the context of traumatic brain injury and injury-elicited neuropsychiatric complications.
Matthew Robson, Ph.D. (Committee Chair)
Gary Gudelsky, Ph.D. (Committee Member)
Jason Gardner (Committee Member)
Nathan Evanson, M.D. Ph (Committee Member)
Timothy Phoenix, Ph.D. (Committee Member)
215 p.
Pharmaceuticals
Traumatic Brain Injury; Serotonin; RNA-sequencing; Transcriptomic Remodeling; Metabolism; Midbrain

Recommended Citations

Citations

  • O''Connell, C. (2024). Functional and Transcriptomic Dynamics Governing Serotonergic Dysregulation in Mild Traumatic Brain Injury [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin171291269500856

    APA Style (7th edition)

  • O''Connell, Christopher. Functional and Transcriptomic Dynamics Governing Serotonergic Dysregulation in Mild Traumatic Brain Injury. 2024. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin171291269500856.

    MLA Style (8th edition)

  • O''Connell, Christopher. "Functional and Transcriptomic Dynamics Governing Serotonergic Dysregulation in Mild Traumatic Brain Injury." Doctoral dissertation, University of Cincinnati, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=ucin171291269500856

    Chicago Manual of Style (17th edition)

ucin171291269500856
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© 2024, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.