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FINAL FINAL DISSERTATION PECHACEK.pdf (4.91 MB)

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Neuroinflammatory contributions to psychiatric dysfunction in brain injury

Pechacek, Kristen Marie
http://rave.ohiolink.edu/etdc/view?acc_num=osu1692565783282203

Abstract Details

2023, Doctor of Philosophy, Ohio State University, Neuroscience Graduate Studies Program.
Traumatic brain injury (TBI) is damage to the brain that is caused by an external force. As a leading cause of disabilities worldwide, TBIs can lead to long-term symptoms such as physical, cognitive, and psychological symptoms, including headaches, photosensitivity, seizures, attentional impairment, memory problems, impulsivity, increased anxiety, depression, and substance use disorders. Nearly 40% of TBI patients report two or more psychiatric symptoms after injury. Despite the high proportion of individuals that report psychiatric symptoms after TBI, there are no FDA-approved treatments for such impairments. Additionally, the mechanisms behind the development of psychiatric symptoms are poorly understood, but chronic neuroinflammation is believed to play an important role. Following injury, microglia propagate a chronic neuroinflammatory response that lasts years after the initial event and is linked to increases in psychiatric conditions. This work aimed to better understand the relationship between neuroinflammation and the development of psychiatric symptoms of lack of motivation, impulsivity, and inattention. First, it was examined if lipopolysaccharide (LPS) could model the chronic depressive-like symptoms (lack of motivation) of TBI to establish that long-term neuroinflammation leads to psychiatric symptoms. Motivation was measured with an operant task, the progressive ratio, which works by progressively increasing the effort required to earn a single reinforcer. A 14-day continuous LPS exposure (5 mg/kg/week) subcutaneously did not induce motivational deficits. LPS infused directly into the lateral ventricles (10.5 ug/kg/week) for 14 days caused a significant drop in motivation. However, this decrease in motivation did not mimic the effects of post-TBI depressive-like motivational impairments. Collectively demonstrating that chronic LPS cannot be used as a model for post-TBI depressive-like phenotypes. The next study focused on finding a treatment for chronic impulsivity and inattention after TBI. Here, a bilateral frontal controlled cortical impact (CCI) injury induced a moderate-to-severe TBI. The five-choice serial reaction time task (5CSRT), an operant task that pits the need to respond quickly against and the need to inhibit responding, measured impulsivity and attention. Minocycline, a drug with anti-inflammatory properties, was administered (45 mg/kg) at either an early (1 h post-injury) or late (9 weeks post-injury) timepoint to determine if it could either prevent or attenuate post-TBI impulsivity and inattention. TBI-induced chronic impulsive and attention deficits. Minocycline failed to treat post-injury impulsivity and inattention at the early or late time point. Concluding that minocycline is not an effective treatment for TBI-induced psychiatric impairments. The final study examined the inflammatory response and gene expression profile to bilateral frontal CCI and determined the role of forced microglia turnover on post-TBI impulsivity and attentional impairments. As with the previous study, injuries were induced with a bilateral frontal CCI and impulsivity and attention measured with the 5CSRT. An inflammatory gene panel examination of the frontal cortex at 7- and 14-days post-injury (DPI) revealed a significant increase in inflammatory gene expression at both 7 and 14 DPI. Next, gene expression in the nucleus accumbens was examined via single-nucleus RNA sequencing at 14 DPI. This revealed significant changes to cell-signaling and plasticity-related gene expression in the TBI rats. Finally, forced microglia turnover, induced with BLZ945, started at 13 DPI. Forced microglia turnover did not decrease TBI-induced impulsivity or inattention. Collectively, these studies revealed that the CCI is a great model for inducing chronic psychiatric-like symptoms after TBI. The 5CSRT accurately measured long-term impulsivity and inattentive deficits of TBI. Finally, based on the lack of effects of minocycline and forced microglia turnover, it appears that microglia-targeted anti-inflammatory treatments are not sufficient to overcome post-TBI impulsivity and inattention.
Cole Vonder Haar (Committee Chair)
Jonathan Godbout (Committee Member)
Olga Kokiko-Cochran (Committee Member)
Kathryn Lenz (Committee Member)
203 p.
Neurosciences
Traumatic brain injury, microglia, neuroinflammation, impulsivity, attention, motivation, progressive ratio, 5-choice serial reaction time task, behavioral neuroscience

Recommended Citations

Citations

  • Pechacek, K. M. (2023). Neuroinflammatory contributions to psychiatric dysfunction in brain injury [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1692565783282203

    APA Style (7th edition)

  • Pechacek, Kristen. Neuroinflammatory contributions to psychiatric dysfunction in brain injury. 2023. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1692565783282203.

    MLA Style (8th edition)

  • Pechacek, Kristen. "Neuroinflammatory contributions to psychiatric dysfunction in brain injury." Doctoral dissertation, Ohio State University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=osu1692565783282203

    Chicago Manual of Style (17th edition)

osu1692565783282203
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This open access ETD is published by The Ohio State University and OhioLINK.