Alyssa F. Pybus

BioE PhD Defense Presentation

Date and Time: Thursday, April 20th, 2023, at 1:00 PM

Location: Pettit Building (Microelectronics Research Center) 102B

Zoom Link: https://gatech.zoom.us/j/97975985202

Advisor:

Levi Wood, PhD (Georgia Institute of Technology)

Committee:

Erin Buckley, PhD (Georgia Institute of Technology)

Michelle LaPlaca, PhD (Georgia Institute of Technology)

Manu Platt, PhD (Georgia Institute of Technology, NIH NIBIB)

Srikant Rangaraju, MD MS (Emory University) 

Profiling the Neuroimmune Cascade after Repetitive Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) is responsible for about 2 million emergency department visits and an estimated cost burden of $17 billion in the United States every year. Moreover, repeated mTBI (rmTBI) can result in cumulative effects and worse clinical outcomes than a single injury. Despite its prevalence and cost, current treatment for mTBI is severely lacking and targets symptoms rather than drivers of adverse clinical outcomes. Research into new therapeutic strategies for the treatment of mTBI patients is constrained by our limited understanding of the biological mechanisms behind how brain injury impacts outcomes, such as cognitive deficit and neurodegenerative pathology similar to that seen in Alzheimer’s disease (AD). Recent studies unveil new evidence that neuroimmune signaling may be a key driver of long-term outcome after single or repeated mTBI, but there remains an urgent need to identify the specific cellular and molecular pathways involved to assess their potential for targeting in new therapeutic intervention strategies. The work of this dissertation seeks to comprehensively define the neuroimmune response to single and repeated mTBI alongside cognitive and pathological outcome measures to improve our understanding of brain injury and propose potential targets for therapeutic intervention. 

The present work uses in vivo murine models of rmTBI to determine the acute effects of injury on neuroimmune signaling in correlation to biomarkers of cognitive and pathological outcome. Our findings in wild type mice suggest that elevated neuroimmune signaling is strongly linked to cognitive outcome (Aim 1). Next, we used transgenic mice capable of displaying human-like pathology to relate neuroimmune signaling to pathological outcomes (Aim 2). We identified specific cytokines elevated after injury in correlation to markers of AD-like pathology, suggesting involvement with brain injury-induced pathogenesis and potential for use as diagnostic or prognostic clinical biomarkers. Interestingly, we found that cytokines correlated to outcome in both aims were primarily localized to neurons, suggesting a previously unappreciated role of immune regulation by neurons. Lastly, transcriptional profiling revealed rapid neuronal dysfunction within 24 hours after injury followed by changes in astrocyte- and microglia-related gene expression within days.  Collectively, our data suggest rapid changes in specific neuronal pathways involved in immune signaling after injury, followed by changes in other cell types. These findings support the need for future work to assess the efficacy of therapeutic targeting of neuroimmune signaling to improve outcomes after single and repeated mTBI.