Center for Integrative Neuroscience

PROJECT SUMMARY (supplement) The long-term goal of this project is to understand the mechanisms underlying the pathogenesis and neural symptoms of long-COVID/PASC, including cognitive impairments, fatigue, and loss of smell. Distinct mechanisms may be at play due to multiple potentially overlapping causes of long-COVID. There is thus an urgent need to merge diverse perspectives and approaches to study long-COVID's pathogenesis and neural symptoms. The short-term goal of this pilot study is to establish a research framework and strengthen a collaboration of investigators with diverse backgrounds and skill sets to mount a truly multidisciplinary proposal to understand the neuropathology of long-COVID. Toward this goal, aim 1 of this project will leverage the C. elegans model organism to understand the role of the inflammatory kynurenine pathway (KP) and its neuroactive metabolites in viral infection-induced sleepiness/fatigue. Aim 2 will use the Drosophila olfactory sensory neurons as a model to study the molecular interactions between the Covid-ACE2 (viral) and insulin (diabetic) pathways and their relationship to smell loss. Aim 3 will use human patients diagnosed with long-COVID to assess changes in brain network topology. Aim 4 will use human specimens to investigate serum protein biomarkers by performing longitudinal analysis of specific inflammatory biomarkers (e.g., cytokines, kynurenine, etc.) early following COVID-19 infection and in those that develop long-COVID. The results will shed light on candidate inflammatory biomarkers such as cytokines, kynurenine, and changes in brain connectivity in patients with long- COVID symptoms. They could lead to a more accurate diagnosis and prognosis of long-COVID. Finally, the results will help us reinforce this unique collaboration and optimize future directions to study long-COVID mechanisms. Our proposal synergizes well with the broader goals of the Integrative Neuroscience COBRE at UNR, which aims to synergize and elevate neuroscience research capacity at UNR and across Nevada. First, this unique multidisciplinary collaboration fulfills the central goal of the COBRE to cross-fertilize research units that have already developed expertise in cognitive and cellular neuroscience. Second, by extensively using core facilities, such as the Neuroimaging, and Cellular and Molecular Imaging cores, the project takes advantage of the modern infrastructure established at UNR and Renown Medical Center by COBRE Phases I and II to mount impactful research in neuroscience. Third, our extensive use of computational analytics and the incorporation of artificial intelligence in our data analysis plans align with the future vision of Phase III of COBRE, which is to expand data analytics service to include AI and deep learning facilities. Lastly, this project combines diverse approaches and perspectives to tackle important questions about neurological long-COVID, which will lead to unique collaborative research and training opportunities in the future, further advancing COBRE's goals to build research capacity at UNR and new funding opportunities in neuroscience.