Chronic cortical inflammation and cognitive impairment associated with diffuse brain injury is ameliorated by forced turnover of microglia

Booklet CBI RESEARCH DAY 2021 1. Chronic cortical inflammation and cognitive impairment associated with diffuse brain injury is ameliorated by forced turnover of microglia Chelsea E. Bray, Kristina G. Witcher, Dunni Adelkunle-Adegbite, Michelle Ouvina, Mollie Witzel, Fangli Zhao, Titikorn Chunchai, Emma Hans, Julia E. Dziabis, Zoe M. Tapp, Olga N. Kokiko-Cochran, Candice Askwith, and Jonathan P. Godbout Presenting Author: Chelsea Bray –Research Staff, Department of Neuroscience Traumatic brain injury (TBI) is associated with cognitive, psychiatric, and neurodegenerative complications that may develop years after injury. Increased microglial reactivity following TBI may set the stage for chronic neuroinflammation, neuropathology and exaggerated responses to secondary immune challenges. Therefore, the goal of this study was to force the turnover of microglia sub acutely post-injury and determine if microglial reactivity was reversed 30dpi. Here, mice were injured by midline fluid percussion injury and 7 d later were subjected to a forced turnover paradigm using the CSFR1 antagonist, PLX5622. At 30 dpi, cortical gene expression was determined using Nano String’s Neuropathology panel (760 genes). Myriad neuropathology-related genes were increased 30 dpi in the cortex, and these genes were reversed by forced microglia turnover. In terms of neuroplasticity, reduced neuronal connectivity (N1 and N2 compound action potentials) was evident 30dpi and these deficits were attenuated by microglia turnover. Dendritic remodeling in the cortex, however, remained 30 dpi and was independent of microglia turnover. Assessment of functional recovery showed depressive-like behavior and cognitive impairment 30 dpi, which were ameliorated by microglia turnover. A secondary immune challenge elicited by peripheral LPS challenge 30 d after TBI caused amplified neuroinflammation and prolonged sickness behavior. We provide novel evidence that microglia repopulation after TBI alleviates prolonged sickness behaviors associated with microglial priming. Together, these data suggest microglia are a potential therapeutic target to treat persistent neuroinflammation and improve functional impairments sustained by TBI. DATA BLITZ CBI RESEARCH DAY 2021 2. DHA prevents diet-induced memory impairments in aged rats and microglial inflammatory gene expression. Michael J. Butler, Nashali Massa, & Ruth M. Barrientos. Institute for Behavioral Medicine Research, Ohio State Wexner Medical Center, Columbus, OH. Postdoctoral Researcher It is known that diets high in refined carbohydrates can lead to impairments in brain aging and cognitive performance, but the underlying mechanisms of these impairments are not well understood. Our lab has previously demonstrated that aging is associated with a decrease in the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) in the brain. DHA is involved in many beneficial functions in the brain including neuronal signaling, altering membrane structure and function, lipid mediator production, and regulating immune cells to resolve inflammation. Thus, this age-dependent decrease in DHA may contribute to the refined diet-induced memory impairment. Here, we studied the impact of a refined-ingredients diet with and without DHA on learning and memory in aged rats. In addition, we examined the impact of DHA on microglia-mediated inflammation in vitro. Our data indicate that consuming a diet high in refined ingredients for one month led to memory impairments in aged, but not young rats, relative to control rat fed the standard chow diet. In contrast, the same processed diet supplemented with DHA produced no changes in memory in either young or aged rats, suggesting that DHA may mitigate the impact of diet-induced memory deficits in aged rats. It is important to note that in addition to reduced complex carbohydrates and fiber, processed foods are also often high in saturated fatty acids, (SFAs) such as palmitic acid (PA). In vitro, BV2 microglial cells treated with PA exhibited increased inflammatory and mitochondrial stress gene expression relative to vehicle-treated cells. Furthermore, DHA pretreatment prevented these SFAinduced responses. Together, these data suggest that DHA can prevent diet-induced behavioral and cellular changes elicited by processed ingredients and SFAs, respectively. SPOTLIGHT CBI RESEARCH DAY 2021 3. Resilience through a new lens: Leveraging photo elicitation methods to define resilience among adults with TBI and opioid use disorder Kathryn A. Coxe, MSW; Erica K. Pence, MSW Audrey Begun, PhD, MSW Affiliation: College of Social Work, The Ohio State University, 1947 College Road, Columbus, OH 43210Corresponding Author: Kathryn Coxe (PhD Candidate) Background: Traumatic brain injury (TBI) and opioid use disorder (OUD) are debilitating conditions presenting unique challenges for adults with these comorbidities. Although deficits associated with TBI and OUD are often focal to rehabilitation and recovery, treatment paradigms are shifting to strength-based models that emphasize resilience. Centering resilience around outcomes rather than fixed traits may illuminate modifiable factors in the recovery process. However, resilience outcomes are poorly researched and difficult to ascertain through quantitative metrics due to memory and communication problems post-injury. Visual methods are a powerful mechanism to engage adults in research to establish a deeper understanding of resilient outcomes from the individual’s perspective. Objective: This study aimed to investigate resilience outcomes among adults with co-occurring TBI and OUD, and to identify risk factors contributing to continued vulnerability. Methods: Using qualitative phenomenology, participants were purposively recruited through an urban, hospital outpatient program that specializes in TBI and substance misuse treatment for adults. Participants were included who had lifetime history of TBI identified through the Ohio State University TBI Identification method, DSM-5 diagnosed OUD, and Orientation Log score≥25.Photographs, descriptive text messages, and semi-structured interviews were collected between December 2019 and March 2020 using photo elicitation methodology. Data were co-coded and analyzed using document analysis. Themes were developed according to tenets of Resilience Theory. Results: A total of N =126photographs,47 text messages, and four interview transcripts were included for analysis. Resilience was demonstrated through psychological flexibility, use of existing resources, and compensatory strategies to overcome stressors. Specifically, participants reported:1) commitment to cognitive, physical, and emotional growth; 2) the ability reframe negative experiences associated with the injury, opioid use, pain, and daily stressors into a positive appraisal of the circumstances; 3) social support from family, friends, and peer supporters; and 4) healthy coping skills and feelings of empowerment through physical activity, technology use, and the arts. Participants unanimously documented chronic pain as a major barrier to daily functioning. Participants also reported that lack of transportation and difficulty navigating urban city transportation systems were primary barriers to accessing available health services. Yet, while supportive services specific to TBI and OUD were desired, participants described these as largely unavailable. Conclusion: This study is a first step toward a better understanding of resilience outcomes among adults with comorbid TBI and OUD. Results can inform the development of future strengths-based interventions in TBI and OUD care that promote resilient outcomes post-injury. DATA BLITZ CBI RESEARCH DAY 2021 4. Post-surgical morphine prolongs hippocampal dysfunction in aged rats: Implications for neuroinflammation and neuronal structure Nicholas P. Deems (1,2), Stephanie M. Muscat (1,3), Heather D’Angelo (4), Meagan M. Kitt (4), Peter M. Grace (5), Nathan D. Andersen (4), Shaelyn N. Silverman (4), Kenner C. Rice (6), Linda R. Watkins (4), Steven F. Maier (4),Ruth M. Barrientos (1, 7, 8, 9) Post-operative cognitive dysfunction (POCD) is a constellation of impaired cognitive symptoms that can occur following surgery, most typically in elderly individuals. Cognitive impairment can last days to months with more persistent durations associated with greater susceptibility to mortality and dementia. Mechanisms driving susceptibility for persistent POCD are not well understood. Preclinical models have only recapitulated shorterdurations of post-surgical memory impairments and these models overlook the common use of post-operative opioids. Here we report that treatment with post-surgical morphine robustly impairs hippocampal function for at least eight-weeks in aged rats that underwent an exploratory abdominal surgery (i.e., laparotomy). Short-term memory remained intact, suggesting that these three factors (age, surgery, and morphine) combine to compromise memory processes critical for long-term memory formation. Furthermore, we provide evidence that this is driven through a neuroinflammatory mechanism independent of the opioid receptor. It is well known that excessive neuroinflammation in brain regions such as the hippocampus can have deleterious consequences on neuronal structure & function which can ultimately undermine learning, memory, and cognition. In support of this, we found gene expression of synaptophysin and PSD95, two markers found in pre-and postsynaptic structures, respectively, to be significantly dysregulated in the hippocampus of aged, laparotomized, morphine-treated rats. Moreover, preliminary histological data suggests that dendritic spine density may also be altered in these animals. These data tentatively suggest that aging, surgery, and morphine may compromise neuronal structure and play a role in this persistent memory deficit. Altogether, this rat model of POCD closely mirrors the timeline of pers