A multimodal investigation of positive and negative modulators of the medial temporal hippocampal system

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PROJECT SUMMARY/ABSTRACT The United States is grappling with racism as an ongoing public health crisis. A salient socioenvironmental chronic stressor in the lives of Black Americans, racism is associated with negative mental and physical health outcomes. The integrity of the medial temporal hippocampal (MTH) system is modifiable by extrinsic experiential factors, which can also increase its vulnerability. Opposite modulators of this system include cardiorespiratory fitness and chronic stress, which are differentially associated with pattern separation, a neurocomputational pro- cess reliant on the hippocampus that is vital for disambiguating highly similar stimuli during memory encoding. Our lab has shown that increased cardiorespiratory fitness positively impacts the MTH system in both young and older adults. In contrast, animal models and human neuroimaging studies of socioenvironmental chronic stress have shown extensive structural and functional reorganization of this system. The hippocampal long-axis also shows affective (anterior) and cognitive (posterior) differentiation, suggesting a neural substrate perturbed in mood disorders and by chronic stress. There is evidence of MTH neurocognitive deficits in young adulthood related to acute stress and mood disorders, but this has not been investigated as a consequence of chronic stress. The negative impact of racism may explain disparities in the severity and chronicity of mood disorders in Black Americans. In Aim 1, we demonstrate that 1) greater cardiorespiratory fitness predicts increased MTH cortical thickness in young but not older adults and 2) greater perceived discrimination predicts reduced MTH volume in a diverse group of older adults. In Aim 2 we hypothesize that greater perceived racism will be associ- ated with MTH neurocognitive deficits in Black young adults. Technical training will focus on gaining expertise in task-based high-resolution fMRI and advanced multivariate statistical modeling of behavioral and fMRI data. Thus, in relation to greater perceived racism, we seek to behaviorally examine associations with spatial and non- spatial pattern separation performance. Next, we will conduct advanced multivariate statistical modeling to quan- tify whether greater perceived racism modulates fMRI activity associated with a NIMH Research Domain Criteria correlate of hippocampal function, the Mnemonic Similarity Task. Finally, in Aim 3 we propose to identify a post- doctoral mentor with expertise in mood disorders, chronic stress, and/or neuroinflammation who can train me in experimental design and data analysis using modalities such as Positron Emission Tomography to investigate neuroinflammation, due to its well-established link to stressors.The broad, long term goal is to build brain health equity research capacity, identifying modifiable or mitigating factors of chronic stress due to intersecting margin- alized identities. Finally, this proposal seeks to address the BRAIN Initiative’s Scientific Review and High Priority Research Area for using multimodal methods to investigate the human brain in relation to behavioral and cogni- tive outcomes, answers a recent call by the NIMH to investigate socioenvironmental stressors and mitigating factors, and a push by the NIH to investigate how social determinants of health impact healthy living.