The role of neuroactive kynurenine metabolites in the chronic sequelae of concussion and contact sport exposure

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Project Summary/Abstract There is an urgent need to characterize the long-term effects of contact sport exposure with and without prior concussion, and to identify potential molecular mechanisms that may underlie these effects. An imbalance in glutamatergic activity caused by neuroactive kynurenine pathway metabolites is one such mechanism behind abnormalities of limbic system structure and function in a variety of disorders. The objective of this proposal is to elucidate the relationship between neuroactive kynurenine pathway metabolites and chronic abnormalities in the limbic system associated with repetitive concussion and head impact exposure from contact sport participation. The central hypothesis is that prior concussion and/or exposure to contact sport lead to structural and functional alterations in a limbic system centered on the rostral anterior cingulate cortex and hippocampus resulting in sub-clinical mood-dysregulation, and that these changes are driven by neurotoxic kynurenine pathway metabolites in the brain that are reflected by concentrations in blood. Male and female adults (age 18- 26) will be enrolled across three groups, including (1) contact sport athletes with a prior concussion, (2) contact sport athletes with no prior concussion, and (3) non-contact sport athletes to separate the effects of contact sport exposure with and without previous concussion. An advanced neuroimaging battery, a clinical battery, and blood specimen will be collected in a single visit to address the following aims: (Aim 1) Test the hypothesis that concussion and contact sport exposure are associated with structural differences in the limbic system that correlate with neuroactive KP metabolites, and (Aim 2) Test the hypothesis that concussion and contact sport exposure are associated with differences in limbic system functional connectivity and behavior that correlate with neuroactive KP metabolites. We expect that this work will delineate the potential role of neuroactive KP metabolites in the neurobiobehavioral sequelae of concussion and contact sport exposure for the millions of athletes currently participating in contact sport. This information is of major public health significance because it will stimulate bidirectional translational research that will ultimately lead to the development of pharmaceutical treatments to prevent or reverse these effects in at-risk contact sport athletes. This hypothesis- driven proposal is scientifically innovative because it will study the relationship between the long-term effects of concussion/head impact exposure and one molecular pathway implicated in limbic system dysregulation in parallel neuroscience research. !