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

项目总结/摘要 有一个迫切需要的特点接触运动暴露的长期影响，有和没有事先 脑震荡，并确定可能导致这些影响的潜在分子机制。的不平衡 由神经活性犬尿氨酸途径代谢物引起的多巴胺能活性是一种这样的机制， 边缘系统结构和功能异常的各种疾病。本提案的目的是 为了阐明神经活性犬尿氨酸途径代谢物与慢性异常之间的关系， 与接触性运动中反复脑震荡和头部撞击暴露相关的边缘系统 参与的中心假设是，先前的脑震荡和/或接触运动导致结构性 以及以头端前扣带皮层和海马为中心的边缘系统的功能改变 导致亚临床情绪失调，这些变化是由神经毒性犬尿氨酸驱动的 通过血液中的浓度反映的大脑中的代谢途径。男性和女性成年人（18- 26)将分三组入组，包括（1）既往脑震荡的接触性运动员，（2）接触性运动员， 运动员没有先前的脑震荡，和（3）非接触性运动员，以分离接触的影响 运动暴露有无脑震荡一种先进的神经成像电池，临床电池， 将在单次访视中采集血液样本，以实现以下目的：（目的1）检验假设 脑震荡和接触性运动暴露与边缘系统的结构差异有关， 与神经活性KP代谢物相关，（目的2）检验脑震荡和接触性运动 暴露与边缘系统功能连接和行为的差异相关， 神经活性KP代谢物我们希望这项工作将描绘神经活性KP的潜在作用， 脑震荡和接触性运动暴露的神经生物行为后遗症中的代谢物， 运动员目前正在参加体育运动。这一信息具有重大的公共卫生意义，因为 它将刺激双向转化研究，最终导致发展 药物治疗，以防止或逆转这些影响在风险接触运动员。这个假设- 驱动的建议是科学创新，因为它将研究长期影响之间的关系， 脑震荡/头部撞击暴露和一种与边缘系统失调有关的分子途径， 平行神经科学研究 !

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. !