Altered dopaminergic function after repetitive closed head injury in adolescent mice

青少年轻度创伤性脑损伤（mTBI）或脑震荡是一个主要的公共卫生问题。主要症状 mTBI导致的症状包括认知能力下降，对于一些患者，还包括获得性注意力缺陷多动 多动症（ADHD）症状。这些缺陷通常在头部受伤时并不存在，而是 诊断为延迟发作，提示由头部创伤引起的进行性功能恶化。 标准诊断技术如MRI和CT通常不显示mTBI脑中的异常， 迫切需要确定与mTBI诱导的缺陷相关的关键神经元因子。一样多 已知认知/注意力缺陷与大脑中异常的多巴胺（DA）传递有关， 表明DA功能改变可能在某些mTBI诱导的异常中起重要作用。TBI- 多巴胺的联系得到了以下证据的支持，即利他林（哌甲酯）或Adderall（d-安非他明），两类 多巴胺转运蛋白阻滞剂，已被报道暂时缓解mTBI相关的认知障碍 和ADHD症状虽然新兴的DA假说开始在TBI研究中受到关注， 目前仍有很少的证据支持脑损伤与DA功能的直接联系，特别是与脑损伤的关系。 纵向跟踪体内DA功能的能力。在本提案中，我们将研究假设： mTBI相关的缺陷与大脑中多巴胺能功能的进行性恶化有关， 生物标志物，其可用于在体内追踪脑损伤程度和脑震荡后的恢复， 纵向。我们建议使用临床相关的青少年重复性啮齿动物模型来验证这一假设。 闭合性脑损伤（RCHI）。我们将使用功能性磁共振成像（fMRI）与d-苯丙胺 探索多巴胺神经支配及其受mTBI影响的下游回路的变化的挑战。我们将 然后使用DA受体激动剂的fMRI评估多巴胺能（D1样和D2样）的特异性变化， rCHI后的受体功能。将D1样/D2样激动剂诱导的fMRI结果与DAR进行比较 关键DA脑区的蛋白质密度（蛋白质印迹）。除了药理学功能磁共振成像，我们将使用休息 状态fMRI探测整个大脑神经元连接的变化，特别强调 多巴胺能回路功能磁共振成像的非侵入性测量将使我们能够评估DA的变化- 在相同的动物纵向相关的功能。成像结果将与认知和 与mTBI小鼠的多巴胺缺乏相关的行为测试。总的来说，成功识别多巴胺能 作为mTBI的生物标志物，可以跟踪脑震荡的恶化影响， 研究脑损伤解决标准，并将提供临床翻译的机会。

Mild traumatic brain injury (mTBI) or concussion in adolescents is a major public health concern. Major symptoms resulting from mTBI include cognitive decline and, for some patients, acquired attention deficit hyperactivity disorder (ADHD)-like symptoms. These deficits often are not present at the time of head injury, but rather are diagnosed with a delayed onset, suggesting of progressive functional deterioration initiated by head trauma. Standard diagnostic techniques such as MRI and CT typically do not reveal abnormality in mTBI brains, leaving a pressing need to identify key neuronal factors associated with deficits induced by mTBI. As many cognitive/attention deficits are known to link to abnormal dopamine (DA) transmission in the brain, it has been suggested that altered DA function may play an important role in certain mTBI-induced abnormalities. The TBI- DA link is supported by the evidence that Ritalin (methylphenidate) or Adderall (d-amphetamine), two classes of dopamine transporter blockers, have been reported to temporarily alleviate mTBI-related cognitive impairment and ADHD-like symptoms. Although the emerging DA hypothesis is starting to gain attention in TBI research, there are still very few evidences to support the direct link of brain injury and DA function, especially with the ability of following DA-functionality in vivo longitudinally. In this proposal, we will investigate the hypothesis: mTBI-related deficits are linked to a progressive deterioration of dopaminergic function in the brain, providing a biomarker that can be used to track degree of brain injury and recovery after concussion in vivo and longitudinally. We propose to test this hypothesis using a clinically relevant rodent model of adolescent repetitive closed head injury (rCHI). We will use functional magnetic resonance imaging (fMRI) with d-amphetamine challenge to probe changes in dopamine innervation and in its downstream circuitries affected by mTBI. We will then use fMRI with DA receptor agonists to assess specific changes in dopaminergic (D1-like and D2-like) receptor function after rCHI. The fMRI results induced by D1-like/D2-like agonists will be compared to DAR protein density in key DA brain areas (western blot). In addition to pharmacological fMRI, we will use resting state fMRI to probe changes in neuronal connectivity throughout the whole brain, with specific emphasis on the dopaminergic circuitry. The non-invasive measurement of fMRI will allow us to assess changes in the DA- relevant functionality in the same animals longitudinally. Imaging results will be cross-checked with cognitive and behavioral tests relevant to dopamine deficits of mTBI mice. Overall, success in identifying dopaminergic function as a biomarker for mTBI that can track deteriorating effects of concussion will help to provide objective criteria for studying brain injury resolution and will offer an opportunity for clinical translation.