Altered dopaminergic function after repetitive closed head injury in adolescent mice

青春期小鼠重复闭合性头部损伤后多巴胺能功能的改变

• 批准号: 9895238
• 负责人: Yin-Ching Iris Chen
• 金额: $ 45.83万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895238
• 关键词: Adderall; Adolescence; Adolescent; Affect; Age; Agonist; Amphetamines; Animals; Anxiety; Area; Attention; Attention deficit hyperactivity disorder; Attentional deficit; Axon; Behavioral; Biological Markers; Birth; Brain; Brain Concussion; Brain Injuries; Brain region; Case Study; Clinical; Closed head injuries; Cognitive; Cognitive deficits; Craniocerebral Trauma; DRD2 gene; Data; Deterioration; Development; Dextroamphetamine; Diagnosis; Diagnostic Procedure; Dopamine; Dopamine Agonists; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Family; Functional Magnetic Resonance Imaging; Functional disorder; Future; Global Change; Health Hazards; Hyperactive behavior; Image; Impaired cognition; Impairment; Injury; Ligands; Link; Magnetic Resonance Imaging; Measurement; Mental Depression; Motor Activity; Mus; Neurodegenerative Disorders; Neurons; Nucleus Accumbens; Pathologic; Patients; Pharmacology; Phenotype; Physiological; Play; Public Health; Quinpirole; Reporting; Research; Resolution; Rest; Ritalin; Rodent Model; Role; Signal Transduction; Symptoms; Synapses; System; Testing; Time; Traumatic Brain Injury; Ventral Tegmental Area; Western Blotting; base; behavior test; blood oxygen level dependent; chronic traumatic encephalopathy; clinical translation; clinically relevant; cognitive testing; density; dopamine transporter; functional status; in vivo; injured; injury recovery; median forebrain bundle; mild traumatic brain injury; mouse model; nerve supply; neurodevelopment; neurotransmission; preservation; prevent; protein expression; receptor; receptor function; response; success; transmission process; young adult

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.

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，对于某些患者来说，还会出现获得性注意力缺陷多动症 障碍（ADHD）样症状。这些缺陷通常在头部受伤时并不存在，而是在头部受伤时出现。 诊断为延迟发病，表明头部外伤引发的进行性功能恶化。 MRI 和 CT 等标准诊断技术通常不会揭示 mTBI 大脑的异常情况，因此 迫切需要确定与 mTBI 引起的缺陷相关的关键神经元因素。一样多 众所周知，认知/注意力缺陷与大脑中多巴胺 (DA) 传输异常有关， 表明 DA 功能的改变可能在某些 mTBI 引起的异常中发挥重要作用。 TBI- 有证据支持 DA 关联，即利他林（哌醋甲酯）或阿得拉（d-安非他明）是两类药物 据报道，多巴胺转运蛋白阻滞剂可暂时缓解 mTBI 相关的认知障碍 和多动症样症状。尽管新兴的 DA 假说开始在 TBI 研究中受到关注， 仍然很少有证据支持脑损伤和 DA 功能之间的直接联系，尤其是与 体内纵向跟踪 DA 功能的能力。在本提案中，我们将研究以下假设： mTBI 相关缺陷与大脑中多巴胺能功能的逐渐恶化有关，从而提供了 可用于跟踪体内脑震荡后脑损伤程度和恢复情况的生物标记物 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检验这一假设 闭合性头部损伤（rCHI）。我们将使用功能性磁共振成像 (fMRI) 和 d-苯丙胺 探索受 mTBI 影响的多巴胺神经支配及其下游回路的变化的挑战。我们将 然后使用功能磁共振成像和 DA 受体激动剂来评估多巴胺能（D1 样和 D2 样）的具体变化 rCHI 后受体功能。 D1 样/D2 样激动剂诱导的 fMRI 结果将与 DAR 进行比较 关键 DA 大脑区域的蛋白质密度（蛋白质印迹）。除了药理学功能磁共振成像之外，我们还将使用静息 状态功能磁共振成像来探测整个大脑神经元连接的变化，特别强调 多巴胺能电路。 fMRI 的非侵入性测量将使我们能够评估 DA 的变化 同一动物的相关功能纵向。影像结果将与认知和认知进行交叉检查 与 mTBI 小鼠多巴胺缺乏相关的行为测试。总体而言，成功识别多巴胺能 作为 mTBI 的生物标志物，可以追踪脑震荡恶化的影响，这将有助于提供客观的结果 研究脑损伤解决的标准并将提供临床转化的机会。