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.

青少年的轻度创伤性脑损伤（MTBI）或脑震荡是一个主要的公共卫生问题。主要症状 由MTBI导致的包括认知能力下降，对于某些患者而言，注意力不足多动症 疾病（ADHD）类似症状。这些缺陷通常在头部受伤时不存在，而是 诊断出发作延迟，表明由头部创伤引发的进行性功能恶化。 标准诊断技术（例如MRI和CT）通常不会揭示MTBI大脑中的异常，离开 迫切需要确定与MTBI诱发的缺陷相关的关键神经元因素。就像许多 已知认知/注意力缺陷与大脑中异常多巴胺（DA）的传播有关 建议改变DA功能可能在某些MTBI诱导的异常中起重要作用。 tbi- DA连接得到了证据支持Ritalin（哌醋甲酯）或Adderall（D-苯丙胺），两类 据报道，多巴胺转运蛋白阻滞剂暂时减轻与MTBI相关的认知障碍 和类似ADHD的症状。尽管新兴的DA假设开始在TBI研究中引起关注，但 仍然很少有证据支持脑损伤和DA功能的直接联系，尤其是在 在纵向体内遵循DA功能的能力。在此提案中，我们将研究以下假设： 与MTBI相关的缺陷与大脑多巴胺能功能的进行性恶化有关，从而提供了 可用于跟踪体内脑震荡后脑损伤和康复程度的生物标志物 纵向。我们建议使用青少年重复的临床相关啮齿动物模型来检验这一假设 闭合头部受伤（RCHI）。我们将与D-苯丙胺一起使用功能性磁共振成像（fMRI） 探测多巴胺神经及其受MTBI影响的下游电路的探针变化的挑战。我们将 然后使用fMRI与DA受体激动剂一起评估多巴胺能的特定变化（D1样和D2样） RCHI后的受体功能。 D1样/D2样激动剂引起的fMRI结果将与DAR进行比较 关键DA脑区域中的蛋白质密度（蛋白质印迹）。除了药理功能磁共振成前，我们还将使用休息 状态fMRI探测整个大脑神经元连接性的变化，并特别强调 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。成像结果将与认知和 与MTBI小鼠多巴胺缺陷有关的行为测试。总体而言，成功识别多巴胺能 作为MTBI的生物标志物，可以跟踪脑震荡的恶化影响将有助于提供目标 研究脑损伤解决方案的标准，并将为临床翻译提供机会。