Molecular and neural mechanisms associated with injury and recovery from traumatic brain injury

与创伤性脑损伤的损伤和恢复相关的分子和神经机制

• 批准号: 10693653
• 负责人: Miranda Francoeur Koloski
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693653
• 关键词: Acute; Address; Afghanistan; Animal Model; Animals; Anxiety; Area; Attentional deficit; Automobile Driving; Axon; Behavior; Behavioral; Behavioral inhibition; Bilateral; Biological; Biological Markers; Brain; Brain Concussion; Brain Injuries; Brain region; Central Nervous System; Chronic; Clinical Research; Cognition; Cognitive; Cognitive deficits; Cognitive remediation; Communication; Contusions; Corpus striatum structure; Coupling; Decision Making; Discrimination; Effectiveness; Electric Stimulation; Encephalitis; Frequencies; Goals; Hemorrhage; Human; Impairment; Impulsivity; Inflammation; Inflammatory; Injury; Interruption; Intervention; Iraq; Knowledge; Lateral; Learning; Location; Measures; Mediating; Mental Depression; Mental disorders; Methods; Military Personnel; Mission; Modeling; Molecular; Mood Disorders; Moods; Neurobehavioral Manifestations; Neuronal Plasticity; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Pattern; Periodicals; Periodicity; Persons; Pre-Clinical Model; Preclinical Testing; Prefrontal Cortex; Procedures; Psychological reinforcement; Rattus; Reproducibility; Research; Reversal Learning; Rewards; Risk; Rodent; Rodent Model; Role; Running; Severities; Soldier; Structure; Symptoms; Techniques; Testing; Therapeutic Intervention; Training; Trauma; Traumatic Brain Injury; Traumatic Brain Injury recovery; United States; Update; Veterans; associated symptom; behavioral impairment; brain based; clinically relevant; cognitive function; cohort; controlled cortical impact; cranium; disabling symptom; effectiveness testing; electrical potential; experience; flexibility; gray matter; improved; insight; neural; neuromechanism; neurophysiology; neuroregulation; new therapeutic target; novel; persistent symptom; pre-clinical; precision medicine; psychiatric symptom; remediation; translational potential; white matter

Optimal reward-guided behavior relies on intact connections between prefrontal cortex and striatum: circuitry that is disrupted by frontal brain injury1,2. Sustaining a brain injury increases risk for developing depression, anxiety, attention deficits, mood disorders and problems with impulse control3,4. The symptoms of frontal traumatic brain injury (TBI) strongly resemble psychiatric disorders with regards to disruptions in reward-guided behavior, and therefore may share common mechanisms driving behavioral impairments. Mechanisms may include a combination of inflammatory, molecular, and cellular changes that are triggered by injury. Determining which factors mediate persistent effects of behavior is necessary to understand chronic impacts of TBI and develop treatments addressing the often debilitating symptoms enduring after injury. The proposed research will examine how severe and mild frontal TBI impacts neural communication with its distributed striatal network to influence reward-guided behavior. Identifying a neurophysiology signature associated with reward deficits would provide a new target for brain-based treatment options. Neuromodulation, altering the electrical potentials of the brain, may serve as a potential intervention to remediate behavioral deficits by restoring rhythmic brain patterns and structural integrity of their underlying connections following injury. Preclinical testing in translational animal models is critical to better understand the structural and functional mechanisms driving behavioral impairments, and to test repetitive brain stimulation as a method to remediate effects of injury. The first goal of this proposal is to quantify behavioral consequences of severe and mild frontal TBI made using a controlled cortical impact (CCI) in rodents. TBI causes axonal shearing of white matter tracts and chronic inflammation resulting in long-term changes to the brain’s microstructure. Abnormalities in corticostriatal connectivity is being implicated in the onset of psychiatric-like symptoms, yet the relationship with TBI-induced impairments remains unclear. As one of the most widely used injury models in animals, CCI produces focal damage in rats that mirrors concussion, contusion, and hemorrhage in humans by driving an impactor directly into the brain through a surgical opening in the skull30. The injury severity and location are controlled by the experimenter and highly reproducible across animals. After injury, rats will perform a probabilistic reversal learning task which requires reward-guided decision making, behavioral inhibition, flexible behavior, and conditional discrimination: cognitive functions that all depend on intact prefrontal cortex. Reward-related behavioral impairments on the reversal learning task will be related to microstructural changes. To capture disturbances in the cortico-striatal network after TBI, brain activity will be recorded as rats run the probabilistic reversal learning task. Neural activity is not random, it oscillates at periodic frequencies to coordinate communication within and between distributed brain areas. Each of these frequency bands are predicted to coordinate different aspects of behavior through long-range coupling in functional networks. Large-scale local field potential probes will be used to record from 32 brain areas simultaneously capturing these oscillatory dynamics during reward-guided behavior. Identifying frequency-specific activity that is disrupted by TBI, would offer insight into the neural mechanisms of reward-guided behavior and point to a new therapeutic target. Lastly, brain stimulation targeting the cortico-striatal network will be used to assess its effectiveness at inducing neuroplasticity changes to remediate effects of TBI. We will follow neuromodulation procedures known to be successful in humans with the goal of studying the structural and functional mechanisms associated with restored reward-guided behavior. The proposal will examine if stimulation to lateral orbitofrontal cortex can improve reward-guided behavior, restore cortico-striatal network activity, and induce long-term structural changes. This research is critical to identify mechanisms of TBI and remediate reward-related impairments.

最佳奖励导向行为依赖于前额叶皮层和纹状体之间的完整连接：电路 这是由额叶脑损伤中断1，2.持续的脑损伤会增加患抑郁症的风险， 焦虑、注意力缺陷、情绪障碍和冲动控制问题3，4.额叶的症状 创伤性脑损伤（TBI）在奖励引导的 行为，因此可能共享驱动行为障碍的共同机制。机构可以 包括由损伤引发炎性、分子和细胞变化的组合。确定 哪些因素介导行为的持续影响是理解TBI的慢性影响所必需的， 开发治疗方法，解决受伤后持续存在的通常使人衰弱的症状。拟议的研究将 研究严重和轻度额叶TBI如何影响其分布式纹状体网络的神经通信， 影响奖励导向行为。识别与奖励缺陷相关的神经生理学特征将 为基于大脑的治疗方案提供了一个新的目标。神经调节，改变 大脑，可以作为一个潜在的干预，以纠正行为缺陷，通过恢复节奏的大脑 受伤后其潜在连接的模式和结构完整性。临床前试验， 翻译的动物模型是至关重要的，以更好地了解结构和功能机制， 行为障碍，并测试重复脑刺激作为一种方法，以补救伤害的影响。 该提案的第一个目标是量化严重和轻度额叶TBI的行为后果， 啮齿类动物的受控皮质撞击（CCI）。TBI引起白色物质束的轴突剪切， 炎症导致大脑微观结构的长期变化。皮质纹状体脱落细胞 连接性与精神病样症状的发作有关，但与TBI诱导的 损伤仍不清楚。CCI是目前应用最广泛的动物损伤模型之一， 直接驱动冲击器对大鼠造成的伤害与人类的脑震荡、挫伤和出血相似 通过头骨上的手术开口进入大脑。损伤的严重程度和位置由 实验者和高度可重复的动物。受伤后，大鼠会进行概率逆转， 学习任务，需要奖励引导的决策，行为抑制，灵活的行为， 条件辨别：认知功能都依赖于完整的前额叶皮层。奖赏相关 反向学习任务的行为障碍将与微观结构变化有关。 为了捕获TBI后皮质-纹状体网络中的干扰，当大鼠运行TBI时，将记录脑活动。 概率逆向学习任务神经活动不是随机的，它以周期性的频率振荡以协调 分布的大脑区域内部和之间的通信。这些频带中的每一个被预测为 通过功能网络中的长程耦合来协调行为的不同方面。当地大规模 场电位探针将被用来记录从32个脑区同时捕捉这些振荡 奖励导向行为的动力学。识别被TBI破坏的频率特异性活动， 提供了对奖励导向行为的神经机制的深入了解，并指出了一个新的治疗目标。 最后，将使用针对皮质-纹状体网络的脑刺激来评估其诱导 神经可塑性改变以补救TBI的影响。我们将遵循神经调节程序， 在人类中取得了成功，目的是研究与以下相关的结构和功能机制： 恢复了奖励导向的行为该提案将研究对外侧眶额皮层的刺激是否可以 改善奖励导向行为，恢复皮质-纹状体网络活动，诱导长期结构性 变化这项研究对于确定TBI的机制和修复与奖励相关的损害至关重要。