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.

最佳奖励指导行为依赖于前额叶皮层和纹状体之间的完整连接：电路 额脑损伤残疾1,2。维持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的问题3,4。额叶的症状 创伤性脑损伤（TBI）与奖励引导中的干扰非常类似于精神疾病 行为，因此可能具有驱动行为障碍的共同机制。机制可能 包括炎症，分子和细胞变化的结合，这些变化是由损伤触发的。确定 哪些因素介导行为的持续作用是理解TBI和 开发治疗方法解决了受伤后经常衰弱的症状。拟议的研究将 检查严重和轻度的额叶TBI如何影响其分布式纹状体网络的神经通信 影响奖励指导的行为。确定与奖励防御相关的神经生理学签名将 为基于大脑的治疗选择提供了新的目标。神经调节，改变 大脑可以通过恢复节奏大脑来补救行为定义的潜在干预措施 受伤后其基础连接的模式和结构完整性。临床前测试 翻译动物模型对于更好地了解驱动结构和功能机制至关重要 行为障碍，并测试重复的大脑刺激，以治疗损伤的影响。 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 啮齿动物中的受控皮质冲击（CCI）。 TBI导致白质和慢性的轴突剪切 炎症导致大脑的微观结构的长期变化。皮质纹状体异常 连通性与精神病症状的发作有关，但与TBI引起的关系 损害仍然不清楚。作为动物中使用最广泛的伤害模型之一，CCI会产生局灶性 通过直接驾驶撞击器来反映人类咨询，挫伤和出血的大鼠损害 通过Skull30中的手术开口进入大脑。伤害的严重程度和位置由 实验者和高度可重现的动物。受伤后，大鼠将进行概率逆转 需要奖励指导决策，抑制行为，灵活行为和 条件歧视：完全取决于完整前额叶皮质的认知功能。奖励相关 反向学习任务上的行为障碍将与微观结构变化有关。 为了在TBI之后捕获Cortico-Striatal网络中的灾难，将记录大脑活动的记录 概率逆转学习任务。神经活动不是随机的，它以周期性的频率振荡以坐标 分布式大脑区域内和之间的沟通。这些频段中的每一个都被预测 通过功能网络中的远程耦合来协调行为的不同方面。大规模本地 现场潜在问题将用于记录来自32个大脑区域的记录，简单地捕获这些振荡 奖励引导行为期间的动态。识别被TBI中断的频率特异性活动，将会 提供有关奖励引导行为的神经机制的洞察力，并指向新的治疗靶点。 最后，针对皮质 - 纹状体网络的大脑刺激将用于评估其在诱导的 神经塑性变化以补救TBI的影响。我们将遵循已知的神经调节程序 在人类中成功，目的是研究与 恢复奖励指导的行为。该提案将检查向横向眶额皮质的刺激是否可以 改善奖励指导的行为，恢复皮质 - 纹状体网络活动并诱导长期结构 更改。这项研究对于确定TBI机制并补救与奖励相关的障碍至关重要。