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.

最佳奖励引导行为依赖于前额皮质和纹状体之间的完整连接：电路 额叶脑损伤会扰乱这种状态1,2 持续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。 创伤性脑损伤（TBI）在奖赏导向中断方面与精神疾病非常相似 行为，因此可能具有共同的驱动行为障碍的机制。 包括由损伤引发的炎症、分子和细胞变化的组合。 哪些因素介导行为的持续影响对于了解 TBI 的慢性影响和 开发治疗方法来解决受伤后持续出现的衰弱症状。 检查严重和轻微的额叶 TBI 如何影响其分布式纹状体网络的神经通讯，以 影响奖励引导的行为 识别与奖励缺陷相关的神经生理学特征。 为基于大脑的治疗方案提供新的目标，改变神经电位。 大脑，可能作为一种潜在的干预措施，通过恢复大脑节律来纠正行为缺陷 损伤后的临床前测试其潜在连接的模式和结构完整性。 转化动物模型对于更好地理解驱动的结构和功能机制至关重要 行为障碍，并测试重复性脑刺激作为修复损伤影响的方法。 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冲击（CCI）会导致白质束的轴突剪切和慢性损伤。 炎症导致大脑微观结构的长期变化。 连接性与精神类症状的发生有关，但与 TBI 诱发的关系 作为最广泛使用的动物损伤模型之一，CCI 产生局灶性损伤。 直接驱动冲击器对大鼠造成的损伤与人类脑震荡、挫伤和出血类似 通过颅骨上的手术开口进入大脑30。损伤的严重程度和位置由 实验者在动物中具有高度可重复性，受伤后，大鼠将进行概率逆转。 学习任务需要奖励引导的决策、行为抑制、灵活的行为和 条件歧视：认知功能全部依赖于完整的前额叶皮层。 逆向学习任务的行为障碍将与微观结构的变化有关。 为了捕捉 TBI 后皮质纹状体网络的紊乱，当大鼠跑动时，将记录大脑活动。 概率逆转学习任务神经活动不是随机的，它以周期性频率振荡来协调。 这些频带中的每一个都被预测为分布式大脑区域内和之间的通信。 通过大规模局部网络中的远程耦合来协调行为的不同方面。 场电位探针将用于记录 32 个大脑区域同时捕获的这些振荡 识别受 TBI 干扰的特定频率活动。 提供对奖励引导行为的神经机制的见解，并指出新的治疗目标。 最后，针对皮质纹状体网络的脑刺激将用于评估其诱导的有效性 我们将遵循已知的神经调节程序来治疗 TBI 的神经可塑性变化。 在人类中取得成功，目标是研究与相关的结构和功能机制 该提案将检查刺激外侧眶额皮层是否可以恢复奖励引导行为。 改善奖励引导行为，恢复皮质纹状体网络活动，并诱导长期结构 这项研究对于确定 TBI 机制和修复与奖励相关的损伤至关重要。