Fluoxetine recovery of synaptic dysfunction following juvenile global cerebral ischemia

氟西汀恢复青少年全脑缺血后突触功能障碍

• 批准号: 10509753
• 负责人: Robert M Dietz
• 金额: $ 42.76万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10509753
• 关键词: Acute; Address; Adolescent; Adult; Age-Years; Applications Grants; Behavior; Binding; Brain; Brain Injuries; Cell Death; Cerebral Ischemia; Cessation of life; Child; Childhood; Chronic; Clinical; Cognitive; Cognitive deficits; Communication; Data; Development; Disease model; Dose; Education; Electrophysiology (science); FDA approved; Face; Fluoxetine; Frequencies; Functional disorder; Genetic; Head; Heart Arrest; Hippocampus (Brain); Hour; Human; Impaired cognition; Impairment; Innovative Therapy; Intervention; Ischemia; Knowledge; Learning; Life; Long-Term Potentiation; LoxP-flanked allele; Memory; Memory impairment; Methods; Modeling; Mus; Neurologic; Neuronal Injury; Neurons; Outcome; Pathway interactions; Persons; Pharmacology; Physiological; Physiology; Protein Tyrosine Kinase; Receptor Signaling; Recovery; Recovery of Function; Reporting; Research; Research Proposals; Role; School-Age Population; Schools; Serotonin; Signal Transduction; Specificity; Stimulus; Stroke; Survivors; Synapses; Synaptic plasticity; Testing; Therapeutic; Time; TimeLine; Translating; Translations; United States; child depression; cholinergic; cognitive ability; cognitive function; developmental plasticity; early childhood; experimental study; functional disability; functional restoration; genetic manipulation; improved; improved functioning; injury and repair; innovation; interest; ischemic injury; mature animal; mouse model; natural hypothermia; negative affect; neonate; neural circuit; neuron loss; neuronal circuitry; neuroprotection; neurorestoration; neurotropic; novel; novel strategies; prepuberty; receptor; repaired; response; reuptake; serotonin receptor; standard of care; synaptic function; therapy design; translational approach; translational potential

ABSTRACT Global cerebral ischemia caused by cardiac arrest results in many neurological sequelae, including deficits in learning and memory. These deficits are as evident in children as they are in adults, though some report that there is improved recovery in the developing brain over time. The resulting neurological sequelae from pediatric cardiac arrest likely arise from both neuronal death and altered physiology in surviving neurons. Surprisingly, while we know a great deal about ischemic consequences in adults, very little is known about the juvenile brain in response to global ischemic insults, thus leading to very few, if any, therapies for children after cardiac arrest. Therefore, we have developed a novel mouse model of juvenile cardiac arrest that mimics very early childhood to address these questions. Our preliminary data suggests that functional impairment in learning and memory occurs in the juvenile brain, followed by recovery at chronic time points. While this recovery is important, we contend that there is a large amount of time in which intervention can occur to maximize the learning potential of children in school age years. A large part of research focuses on discovery of therapeutics to enhance functional recovery. Hence, we have designed an intervention timeline that has the potential to dramatically alter current therapeutic windows. For adults and neonates who suffer global ischemia, the standard of care remains therapeutic hypothermia, or cooling of the head and/or body to limit neuronal injury when started within hours of ischemia. This same strategy does not protect the childhood brain. Additionally, no pharmacologic agents to protect neuronal injury after ischemia have been translated for use in people. Therefore, we have taken a novel approach to improving and restoring function after global cerebral ischemia. This grant application tests the hypothesis that the neurons that survive ischemia have impaired function, and this impairment can be targeted for intervention. Our preliminary data suggests that administration of fluoxetine 7-14 days after ischemic insult can reverse functional impairments. Specifically, there is evidence that fluoxetine increases brain-derived neurotropic factor (BDNF), a molecule that is vital to mechanisms of learning and memory, as well as the BDNF receptor tyrosine kinase B (TrkB), to rescue impaired synaptic plasticity after global cerebral ischemia. We propose experiments using electrophysiology, behavior, pharmacology, genetic manipulation and intracellular signaling interrogation to address the hypothesis: Delayed administration of fluoxetine activates BDNF-TrkB signaling to restore impaired synaptic function and cognitive following juvenile global cerebral ischemia. If the preliminary data presented in this application suggesting delayed administration of fluoxetine reverses functional impairments are supported, then we may be upon a paradigm shifting strategy and high translational potential through extending therapeutic windows after global cerebral ischemia in children through novel neurorestorative strategies, which perhaps, could be extended to adults and neonates as well.

抽象的 心脏骤停引起的全脑缺血会导致许多神经系统后遗症，包括功能缺陷 学习和记忆。这些缺陷在儿童中和在成人中一样明显，尽管有些人报告说 随着时间的推移，发育中的大脑的恢复会有所改善。由此产生的神经系统后遗症 小儿心脏骤停可能是由于神经元死亡和幸存神经元的生理学改变引起的。 令人惊讶的是，虽然我们对成人缺血性后果了解很多，但对它的影响却知之甚少。 幼年大脑对整体缺血性损伤的反应，因此导致对儿童的治疗很少（如果有的话） 心脏停搏。因此，我们开发了一种新颖的青少年心脏骤停小鼠模型，该模型非常模仿 幼儿期就可以解决这些问题。我们的初步数据表明，功能障碍 学习和记忆发生在青少年大脑中，然后在慢性时间点恢复。虽然这 恢复很重要，我们认为有大量的时间可以进行干预 最大限度地发挥学龄儿童的学习潜力。很大一部分研究侧重于发现 的治疗方法以增强功能恢复。因此，我们设计了一个干预时间表 可能显着改变当前的治疗窗口。对于遭受全球苦难的成人和新生儿 缺血，护理标准仍然是治疗性低温，或冷却头部和/或身体以限制 缺血后数小时内开始发生神经元损伤。同样的策略并不能保护儿童的大脑。 此外，还没有用于保护缺血后神经元损伤的药物被转化用于 人们。因此，我们采取了一种新的方法来改善和恢复全球脑损伤后的功能。 缺血。该拨款申请测试了以下假设：在缺血中存活的神经元已受损 功能，并且可以针对这种损伤进行干预。我们的初步数据表明 缺血性损伤后 7-14 天给予氟西汀可以逆转功能损伤。具体来说， 有证据表明氟西汀会增加脑源性神经营养因子（BDNF），这是一种对神经系统至关重要的分子。 学习和记忆机制以及 BDNF 受体酪氨酸激酶 B (TrkB) 来拯救 全脑缺血后突触可塑性受损。我们提出使用电生理学的实验， 行为、药理学、基因操作和细胞内信号转导来解决 假设：延迟服用氟西汀会激活 BDNF-TrkB 信号传导以恢复受损的突触 青少年全脑缺血后的功能和认知。如果本报告中提供的初步数据 支持延迟服用氟西汀可逆转功能障碍的申请， 那么我们可能会通过扩展来实现范式转变策略和高转化潜力 通过新颖的神经恢复策略，儿童全脑​​缺血后的治疗窗口 也许，也可以扩展到成人和新生儿。