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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的由心脏骤停引起的全球脑缺血导致许多神经系统后遗症，包括缺陷学习和记忆。这些赤字在儿童中与成年人一样明显，尽管有些人报告说随着时间的流逝，发展大脑的恢复得到改善。产生的神经后遗症来自儿科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，尽管我们对成年人的缺血后果有很多了解，但对此知之甚少少年大脑应对全球缺血性侮辱，从而导致对儿童的疗法很少（如果有的话）心脏停搏。因此，我们开发了一种新型的少年心脏骤停的老鼠模型，非常模仿童年以解决这些问题。我们的初步数据表明功能障碍学习和记忆发生在少年大脑中，然后在慢性时间点恢复。同时恢复很重要，我们认为有大量时间可以进行干预最大程度地提高儿童在学年中的学习潜力。大部分研究重点是发现用于增强功能恢复的治疗剂。因此，我们设计了一个干预时间表，可能会极大地改变当前的治疗窗口。对于遭受全球遭受全球遭受的成年人和新生儿缺血，护理标准仍然是治疗性体温过低，或者头部和/或身体的冷却以限制缺血数小时内开始神经元损伤。同样的策略不能保护童年的大脑。此外，在缺血后没有保护神经元损伤的药理学剂已被翻译为用于人们。因此，我们采取了一种新颖的方法来改善和恢复全球大脑后的功能缺血。该赠款申请检验了以下假设，即生存缺血的神经元受损功能，这种障碍可以用于干预。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障碍。具体来说，有证据表明，氟西汀增加了脑衍生的神经性因子（BDNF），这对于一种对学习和记忆的机制，以及BDNF受体酪氨酸激酶B（TRKB），以营救全球脑缺血后突触可塑性受损。我们建议使用电生理学的实验，行为，药理学，基因操纵和细胞内信号传导询问，以解决假设：氟西汀延迟施用激活BDNF-TRKB信号传导以恢复突触受损少年全球脑缺血后的功能和认知。如果在此提供的初步数据支持延迟氟西汀逆转延迟给药功能障碍的应用，然后，我们可能会通过扩展来采用范式转移策略和高转化潜力通过新颖的神经训练策略，全球脑缺血后的治疗窗口，这是一种新的神经训练策略也许，也可以扩展到成年人和新生儿。