Fluoxetine recovery of synaptic dysfunction following juvenile global cerebral ischemia

摘要 心脏骤停引起的全脑缺血会导致许多神经后遗症，包括 学习和记忆。这些缺陷在儿童身上和成年人身上都很明显，尽管有些人报告说 随着时间的推移，发育中的大脑会得到更好的恢复。由此产生的神经后遗症 儿童心脏骤停可能是由神经元死亡和存活神经元的生理改变引起的。 令人惊讶的是，虽然我们对成年人的缺血后果知道很多，但对 青少年大脑对全球缺血侮辱的反应，从而导致对儿童的治疗即使有，也很少 心脏骤停。因此，我们开发了一种新的青少年心脏骤停小鼠模型，它模仿了 儿童早期来解决这些问题。我们的初步数据显示， 学习和记忆发生在青少年的大脑中，然后在慢性时间点恢复。虽然这件事 复苏是重要的，我们认为有大量的时间可以发生干预 最大限度地发挥学龄儿童的学习潜力。很大一部分研究的重点是发现 促进功能恢复的治疗方法。因此，我们设计了一个干预时间表，该时间表具有 有可能极大地改变目前的治疗窗口。对于遭受全球疾病折磨的成年人和新生儿 对于脑缺血，治疗的标准仍然是治疗性降温，或限制头部和/或身体的降温。 脑缺血后数小时内出现神经元损伤。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理学药物被翻译成用于 人民。因此，我们采取了一种新的方法来改善和恢复全脑损伤后的功能 缺血症。这项拨款申请检验了这样一个假设，即在缺血中幸存下来的神经元已经受损 功能，这种损害可以有针对性地进行干预。我们的初步数据表明 缺血性损伤后7-14天给予氟西汀可逆转功能损害。具体来说， 有证据表明，氟西汀增加了脑源性神经营养因子(BDNF)，这是一种对 学习和记忆机制，以及BDNF受体酪氨酸激酶B(TrkB)，以拯救 全脑缺血后突触可塑性受损。我们建议使用电生理学进行实验， 行为，药理学，遗传操作和细胞内信号询问，以解决 假设：延迟给药可激活BDNF-TrkB信号以恢复受损的突触 青少年全脑缺血后的功能和认知功能。如果这份报告中提供的初步数据 支持延迟给药氟西汀逆转功能损害的应用， 然后，我们可能会通过扩展实现范式转换策略和高翻译潜力 通过新的神经修复策略治疗儿童全脑缺血后的治疗窗口 也许，也可以扩展到成年人和新生儿。

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.