Deep brain stimulation in Rett syndrome mice: cognitive effects and their mechanisms

项目概要/摘要 在过去的十年中，脑深部电刺激（DBS）治疗运动疾病的成功， 帕金森氏症和肌张力障碍已经扩展到两个方向：它现在被用来治疗神经精神疾病 成年人的疾病，如强迫症和阿尔茨海默病（AD），它正在开始 应用于儿童以治疗运动和神经精神疾病（肌张力障碍和图雷特氏症， 分别）。例如，一项初步研究表明，AD患者的穹窿刺激可改善 在啮齿类动物中，刺激海马伞， 穹窿（FFx）或内嗅皮质改善空间记忆，可能是通过调节海马θ-γ 振荡，成人神经发生，或两者兼而有之。我们最近发现穹窿DBS可以增强海马 小鼠模型的学习和记忆以及海马突触可塑性和齿状核神经发生 Rett综合征（RTT）是女性智力残疾的主要原因。主要由突变引起 这损害了MeCP 2的功能，MeCP 2是一种表观遗传转录调节因子，其精确活性是 作为深入调查的主题，RTT在生命的第一年后出现在女性中， 认知障碍和各种其他特征。受影响的儿童出生时看起来很健康， 达到早期发育里程碑，但在12至18个月之间突然失去获得性运动， 语言和社交技能，并发展出一系列神经和精神特征（手部刻板， 焦虑、自闭症行为、癫痫、自主神经功能障碍和运动缺陷，包括肌张力障碍，痉挛， 以及最终的帕金森症）。几种小鼠模型，要么完全缺乏MeCP 2，要么携带 功能低下的等位基因，再现了疾病的广泛表型，从早期的明显健康到退化 运动功能障碍、社交和认知缺陷的发展;依赖校园的学习和 记忆和海马突触可塑性受损。我们已经证明，DBS挽救了这些 海马特征，但作用机制仍不清楚：我们假设多种机制， (e.g.,海马神经发生，局部场电位振荡，神经调质，海马体积， 和/或全局神经网络活动）正在工作。在本提案中，我们将（1）确定DBS的范围 对年轻成年和老年动物的影响，记忆益处的持续时间，以及最佳频率 治疗;（2）研究DBS使RTT小鼠受益的可能机制;以及（3）确定 穹窿DBS的记忆益处是否可推广到其他小鼠模型， 残疾。这些数据将提供对电路级操作价值的深入了解，并将奠定 为RTT和其他儿童智力障碍的新治疗方法奠定基础 残疾。

PROJECT SUMMARY/ABSTRACT Over the past decade, the success of deep brain stimulation (DBS) to treat motor diseases such as Parkinson's and dystonia has been extended in two directions: it is now being used to treat neuropsychiatric diseases in adults, such as obsessive-compulsive disorder, and Alzheimer's disease (AD), and it is beginning to be applied in children to treat both motor and neuropsychiatric diseases (dystonia and Tourette's, respectively). For example, a pilot study showed that forniceal stimulation in AD patients improves hippocampus-dependent memory tasks and slows cognitive decline, and in rodents, stimulation of the fimbria- fornix (FFx) or entorhinal cortex improves spatial memory, likely by modulating hippocampal theta-gamma oscillation, adult neurogenesis, or both. We have recently shown that forniceal DBS enhances hippocampal learning and memory as well as hippocampal synaptic plasticity and dentate neurogenesis in a mouse model of Rett Syndrome (RTT), the leading cause of intellectual disability in females. Caused mainly by mutations that impair the function of MeCP2, an epigenetic transcriptional modulator whose precise activities are the subject of intensive investigation, RTT manifests in females after the first year of life, causing profound cognitive impairment and a wide range of additional features. Affected children appear healthy at birth and achieve early developmental milestones, but between 12 and 18 months suddenly lose acquired motor, language, and social skills and develop an array of neurological and psychiatric features (hand stereotypies, anxiety, autistic behaviors, seizures, autonomic dysfunction, and motor deficits including dystonia, spasticity, and eventual parkinsonism). Several mouse models, either completely lacking MeCP2 or carrying hypofunctional alleles, reproduce the broad phenotype of the disorder, from early apparent health to regression and development of motor dysfunction, social and cognitive deficits; hippocampus-dependent learning and memory and hippocampal synaptic plasticity are impaired. We have shown that DBS rescues these hippocampal features, but the mechanism of action remains unclear: we hypothesize that multiple mechanisms (e.g., hippocampal neurogenesis, local field potential oscillations, neuromodulators, hippocampal volume, and/or global neural network activity) are at work. In this proposal we will (1) determine the extent of DBS effects in young adult and older animals, the duration of memory benefits, and the optimal frequency of treatments; (2) investigate the possible mechanisms by which DBS benefits RTT mice; and (3) determine whether the memory benefits of forniceal DBS are generalizable to other mouse models of intellectual disability. The data will provide insight into the value of manipulations at the circuit level and will lay the groundwork for new therapeutic approaches to RTT and other childhood disorders causing intellectual disability.