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

雷特综合征小鼠的深部脑刺激：认知效应及其机制

• 批准号: 9900074
• 负责人: Jianrong Tang
• 金额: $ 35.06万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900074
• 关键词: 1 year old; Adult; Affect; Afferent Pathways; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease patient; Animals; Anxiety; Autonomic Dysfunction; Behavior; Behavioral; Birth; Brain; Brain region; CDKL5 disorder; Child; Childhood; Cognition; Cognitive; Cognitive deficits; Complement; Complex; Data; Deep Brain Stimulation; Development; Disease; Dystonia; Electrophysiology (science); Epigenetic Process; Face; Family; Female; Fimbria of hippocampus; Frequencies; Future; Gene Expression; Gene Mutation; Genes; Genetic Transcription; Gilles de la Tourette syndrome; Hand; Health; Hippocampus (Brain); Impaired cognition; Impairment; Intellectual functioning disability; Intervention; Investigation; Language; Learning; Life; Long-Term Effects; Measures; Memory; Methyl-CpG-Binding Protein 2; Modeling; Modification; Motor; Mus; Mutation; Nature; Neurologic; Neuromodulator; Obsessive compulsive behavior; Obsessive-Compulsive Disorder; Parkinson Disease; Parkinsonian Disorders; Patients; Phenotype; Pilot Projects; Property; Research Personnel; Rett Syndrome; Rodent; Seizures; Social Behavior; Structure; Symptoms; Synaptic plasticity; System; Testing; Work; X Chromosome; X Inactivation; adult neurogenesis; autistic; autistic behaviour; coping; entorhinal cortex; improved; insight; motor deficit; motor disorder; motor impairment; mouse model; neural circuit; neural network; neurogenesis; neuropsychiatric disorder; newborn neuron; novel therapeutic intervention; pre-clinical; relating to nervous system; severe intellectual disability; social deficits; social skills; spasticity; spatial memory; stereotypy; success; young adult

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.

项目摘要/摘要 在过去的十年中，深脑刺激（DBS）的成功治疗运动疾病，例如 帕金森氏症和肌张力障 成年人的疾病，例如强迫症和阿尔茨海默氏病（AD），它正在开始 用于治疗运动和神经精神疾病的儿童（肌张力障碍和图雷特， 分别）。例如，一项试点研究表明，AD患者的前进刺激有所改善 海马依赖性记忆任务和减慢认知能力下降，在啮齿动物中，刺激纤维膜 Fornix（FFX）或Entorhinal Cortex可以改善空间记忆，可能通过调节海马theta-gamma 振荡，成人神经发生或两者兼而有之。我们最近显示，Forniceal DBS增强了海马 在小鼠模型中学习和记忆以及海马突触可塑性和齿状神经发生 Rett综合征（RTT），这是女性智力残疾的主要原因。主要由突变引起 这种损害了MECP2的功能，MECP2是一种表观遗传转录调节器，其精确活动是 经过深入调查的主题，RTT在生命的第一年后在女性中表现出来，导致了深刻的 认知障碍和广泛的其他功能。受影响的儿童在出生时看起来很健康， 实现早期发展里程碑，但在12到18个月之间，突然失去了收购电动机， 语言和社交技能，并发展一系列神经和精神病特征（手动刻板印象， 焦虑，自闭症行为，癫痫发作，自主功能障碍和运动缺陷，包括肌张力障碍，痉挛， 和最终的帕金森主义）。几种鼠标模型，要么完全缺少MECP2或携带 低功能等位基因，从早期的健康到回归，再现这种疾病的广泛表型 以及运动功能障碍，社会和认知缺陷的发展；海马依赖性学习和 记忆和海马突触可塑性受损。我们已经证明DBS拯救了这些 海马特征，但作用机理尚不清楚：我们假设有多种机制 （例如，海马神经发生，局部场电位振荡，神经调节剂，海马体积， 和/或全球神经网络活动）正在起作用。在此提案中，我们将（1）确定DBS的程度 对年轻动物和年龄较大的动物的影响，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； （3）确定 Forniceal DBS的记忆益处是否可以推广到其他鼠标智力模型 残疾。数据将洞悉电路级别的操作价值，并将 RTT和其他儿童疾病的新治疗方法的基础。 残疾。