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.

项目概要/摘要 在过去的十年中，深部脑刺激（DBS）在治疗运动疾病（例如 帕金森病和肌张力障碍已向两个方向扩展：现在用于治疗神经精神疾病 成人疾病，例如强迫症和阿尔茨海默病（AD），并且正在开始 用于儿童治疗运动和神经精神疾病（肌张力障碍和抽动秽语症， 分别）。例如，一项试点研究表明，AD 患者的穹窿刺激可以改善 海马体依赖性记忆任务并减缓认知能力下降，在啮齿类动物中，刺激海马体 穹窿 (FFx) 或内嗅皮层可能通过调节海马 theta-gamma 来改善空间记忆 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 小鼠模型中的学习和记忆以及海马突触可塑性和齿状神经发生 雷特综合症（RTT）是导致女性智力障碍的主要原因。主要是突变引起的 损害 MeCP2 的功能，MeCP2 是一种表观遗传转录调节剂，其精确活性是 作为一项深入研究的课题，RTT 在女性一岁后出现，造成了深远的影响 认知障碍和广泛的附加功能。受影响的儿童出生时看起来很健康， 实现早期发育里程碑，但在 12 至 18 个月之间突然失去后天运动能力， 语言和社交技能，并发展一系列神经和精神特征（手部刻板印象、 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 MeCP2，要么携带 功能低下的等位基因，再现该疾病的广泛表型，从早期明显的健康状况到退化 以及运动功能障碍、社交和认知缺陷的发展；海马体依赖性学习和 记忆和海马突触可塑性受损。我们已经证明星展银行可以拯救这些 海马特征，但作用机制仍不清楚：我们假设多种机制 （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/或全局神经网络活动）正在发挥作用。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对RTT小鼠有益的可能机制； (3) 确定 穹窿 DBS 的记忆优势是否可以推广到其他智力小鼠模型 残疾。这些数据将提供对电路级操作价值的深入了解，并奠定基础 为 RTT 和其他导致智力的儿童障碍的新治疗方法奠定基础 残疾。