Studying the effects and mechanisms of deep brain stimulation in Rett syndrome mice

研究深部脑刺激对雷特综合征小鼠的影响和机制

• 批准号: 10709016
• 负责人: Jianrong Tang
• 金额: $ 38.5万
• 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 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709016
• 关键词: Adult; Affect; Affective; Alzheimer' s Disease; Automobile Driving; Basal Ganglia; Behavioral; Brain; Cell Nucleus; Cells; Child; Chronic; Cognition; Corpus striatum structure; Data; Deep Brain Stimulation; Dopamine; Dorsal; Electrophysiology (science); Etiology; Female; Fimbria of hippocampus; Frequencies; Future; Ganglia; Generations; Genetic; Globus Pallidus; Hippocampus; Impairment; Intellectual functioning disability; Intervention; Link; Medial; Membrane; Memory; Methyl-CpG-Binding Protein 2; Midbrain structure; Moods; Morphology; Motor; Motor Cortex; Movement; Movement Disorders; Mus; Neurodevelopmental Disorder; Neurons; Newborn Infant; Pathway interactions; Physiology; Property; Regimen; Rett Syndrome; Role; Signal Transduction; Substantia nigra structure; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic; X Inactivation; dentate gyrus; dopaminergic neuron; gamma-Aminobutyric Acid; improved; insight; mosaic; motor disorder; motor function improvement; motor learning; motor symptom; mouse model; neural circuit; neurogenesis; neuropsychiatric disorder; newborn neuron; optogenetics; signal processing

PROJECT SUMMARY/ABSTRACT Deep brain stimulation (DBS) has expanded therapeutic options in disorders of movement, cognition, and mood. DBS is even beginning to be used to treat both motor and neuropsychiatric disorders in children. Several years ago, inspired by a study showing DBS can improve memory in Alzheimer's disease, my lab tested forniceal DBS in a mouse model of Rett Syndrome (RTT), a severe neurodevelopmental disorder that affects the entire brain, producing intellectual disability, motor, and affective abnormalities. One ramification of MeCP2 loss is the reduction of hippocampal neurogenesis. Importantly, we found that forniceal DBS stimulated neurogenesis in the dentate gyrus and dramatically rescued hippocampal memory in RTT mice. While suggestive, no direct causality has been drawn between DBS-induced neurogenesis and enhanced memory. Moreover, given that new neurons are born daily, and DBS is applied over a two-week period, it is conceivable that DBS is not only stimulating the generation of newborn neurons but also influencing their maturation and integration into the hippocampal circuit. Identifying a link between DBS, neurogenesis and the integration of newborn neurons is critical to understanding how DBS is enhancing hippocampal memory. Furthermore, although DBS induced neurogenesis may account for memory improvements in RTT, it is insufficient to explain how DBS of the nuclei in the basal ganglia, where neurogenesis does not occur, improves motor function. Our preliminary data show that DBS applied to the dorsal striatum improves the motor symptoms of RTT mice. We will capitalize on this progress to understand DBS effects in two different types of neurons and two different neural circuits in the same genetic context. In Aim 1, we will first examine the causation between forniceal DBS induced hippocampal neurogenesis and the memory enhancement. Then, we will determine how forniceal DBS affects the maturation and functioning of the newborn hippocampal neurons. In Aim 2, we will determine the duration of motor benefits induced by chronic striatal DBS and optimize the frequency of DBS treatment. Then we will elucidate the possible mechanisms of striatal DBS on motor benefits at the neuronal and circuit levels as well as the role of midbrain dopaminergic signaling in the benefits. Collectively, these studies will generate proof-of-concept data to validate DBS as an intervention to treat RTT and, potentially, other neurodevelopmental diseases.

项目概要/摘要 深部脑刺激 (DBS) 扩大了运动、认知和运动障碍的治疗选择 情绪。 DBS 甚至开始用于治疗儿童运动和神经精神疾病。 几年前，受一项研究的启发，该研究表明深部脑刺激可以改善阿尔茨海默病患者的记忆力，我的实验室 在 Rett 综合征 (RTT) 小鼠模型中测试了穹窿 DBS，RTT 是一种严重的神经发育障碍， 影响整个大脑，导致智力障碍、运动和情感异常。其后果之一是 MeCP2 损失是海马神经发生的减少。重要的是，我们发现穹窿 DBS 刺激 齿状回的神经发生并显着挽救了 RTT 小鼠的海马记忆。尽管 提示性的是，DBS 诱导的神经发生和记忆增强之间没有直接的因果关系。 此外，鉴于每天都有新的神经元诞生，并且 DBS 的应用时间超过两周，因此可以想象 DBS 不仅刺激新生神经元的生成，还影响它们的成熟和 融入海马回路。确定 DBS、神经发生和整合之间的联系 新生神经元对于理解 DBS 如何增强海马记忆至关重要。此外， 尽管 DBS 诱导的神经发生可能是 RTT 记忆改善的原因，但这不足以解释 基底神经节（不发生神经发生）的细胞核的 DBS 如何改善运动功能。我们的 初步数据表明，DBS应用于背侧纹状体可改善RTT小鼠的运动症状。我们 将利用这一进展来了解 DBS 对两种不同类型的神经元和两种不同类型的神经元的影响 相同遗传背景下的神经回路。在目标 1 中，我们将首先检查穹窿 DBS 之间的因果关系 诱导海马神经发生和记忆增强。然后，我们将确定如何 DBS 影响新生海马神经元的成熟和功能。在目标 2 中，我们将确定 慢性纹状体 DBS 引起的运动益处的持续时间并优化 DBS 治疗的频率。 然后我们将阐明纹状体 DBS 对神经元和回路运动益处的可能机制 水平以及中脑多巴胺能信号传导在益处中的作用。总的来说，这些研究将 生成概念验证数据以验证 DBS 作为治疗 RTT 和其他潜在疾病的干预措施 神经发育疾病。