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

项目摘要/摘要 脑深部刺激(DBS)扩大了运动、认知和运动障碍的治疗选择 心情。DBS甚至开始被用于治疗儿童的运动和神经精神障碍。 几年前，受到一项研究表明DBS可以改善阿尔茨海默病患者记忆的启发，我的实验室 在Rett综合征(RTT)小鼠模型上测试穹窿DBS，RTT是一种严重的神经发育障碍， 影响整个大脑，产生智力残疾、运动和情感异常。的一个分支 MeCP2缺失是海马神经发生的减少。重要的是，我们发现私通的DBS刺激 齿状回的神经再生和显著挽救了RTT小鼠的海马区记忆。而当 DBS诱导的神经发生和记忆增强之间没有直接的因果关系，这一点很有启发意义。 此外，考虑到每天都有新的神经元诞生，并且DBS在两周内应用，这是可以想象的 DBS不仅刺激新生神经元的产生，而且还影响它们的成熟和 整合到海马体回路中。确定DBS、神经发生和整合之间的联系 新生神经元对于了解DBS是如何增强海马体记忆至关重要的。此外， 虽然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 基底节核团的DBS是如何改善运动功能的？我们的 初步数据显示，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 在相同的遗传背景下的神经回路。在目标1中，我们将首先检查隆起DBS之间的因果关系 诱导海马神经发生和记忆增强。然后，我们将确定如何私通 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 延长慢性纹状体DBS所致运动的持续时间，优化DBS的治疗频率。 然后，我们将阐明纹状体DBS在神经元和回路中对运动益处的可能机制 以及中脑多巴胺能信号在益处中的作用。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。

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.