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

项目总结/摘要 脑深部电刺激（DBS）扩大了运动、认知和神经功能障碍的治疗选择， 心情DBS甚至开始用于治疗儿童的运动和神经精神疾病。 几年前，受一项研究的启发，DBS可以改善老年痴呆症患者的记忆力，我的实验室 在Rett综合征（RTT）的小鼠模型中测试穹窿DBS，RTT是一种严重的神经发育障碍， 影响整个大脑，造成智力残疾、运动和情感异常。的一个分支 MeCP 2丢失是海马神经发生的减少。重要的是，我们发现穹窿DBS刺激了 在RTT小鼠的齿状回神经发生和显着挽救海马记忆。而 提示，DBS诱导的神经发生和增强的记忆之间没有直接的因果关系。 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， DBS不仅刺激新生神经元的产生，而且影响它们的成熟， 整合到海马回路中。确定DBS，神经发生和整合之间的联系 新生神经元对于理解DBS如何增强海马记忆至关重要。此外，委员会认为， 尽管DBS诱导的神经发生可能解释RTT中记忆的改善，但这不足以解释 在基底神经节的核团中DBS如何改善运动功能，而基底神经节中没有发生神经发生。我们 初步数据显示，施加于背侧纹状体的DBS改善了RTT小鼠的运动症状。我们 将利用这一进展来了解DBS在两种不同类型的神经元和两种不同类型的神经元中的作用。 在相同的遗传背景下的神经回路。在目标1中，我们将首先检查穹窿DBS与 诱导海马神经发生和记忆增强。然后我们会确定 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诱导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在益处中的作用。这些研究将 生成概念验证数据，以验证DBS作为治疗RTT的干预措施，以及其他潜在的 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.