Dissecting arousal impact on sensory processing in Rett Syndrome

摘要 Rett综合征(RTT)是一种罕见的X连锁发育性脑疾病，由新生的致病变种引起 甲基氯丙烷2，主要影响女孩。值得注意的是，RTT个体在第一个阶段就达到了典型的发展里程碑 6-18个月的生命，随后是停滞，然后是获得的技能倒退。严重的认知延迟， 感觉处理缺陷和行为状态失调对患者和家人都有深远的影响 生活质量。我们仍然不知道自主和中枢大脑网络何时以及如何开始脱离 神经典型发育轨迹，我们也没有针对这些损伤的有效治疗方法。因此， 迫切需要客观的、定量的、非侵入性的和可翻译的早期生物标志物 RTT患者认知和行为状态的评估及其随时间的进展和对治疗的反应 干预措施。我们的目标是建立1)自发的瞳孔和心率波动作为新的生物标志物 对于RTT，2)觉醒如何影响RTT的皮质病理生理学进展以及3)有针对性地开发 干预措施。我们将在RTT女孩和清醒的人中使用多电平电路方法来解决这些挑战 MeCP2雌性杂合子小鼠在疾病进展过程中。拟议的工作将完善和 建立自发的瞳孔和心率波动作为追踪自主神经的高度翻译的生物标志物 系统功能，同时解剖神经调节如何以及何时影响RTT中的感觉过程。同舟共济 这些方法将允许在患者身上开发新的基于电路的疗法。我们的结果将是铺平的 未来对RTT相关疾病如MECP2重复、CDKL5缺乏症和 FOXG1综合征。

ABSTRACT Rett Syndrome (RTT) is a rare X-linked developmental brain disorder due to de novo pathogenic variants in MECP2 and mainly affecting girls. Notably, RTT individuals reach typical developmental milestones in the first 6-18 months of life, followed by stagnation and then regression of acquired skills. The severe cognitive delays, deficits in sensory processing and dysregulated behavioral states profoundly impact both patient and family quality of life. We still do not know when and how autonomic and central brain networks begin to derail from the neurotypical developmental trajectory, nor we have effective treatments targeting these impairments. Hence, there is an urgent need for objective, quantitative, non-invasive, and translational biomarkers for early assessment of cognition and behavioral states in RTT, their progression over time and response to therapeutic interventions. Our goals are to establish 1) spontaneous pupil and heart rate (HR) fluctuations as new biomarkers for RTT, 2) how arousal impacts the progression of RTT cortical pathophysiology and 3) develop targeted interventions. We will address these challenges using a multi-level circuit approach both in RTT girls and awake Mecp2 female heterozygote mice during the progression of the disorder. The proposed work will refine and establish spontaneous pupil and HR fluctuations as highly translational biomarkers to track autonomic nervous system function, while dissecting how and when neuromodulation impacts sensory processes in RTT. Together these approaches will allow the development of new circuit-based therapies in patients. Our results will be pave the way to future studies of RTT related disorders such as MECP2 duplication, CDKL5 deficiency disorder and FOXG1 syndrome.