Dissecting arousal impact on sensory processing in Rett Syndrome

剖析唤醒对雷特综合症感觉处理的影响

基本信息

批准号：
10239469
负责人：
Michela Fagiolini
金额：
$ 16.58万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-22 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10239469
关键词：
Address Adolescent Affect Animal Behavior Animal Model Animals Arousal Autonomic nervous system Behavior Behavioral Biological Markers Biology Boston Brain Brain Diseases Brain region CDKL5 disorder Cells Clinic Clinical Cognition Cognitive Collaborations Coupled Data Development Disease Ecosystem Electrocardiogram Electrodes Electroencephalography Exhibits FOXG1B gene Family Female Functional disorder Future Genetic Goals Heart Rate Heterozygote Human Image Impaired cognition Impairment Individual Intellectual and Developmental Disabilities Research Centers Interdisciplinary Study Intervention Life Link Machine Learning Maps Measures Mediating Methyl-CpG-Binding Protein 2 Modeling Mus Nervous System Physiology Neural Network Simulation Neurodevelopmental Disorder Neurons Outcome Participant Pathogenicity Patients Pattern Pediatric Hospitals Phenotype Physiology Pre-Clinical Model Proxy Pupil Quality of life Registries Research Research Project Grants Rett Syndrome Sensory Sensory Process Severities Signal Transduction Syndrome System Technology Testing Therapeutic Intervention Time Ultrasonography Variant Visual evoked cortical potential Work awake base bench to bedside cellular imaging cholinergic cortex mapping density design early detection biomarkers effective therapy experience genetic analysis girls in vivo imaging mathematical model medical schools mouse model neurobehavioral neuronal circuit disruption neuronal circuitry neurophysiology neuroregulation programs relating to nervous system research clinical testing response sensory stimulus skills targeted treatment two-photon

项目摘要

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.

抽象的 Rett 综合征 (RTT) 是一种罕见的 X 连锁发育性脑部疾病，由新发致病变异引起 MECP2 主要影响女孩。值得注意的是，RTT 个体在第一时间就达到了典型的发展里程碑。生命中的6-18个月，随后是所获得技能的停滞和退化。严重的认知迟缓，感觉处理缺陷和行为状态失调对患者及其家人产生深远影响生活质量。我们仍然不知道自主神经网络和中枢大脑网络何时以及如何开始脱离正常状态。神经典型的发育轨迹，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、定量、非侵入性和转化性生物标志物来进行早期诊断评估 RTT 中的认知和行为状态、其随时间的进展以及对治疗的反应干预措施。我们的目标是建立 1) 自发瞳孔和心率 (HR) 波动作为新的生物标志物对于 RTT，2) 唤醒如何影响 RTT 皮质病理生理学的进展，以及 3) 制定有针对性的治疗干预措施。我们将在 RTT 女孩和清醒状态下使用多级电路方法来解决这些挑战疾病进展期间的 Mecp2 雌性杂合子小鼠。拟议的工作将得到完善和建立自发瞳孔和心率波动作为高度转化的生物标志物来追踪自主神经系统功能，同时剖析神经调节如何以及何时影响 RTT 中的感觉过程。一起这些方法将有助于为患者开发新的基于回路的疗法。我们的结果将铺平未来研究 RTT 相关疾病的方法，例如 MECP2 重复、CDKL5 缺乏症和 FOXG1 综合征。