High-resolution characterization of functional connectivity and behavior in healthy and transgenic mice from the neonatal period through adulthood

对健康转基因小鼠从新生儿期到成年期的功能连接和行为进行高分辨率表征

基本信息

项目摘要

The development of the brain and its neuronal networks depends on a complex sequence of events during which neurons are born, migrate, arborize, and establish transient or persistent synaptic connections. Alterations in any of these processes can result in neurodevelopmental disorders that persistently affect cognitive functions. The neurodevelopmental hypothesis suggests that neurological disorders such as autism, ADHD, schizophrenia, or epilepsy arise from dysfunctions during early brain development and/or impaired postnatal maturation of the brain. Common causes of neurodevelopmental disorders in humans include birth complications, environmental factors, or genetic disorders. For instance, channelopathies caused by mutations in ion channel genes such as SCN2A or KCNQ2 may cause a range of encephalopathies, both in humans and mice. We have shown that mice lacking KCNQ/Kv7/M-currents exhibit pathological changes in behavior and develop an epilepsy phenotype only when functional M-currents are suppressed during the first two postnatal weeks. This is a key developmental period in rodents, during which spontaneous waves of electrical activity play an important role in brain maturation. Data from animal models and humans suggest that early neuronal activity patterns play an important role in neuronal circuit formation and in the establishment of functional connections between different brain areas. Increasing evidence suggests the presence of altered functional connectivity between prefrontal cortical (PFC) and hippocampal (HPC) regions in cognitive disorders and respective animal models.To be able to follow the process of functional maturation of connectivity in the mouse brain we aim at developing a digital, custom-chip-based recording electrode array using advanced CMOS technology for chronic recordings from freely moving mouse pups and adult mice. This will enable a longitudinal characterization of temporal maturation of PFC and HPC network activities and their functional connectivity in control mice and in mice with altered activities of Kv7/M-, HCN/h-, or SCN2A/Nav1.2-mediated currents.The digital recording array will be used in combination with optogenetic manipulation of GABAergig interneurons to characterize the dynamics of network interaction between PFC and HPC and its changes in our channelopathy mouse models.Furthermore, we will investigate whether attenuation or stimulation of network activity in early brain development will ameliorate the behavioral phenotype in adult mutant mice. Thus, our study will for the first time provide longitudinal data on the dynamics of electrical brain development in channelopathy mouse mutants. The analysis of circuit dynamics in the adult mouse brain of healthy, mutant and mutant mice treated in the neonatal period will lead to a to better understanding of the causal link between early network patterns and delay or impairment in neurobehavioral development.
大脑及其神经元网络的发育取决于一系列复杂的事件,在这些事件中,神经元诞生、迁移、树形化,并建立短暂或持久的突触连接。这些过程中的任何改变都可能导致持续影响认知功能的神经发育障碍。神经发育假说认为,自闭症、多动症、精神分裂症或癫痫等神经系统疾病是由早期大脑发育和/或出生后大脑成熟受损引起的。人类神经发育障碍的常见原因包括出生并发症、环境因素或遗传疾病。例如,由离子通道基因(如SCN2A或KCNQ2)突变引起的通道病变可能在人类和小鼠中引起一系列脑病。我们已经证明,缺乏KCNQ/Kv7/ m电流的小鼠,只有在出生后的前两周,当功能性m电流被抑制时,才会表现出行为的病理变化,并发展为癫痫表型。这是啮齿动物发育的关键时期,在此期间,脑电活动的自发波在大脑成熟中起着重要作用。来自动物模型和人类的数据表明,早期神经元活动模式在神经元回路的形成和不同脑区之间功能连接的建立中起着重要作用。越来越多的证据表明,在认知障碍和相应的动物模型中,前额皮质(PFC)和海马(HPC)区域之间的功能连接存在改变。为了能够跟踪小鼠大脑连接功能成熟的过程,我们的目标是使用先进的CMOS技术开发一种基于定制芯片的数字记录电极阵列,用于自由移动的小鼠幼崽和成年小鼠的慢性记录。这将使得在对照小鼠和Kv7/M-、HCN/h-或SCN2A/ nav1.2介导电流活动改变的小鼠中,PFC和HPC网络活动的时间成熟及其功能连通性的纵向表征成为可能。数字记录阵列将结合GABAergig中间神经元的光遗传学操作来表征PFC和HPC之间网络相互作用的动力学及其在我们的通道病小鼠模型中的变化。此外,我们将研究早期大脑发育中网络活动的衰减或刺激是否会改善成年突变小鼠的行为表型。因此,我们的研究将首次提供通道病小鼠突变体脑电发育动态的纵向数据。在新生期对健康、突变和突变小鼠的成年小鼠大脑进行电路动力学分析,将有助于更好地理解早期网络模式与神经行为发育延迟或损伤之间的因果关系。

项目成果

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Professor Dr. Dirk Isbrandt其他文献

Professor Dr. Dirk Isbrandt的其他文献

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{{ truncateString('Professor Dr. Dirk Isbrandt', 18)}}的其他基金

Consequences of HCN/h pacemarker channel deficency for cortico-basal ganglia circuit function
HCN/h 起搏器通道缺陷对皮质基底节回路功能的影响
  • 批准号:
    257996791
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
    Clinical Research Units
Untersuchungen zur Pathophysiologie von Epilepsien des Neugeborenen- und Säuglingsalters in transgenen Mausmodellen
转基因小鼠模型新生儿和婴儿期癫痫病理生理学研究
  • 批准号:
    66045449
  • 财政年份:
    2008
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Experimentelle Neuropädiatrie
实验神经儿科
  • 批准号:
    66024878
  • 财政年份:
    2008
  • 资助金额:
    --
  • 项目类别:
    Heisenberg Professorships
Analyse von hippocampalen Oszillationen in KCNQ/M-Kanal-defizienten transgenen Mäusen
KCNQ/M通道缺陷转基因小鼠海马振荡分析
  • 批准号:
    37067352
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Analysis of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function in adult heart using conditional transgenic mouse models
使用条件转基因小鼠模型分析成年心脏中超极化激活的环核苷酸门控(HCN)通道功能
  • 批准号:
    13327398
  • 财政年份:
    2005
  • 资助金额:
    --
  • 项目类别:
    Research Units
Centralized data management and analysis facilities
集中数据管理和分析设施
  • 批准号:
    394775100
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Units
Transcriptomic and epigenetic profiles of basal ganglia-cortex networks in developmental epileptic encephalopathies
发育性癫痫脑病中基底节-皮质网络的转录组学和表观遗传学特征
  • 批准号:
    497785435
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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Molecular and functional characterization of olfactory pathways in the arbovirus vector mosquito Aedes aegypti
虫媒病毒载体蚊子埃及伊蚊嗅觉通路的分子和功能特征
  • 批准号:
    10638710
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    2023
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Functional and structural characterization of human auditory cortex using high resolution MRI
使用高分辨率 MRI 表征人类听觉皮层的功能和结构
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    10728782
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    2023
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Characterization of the Neurobiological Profiles of Young Adults with and without Developmental Language Disorder (DLD)
患有和不患有发育性语言障碍 (DLD) 的年轻人的神经生物学特征的表征
  • 批准号:
    10721464
  • 财政年份:
    2023
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    --
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Structural and functional characterization of glycosyltransferases in the Campylobacter concisus N-linked glycoconjugate biosynthetic pathway
弯曲杆菌 N 连接糖复合物生物合成途径中糖基转移酶的结构和功能表征
  • 批准号:
    10607139
  • 财政年份:
    2023
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    --
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Structural characterization of tau aggregation variability and maturity in isolated cell types of the brain
大脑分离细胞类型中 tau 聚集变异性和成熟度的结构表征
  • 批准号:
    10721681
  • 财政年份:
    2023
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    --
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ADVANCED COMPREHENSIVE MAGNETIC RESONANCE SOLUTION FOR THE NONINVASIVE CHARACTERIZATION OF HIGH RESOLUTION METABOLIC BIOMARKERS OF RISK IN PATIENTS WITH ALZHEIMER'S DISEASE AND DEMENTIA
先进的综合磁共振解决方案,用于无创表征阿尔茨海默病和痴呆症患者风险的高分辨率代谢生物标志物
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    10820517
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    2023
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    --
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Structural characterization of APP family proteins
APP 家族蛋白的结构表征
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    10648792
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    2023
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Cardiac Magnetic Resonance Tissue Characterization of Ischemic and Non-Ischemic Myocardium to Predict Left Ventricular Functional Recovery and Outcomes after Multivessel Coronary Revascularization
缺血和非缺血心肌的心脏磁共振组织表征可预测多支冠状动脉血运重建后左心室功能恢复和结果
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    10754011
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    2023
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    --
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Monitor single-cell dynamics using optically computed phase microscopy in correlation with fluorescence characterization of intracellular properties
使用光学计算相位显微镜监测单细胞动力学与细胞内特性的荧光表征相关
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    10589414
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2/2 Large-scale, single-cell characterization of molecular and cellular networks of mood regulation circuitry in major depressive disorder
2/2 重度抑郁症情绪调节回路的分子和细胞网络的大规模单细胞表征
  • 批准号:
    10745412
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