Network Mechanisms of Neurophysiology and Behavior in mouse models of Fragile X Syndromeme

脆性 X 综合征小鼠模型神经生理学和行为的网络机制

• 批准号: 10453463
• 负责人: DEVIN K BINDER
• 金额: $ 40.77万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-25 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453463
• 关键词: Acute; Adult; Auditory; Behavior; Biological Markers; Brain; Brain region; CNR1 gene; Chronic; Clinical; Clinical Trials Design; Cortical Synchronization; Data; Development; Discrimination; Disease; Dose; Drug Tolerance; Electrodes; Electroencephalogram; Electrophysiology (science); Endocannabinoids; Equilibrium; FAAH inhibitor; FMR1; Fragile X Syndrome; Functional disorder; Glutamates; Human; Impaired cognition; Impairment; In Vitro; Individual; Knockout Mice; Measures; Memantine; Metabolism; Molecular; Mus; Neurodevelopmental Disorder; Outcome; Outcome Measure; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Physiological; Physiology; Preparation; Research; Research Personnel; Rest; Reversal Learning; Sensory; Sensory Process; Slice; Symptoms; Synapses; Technology; Testing; Time; Translating; Treatment Efficacy; United States National Institutes of Health; analysis pipeline; auditory stimulus; awake; base; behavior test; behavioral outcome; cell type; clinically relevant; cognitive process; density; drug testing; endogenous cannabinoid system; improved; inhibitor; inhibitory neuron; mouse model; multi-electrode arrays; neural circuit; neurophysiology; novel marker; novel therapeutic intervention; overtreatment; response; rimonabant; social communication; sound; targeted treatment; translational medicine

Project 2: Network mechanisms of neurophysiology and behavior in mouse models of Fragile X Syndrome. Translational biomarkers for Fragile X Syndrome (FXS) were suggested from the findings of our research team that sensory circuits are hyperexcitable in both FXS patients and Fmr1 KO mice, as measured with electroencephalogram (EEG) in mice and humans and in in vitro brain slices. Our team of investigators, working closely together within an NIH Collaborative Center for Fragile X Research, has discovered multiple neurophysiological signatures of FXS, both in the resting state and with sound-evoked EEG, that are remarkably conserved between FXS patients and Fmr1 KO mice. Recently, we have employed multi-electrode array (MEA) EEG in awake, behaving mice and discovered enhanced resting state gamma power and impaired auditory chirp- induced cortical synchronization in Fmr1 KO mice, similar to findings in FXS patients. In the current group of studies, we propose to: (1) identify network level deficits that might underlie sensory and cognitive dysfunction in FXS using MEA EEG recordings and analyzing interactions across spectral bands and brain regions in developing (P21-23) and adult WT vs. Fmr1 KO mice; and (2) test the effects of GABAergic and glutamatergic drugs on EEG and behavior in Fmr1 KO mice. Both (1) and (2) will be done in coordination with clinicians in Project 1 to test identical drugs and EEG outcome measures across species. (3) Implement multichannel depth electrodes in Fmr1 KO mice to evaluate layer-specific cortical physiological abnormalities. (4) Test the effects of endocannabinoid drugs and selective deletion of CB1Rs in inhibitory neurons on EEG and behavior in Fmr1 KO mice. Both (3) and (4) will be done in coordination with Project 3 researchers working on in vitro slice preparations to identify synaptic and cellular deficits. Thus, Project 2 will be a critical hub of the center by translating cellular and molecular level analyses to clinical approaches using network and layer-specific MEA EEG analysis and behavior in Fmr1 KO mice. We anticipate identification of novel biomarker-based drug targets for treatment of FXS.

项目2：鼠标模型中神经生理学和行为的网络机制 脆弱的X综合征。 从我们的发现中提出了脆弱X综合征（FXS）的转化生物标志物（FXS） FXS患者和FMR1 KO小鼠的感官电路都可以过度激发的研究团队， 用小鼠和人类以及体外脑切片中的脑电图（EEG）测量。 我们的调查人员团队在NIH脆弱的合作中心紧密合作 X研究发现了FXS的多个神经生理学特征，均在静止状态 状态和发声的脑电图，在FXS患者和 FMR1 KO小鼠。最近，我们在Awake中使用了多电极阵列（MEA）EEG， 行为小鼠并发现了增强的静息状态伽玛的力量和听觉障碍的chirp- 在FMR1 KO小鼠中诱导的皮质同步，类似于FXS患者的发现。在 当前的研究小组，我们建议：（1）确定可能是基础的网络级别缺陷 使用MEA EEG记录和分析相互作用的FXS的感觉和认知功能障碍 在发育中（P21-23）和成人WT与FMR1 KO小鼠的光谱带和大脑区域之间； （2）测试GABA能和谷氨酸能药对脑电图和fMR1 KO行为的影响 老鼠。 （1）和（2）将与项目1的临床医生进行协调以测试相同的 跨物种的药物和脑电图结果。 （3）实施多通道深度电极 在FMR1 KO小鼠中，以评估层特异性皮质生理异常。 （4）测试 内源性大麻素药物的影响和抑制性神经元中CB1R的选择性缺失在脑电图上的影响 和FMR1 KO小鼠的行为。 （3）和（4）都将与项目3进行协调 从事体外切片制剂的研究人员，以鉴定突触和细胞缺陷。因此， 项目2将通过将细胞和分子水平分析转化为中心的关键枢纽 FMR1中使用网络和特异性MEA EEG分析和行为的临床方法 KO老鼠。我们预计可以鉴定出新型的基于生物标志物的药物靶标以治疗FXS。