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: 10669028
• 负责人: DEVIN K BINDER
• 金额: $ 40.88万
• 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/10669028
• 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; Electroencephalography; 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; 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; 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：小鼠神经生理学和行为的网络机制 脆性X综合征。 根据我们的研究结果，提出了脆性X综合征(FXS)的翻译生物标记物 研究小组发现，FXS患者和Fmr1 KO小鼠的感觉回路都是过度兴奋的， 用脑电(EEG)在小鼠和人类以及体外脑片上进行测量。 我们的调查团队，在NIH脆弱合作中心内密切合作 X Research发现了FXS的多个神经生理特征，两者都在休息时 状态和声诱发脑电，在FXS患者和 FMR1KO小鼠。最近，我们在清醒状态下使用了多电极阵列(MEA)脑电， 表现良好的小鼠，发现静息状态伽马功率增强，听觉啁啾受损- 在Fmr1KO小鼠中诱导皮质同步化，类似于在FXS患者中的发现。在 目前的一组研究，我们建议：(1)确定可能存在的网络水平缺陷 应用MEA脑电记录分析FXS患者的感觉和认知功能障碍 跨越发育中(P21-23)和成年WT与Fmr1 KO小鼠的光谱带和大脑区域； (2)检测GABA能和谷氨酸能药对Fmr1 KO大鼠脑电和行为学的影响 老鼠。(1)和(2)将与项目1中的临床医生协调完成，以进行相同的测试 跨物种的药物和脑电结果测量。(3)实现多通道深度电极 在Fmr1KO小鼠中评估蛋鸡特有的皮质生理异常。(4)测试 内源性大麻素类药物和抑制神经元CB1Rs选择性缺失对脑电的影响 以及在Fmr1KO小鼠中的行为。第(3)和(4)项都将与项目3协调完成 研究人员正在进行体外切片准备，以确定突触和细胞缺陷。因此， 项目2将成为中心的关键枢纽，将细胞和分子水平的分析转化为 使用网络和层特异性MEA脑电分析的临床方法和Fmr1的行为 Ko老鼠。我们期待基于生物标记物的治疗FXS的新药物靶点的确定。