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：神经生理学和行为的网络机制在小鼠模型中， 脆性X综合征。 脆性X综合征（FXS）的翻译生物标志物是从我们的研究结果中提出的。 研究小组认为，FXS患者和Fmr 1基因敲除小鼠的感觉回路都是过度兴奋的， 如在小鼠和人类中以及在体外脑切片中用脑电图（EEG）测量的。 我们的研究人员团队在NIH合作中心内密切合作， X Research发现了FXS的多种神经生理学特征，无论是在静息状态下， 状态和声音诱发的EEG，这是显着保守的FXS患者和 Fmr 1 KO小鼠。最近，我们已经采用多电极阵列（MEA）脑电图在清醒， 行为小鼠，并发现增强的静息状态伽马功率和受损的听觉啁啾- 在Fmr 1 KO小鼠中诱导皮质同步，与FXS患者中的发现相似。在 目前的研究组，我们建议：（1）确定网络水平的缺陷，可能是基础 使用MEA EEG记录和分析相互作用的FXS中的感觉和认知功能障碍 在发育中（P21-23）和成年WT与Fmr 1 KO小鼠的光谱带和脑区之间; 检测GABA能和多巴胺能药物对Fmr 1基因敲除小鼠脑电图和行为学的影响 小鼠将与项目1中的临床医生协调完成（1）和（2），以测试相同的 药物和EEG结果指标。(3)实施多通道深度电极 以评价层特异性皮质生理异常。(4)测试 内源性大麻素类药物和抑制性神经元CB 1 Rs选择性缺失对脑电图的影响 在Fmr 1 KO小鼠中的行为。（3）和（4）将与项目3协调进行 研究人员致力于体外切片制备，以确定突触和细胞缺陷。因此，在本发明中， 项目2将成为该中心的关键枢纽，将细胞和分子水平的分析转化为 使用网络和层特异性MEA EEG分析的临床方法和在Fmr 1中的行为 KO小鼠。我们期待识别用于治疗FXS的新的基于生物标志物的药物靶点。