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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

基本信息

批准号：
10271299
负责人：
DEVIN K BINDER
金额：
$ 41.2万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
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/10271299
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/antagonist 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

项目摘要

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：小鼠模型中神经生理学和行为的网络机制脆性 X 综合症。我们的研究结果提出了脆性 X 综合征 (FXS) 的转化生物标志物研究小组发现 FXS 患者和 Fmr1 KO 小鼠的感觉回路均过度兴奋，通过小鼠和人类的脑电图 (EEG) 以及体外脑切片进行测量。我们的研究团队在 NIH 脆弱性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，均在静息状态下状态和声音诱发脑电图，在 FXS 患者和 Fmr1 KO 小鼠。最近，我们在清醒状态下采用了多电极阵列（MEA）脑电图，行为小鼠，发现静息态伽玛能量增强，听觉鸣叫声受损在 Fmr1 KO 小鼠中诱导皮质同步，与 FXS 患者中的发现相似。在在当前的一组研究中，我们建议：（1）确定可能存在的网络层面缺陷使用 MEA 脑电图记录和分析相互作用来评估 FXS 中的感觉和认知功能障碍发育中 (P21-23) 和成年 WT 小鼠与 Fmr1 KO 小鼠的光谱带和大脑区域； (2)测试GABA能和谷氨酸能药物对Fmr1 KO脑电图和行为的影响老鼠。 (1) 和 (2) 都将与项目 1 中的临床医生协调进行，以测试相同的结果跨物种的药物和脑电图结果测量。 (3) 实现多通道深度电极在 Fmr1 KO 小鼠中评估层特异性皮质生理异常。 (4) 测试内源性大麻素药物和抑制性神经元中CB1R选择性缺失对脑电图的影响以及 Fmr1 KO 小鼠的行为。 (3)和(4)都将与项目3协调进行研究人员致力于体外切片制备，以识别突触和细胞缺陷。因此，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 Fmr1 中网络和特定层 MEA EEG 分析和行为的临床方法 KO老鼠。我们预计将鉴定出基于生物标志物的新型药物靶点来治疗 FXS。