Neural coordination and discoordination in Fmr1 null mice

Fmr1 缺失小鼠的神经协调和不协调

基本信息

批准号：
9472717
负责人：
ANDRE ANTONIO FENTON
金额：
$ 41.19万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9472717
关键词：
Action Potentials Area Autistic Disorder Avoidance Learning Behavior Behavioral Biological Biological Neural Networks Brain Budgets Cells Clinical Cognitive Cognitive deficits Conflict (Psychology)Defect Discrimination Disease Dorsal Etiology Evoked Potentials FMR1 Fragile X Syndrome Functional disorder Genes Genetic Genetic Models Hippocampus (Brain)Impaired cognition Impairment Intellectual functioning disability Knock-out Knockout Mice Knowledge Lead Learning Measures Memory Memory impairment Modeling Modification Molecular Mus Mutate Mutation Neurobehavioral Manifestations Pathway interactions Physiology Psyche structure Research Role Stream Synapses Synaptic Transmission System Testing Therapeutic Training Translations Work cognitive disability cognitive system dentate gyrus entorhinal cortex excitatory neuron experience flexibility improved inhibitory neuron mouse model mutant mouse model neural patterning neuroregulation novel null mutation operation relating to nervous system response social synaptic depression synaptic function theories

Action Potentials Area Autistic Disorder Avoidance Learning Behavior Behavioral Biological Biological Neural Networks Brain Budgets Cells Clinical Cognitive Cognitive deficits Conflict (Psychology)Defect Discrimination Disease Dorsal Etiology Evoked Potentials FMR1 Fragile X Syndrome Functional disorder Genes Genetic Genetic Models Hippocampus (Brain)Impaired cognition Impairment Intellectual functioning disability Knock-out Knockout Mice Knowledge Lead Learning Measures Memory Memory impairment Modeling Modification Molecular Mus Mutate Mutation Neurobehavioral Manifestations Pathway interactions Physiology Psyche structure Research Role Stream Synapses Synaptic Transmission System Testing Therapeutic Training Translations Work cognitive disability cognitive system dentate gyrus entorhinal cortex excitatory neuron experience flexibility improved inhibitory neuron mouse model mutant mouse model neural patterning neuroregulation novel null mutation operation relating to nervous system response social synaptic depression synaptic function theories

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项目摘要

ABSTRACT Full mutation of the FMR1 gene causes loss of the fragile X mental retardation protein (FMRP) and fragile X syndrome (FXS) characterized by intellectual disability with devastating cognitive consequences and features of autism. Study of Fmr1 knockout (KO) mouse models of the FXS genetic defect identified that loss of FMRP dysregulates translation at synapses, leading to synaptic dysfunction, for example excessive synaptic depression in response to group 1 mGluR stimulation. Unfortunately, despite substantial knowledge of the molecular consequences of FMR1 alteration, how the molecular changes lead to the clinical, cognitive manifestations is unknown. We consider a systems level analysis and use the hippocampus as a model cognitive system. We propose that impaired cognition in Fmr1 KO mice is due to the inability of information-carrying hippocampus principal cell spike trains to represent distinct streams of information because of the dysregulation of synaptic transmission. As a result, cognitive deficits primarily manifest when FXS model mice are challenged to generate distinctive neural representations in situations that are inconsistent with the information they have previously learned. Preliminary findings from analysis of temporal coordination amongst hippocampal place cell spike trains, local field potentials (LFPs), and conjoint action potential and LFP (spike-field) coordination provide substantial evidence in support of the central “excitation-inhibition discoordination” hypothesis of this work. The hypothesis asserts that cognitive deficits in FXS arise because dysregulated learning-induced changes of synaptic network function cause discoordinated discharge within networks of excitatory and inhibitory neurons. We test the hypothesis by comparing FXS model and control mice in a variety of memory discrimination tasks. We will examine conventional Fmr1 KO mice in which the gene is mutated in all cells, as well as mice in which the mutation is restricted to excitatory (Fmr1 KOe) or inhibitory (Fmr1 KOi) neurons to learn whether dysfunction in one cell class is sufficient to cause cognitive dysfunction. We will also measure how memory training changes synaptic function within the hippocampus circuit by recording evoked potentials across the somatodendritic synaptic compartments of dorsal hippocampus in freely-behaving mice. Finally, we will investigate abnormalities in how memory-related Fmr1 place cell ensemble discharge is controlled by oscillations in the LFP that arise from inputs at distinctive dendritic compartments and causally test whether the abnormality contributes to memory discrimination impairment using chemogenetic manipulations of the inputs. These studies evaluate a novel, circuit-driven neuromodulatory therapeutic concept for reducing cognitive disability in FXS and perhaps other disorders.

抽象的 FMR1基因的完全突变导致脆弱的X智力低下蛋白（FMRP）和脆弱X的丧失综合征（FXS），其特征是具有毁灭性的认知后果和特征的实质性残疾自闭症。 FXS遗传缺陷的FMR1敲除（KO）小鼠模型的研究确定FMRP的丧失在突触处的翻译失调，导致突触功能障碍，例如超级突触响应第1组mglur刺激的抑郁症。不幸的是，使命对 FMR1改变的分子后果，分子变化如何导致临床认知表现未知。我们考虑系统级分析，并使用海马作为模型认知系统。我们提出了这一点 FMR1 KO小鼠的认知受损是由于信息携带海马主细胞所致由于突触传播的失调，尖峰火车代表不同的信息流。结果，当FXS模型小鼠受到挑战以产生独特的时，认知定义了主要清单与他们先前学到的信息不一致的情况下的神经表示。来自海马位置尖峰列车中临时协调分析的初步发现，本地现场电位（LFP）和联合动作电位和LFP（Spike-Field）协调提供了实质性的支持该工作的中心“激发抑制不偶然”假设的证据。假设断言认知在FX中的定义是由于学习诱导的突触变化的失调而出现的网络功能会导致兴奋和抑制神经元网络中不并发放电。我们通过在多种内存歧视任务中比较FXS模型和控制小鼠来检验假设。我们将检查常规FMR1 KO小鼠，其中该基因在所有细胞中都被突变，以及其中的小鼠该突变仅限于兴奋性（FMR1 KOE）或抑制性（FMR1 KOI）神经元，以了解一个细胞类别的功能障碍足以引起认知功能障碍。我们还将衡量记忆的方式通过记录整个整个训练的诱发电位，训练更改海马电路内的突触功能自由行为小鼠的背侧海马的体突触室。最后，我们会的调查与记忆相关FMR1如何控制细胞集合放电的异常 LFP中由独特的树突室的投入产生的振荡，并因果测试是否是否测试绝对有助于使用输入的化学发生操作导致记忆歧视障碍。这些研究评估了一种新型的电路驱动神经调节性治疗概念，以降低认知 FXS和其他疾病中的残疾。