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:
- 金额:$ 41.19万
- 依托单位:
- 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:
- 关键词:Action PotentialsAreaAutistic DisorderAvoidance LearningBehaviorBehavioralBiologicalBiological Neural NetworksBrainBudgetsCellsClinicalCognitiveCognitive deficitsConflict (Psychology)DefectDiscriminationDiseaseDorsalEtiologyEvoked PotentialsFMR1Fragile X SyndromeFunctional disorderGenesGeneticGenetic ModelsHippocampus (Brain)Impaired cognitionImpairmentIntellectual functioning disabilityKnock-outKnockout MiceKnowledgeLeadLearningMeasuresMemoryMemory impairmentModelingModificationMolecularMusMutateMutationNeurobehavioral ManifestationsPathway interactionsPhysiologyPsyche structureResearchRoleStreamSynapsesSynaptic TransmissionSystemTestingTherapeuticTrainingTranslationsWorkcognitive disabilitycognitive systemdentate gyrusentorhinal cortexexcitatory neuronexperienceflexibilityimprovedinhibitory neuronmouse modelmutant mouse modelneural patterningneuroregulationnovelnull mutationoperationrelating to nervous systemresponsesocialsynaptic depressionsynaptic functiontheories
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.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ANDRE ANTONIO FENTON其他文献
ANDRE ANTONIO FENTON的其他文献
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{{ truncateString('ANDRE ANTONIO FENTON', 18)}}的其他基金
Towards a critical test of the synaptic plasticity and memory hypothesis
对突触可塑性和记忆假说进行关键测试
- 批准号:
10681918 - 财政年份:2023
- 资助金额:
$ 41.19万 - 项目类别:
Molecular mechanisms of memory maintenance and dysfunction in neural circuits
记忆维持和神经回路功能障碍的分子机制
- 批准号:
10372932 - 财政年份:2018
- 资助金额:
$ 41.19万 - 项目类别:
Molecular mechanisms of memory maintenance and dysfunction in neural circuits
记忆维持和神经回路功能障碍的分子机制
- 批准号:
9884816 - 财政年份:2018
- 资助金额:
$ 41.19万 - 项目类别:
Neural coordination and discoordination in Fmr1 null mice
Fmr1 缺失小鼠的神经协调和不协调
- 批准号:
9903473 - 财政年份:2017
- 资助金额:
$ 41.19万 - 项目类别:
Hippocampal neurogenesis, pattern separation & age-related cognitive impairments.
海马神经发生,模式分离
- 批准号:
9280819 - 财政年份:2013
- 资助金额:
$ 41.19万 - 项目类别:
Hippocampal neurogenesis, pattern separation & age-related cognitive impairments.
海马神经发生,模式分离
- 批准号:
8723046 - 财政年份:2013
- 资助金额:
$ 41.19万 - 项目类别:
Hippocampal neurogenesis, pattern separation & age-related cognitive impairments.
海马神经发生,模式分离
- 批准号:
9067887 - 财政年份:2013
- 资助金额:
$ 41.19万 - 项目类别:
Hippocampal neurogenesis, pattern separation & age-related cognitive impairments.
海马神经发生,模式分离
- 批准号:
8506187 - 财政年份:2013
- 资助金额:
$ 41.19万 - 项目类别:
Hippocampal neurogenesis, pattern separation & age-related cognitive impairments.
海马神经发生,模式分离
- 批准号:
8876526 - 财政年份:2013
- 资助金额:
$ 41.19万 - 项目类别:
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