权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

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