Circuit-level substrates of ASD-related cognitive and behavioral impairments
ASD 相关认知和行为障碍的电路水平基础
基本信息
- 批准号:10356063
- 负责人:
- 金额:$ 25.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-01 至 2022-04-01
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelBehaviorBehavioralBudgetsClinicalCognitionCognitiveCognitive deficitsComplexConsensusDefectDendritic SpinesDevelopmentDiseaseEtiologyFaceFunctional disorderGenesGeneticGenetic ModelsGlutamatesGoalsHeadImpaired cognitionImpairmentIntellectual functioning disabilityKnockout MiceKnowledgeLeadLearningLinkMeasuresMental HealthModelingMolecularMusMutationNeurobiologyNeuronsNeurosciencesOperant ConditioningOutputPainPathogenicityPatientsPerceptionPopulationProcessProsencephalonPublishingResearchRisk FactorsRoleSYNGAP1SensorySocial DevelopmentSomatosensory CortexStructureSynapsesSystemTactileTask PerformancesTestingTherapeuticTouch sensationTranslatingVibrissaeWorkautism spectrum disorderbarrel cortexbasebehavior influencebehavioral impairmentbehavioral outcomebrain shapecognitive developmentcritical periodexcitatory neuronexperimental studyfunctional disabilityimprovedin vivoin vivo two-photon imaginginnovationinsightmutantneural circuitneural correlateneuropsychiatric disordernovelrelating to nervous systemsensory cortexsocialsomatosensorystemsynaptic functiontool
项目摘要
Project Summary
A goal of basic mental health research is to understand the molecular, cellular and circuit level substrates that
contribute to neuropsychiatric disorders. The goal of this project is to better understand the principles
underlying circuit dysfunction associated with cognitive and social impairments common to these disorders. A
promising approach to better understand these substrates is to perform in-depth studies in animal models with
high construct and face validities. De novo pathogenic SYNGAP1 mutations leading to haploinsufficiency
cause one the most common genetically defined and non-inherited forms of intellectual disability (ID) with
autism spectrum disorder (ASD;? termed MRD5;? OMIN# 612621). Studies supported by the first budget period
identified Syngap1 heterozygous KO mice as an outstanding genetic model of ASD with ID. Using this model,
we discovered a developmental sensitive period of Syngap1 function that promotes the proper function of
cortical networks. The neurobiological studies we published in the last period were significant because they
identified the developmental timing of dendrite and spine maturation selectivity within forebrain excitatory
neurons as a critical substrate that shapes brain function relevant to cognitive and social development.
For this competitive renewal, we will build on our discoveries in the first budget period by studying the key
substrates of circuit dysfunction in the Syngap1 model by probing how this gene regulates cortical sensory
processing relevant to cognition and learning. This approach is significant because sensory impairments are
extremely common in ASD/ID and these impairments influence behavioral adaptations, including learning.
Syngap1 patients express sensory abnormalities related to touch and pain. However, the circuit abnormalities
that underlie sensory dysfunction are unclear. Thus, our approach is innovative because studies will be
performed in the mouse somatosensory cortex, which will enable powerful in vivo experiments that are capable
of directly linking cellular- and circuit-level functional impairments to sensory-based learning and behavioral
abnormalities. The first Aim will investigate the cellular mechanisms underlying impaired somatosensory cortex
network function caused by pathogenic Syngap1 mutations, with an emphasis on how network-level E/I
imbalances emerge within cortical circuits that directly encode sensory representations. Research proposed in
the second Aim will determine the cellular mechanisms that contribute to sensory-driven learning impairments
in Syngap1 mice. The impact of these studies is that they are expected to advance our understanding how
cortical circuit dysfunction leads to behavioral impairments associated with ASD/ID.
项目总结
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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Jason M Christie其他文献
Jason M Christie的其他文献
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缺乏可塑性门控的小脑病理学
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10619581 - 财政年份:2021
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