Neurobiology of Aggression Comorbidity in Autism
自闭症攻击性合并症的神经生物学
基本信息
- 批准号:10201418
- 负责人:
- 金额:$ 43.25万
- 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:2017-09-12 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:15q3-DimensionalAffectAggressive behaviorAllelesAxonBehavior DisordersBehavioralBindingBrainCell NucleusCellsChromosomesCommunicationComplexCopy Number PolymorphismCyclic AMP-Dependent Protein KinasesCytoplasmDataDefectDevelopmentDopamine AntagonistsDopamine D2 ReceptorElectroconvulsive TherapyElectrophysiology (science)EpitopesFDA approvedFamilyFeedbackFoundationsGene DosageGenesGeneticGenetic ModelsGenetic TranscriptionGlutamatesHumanHypothalamic structureInjectionsIsodicentric ChromosomeKnock-outLaboratoriesLearningLifeLightMapsMedicalMessenger RNAMissionModelingMolecularMusMutationNeurobiologyNeuronsNuclear ExportNuclear ImportPeptidesPharmaceutical PreparationsPhosphorylation SiteProblem behaviorRefractoryResearch DesignRoleSiteSocial InteractionSynapsesSynaptic TransmissionTerritorialityTestingTransgenic MiceUBE3A geneWorkautism spectrum disordercell typecomorbiditydesigner receptors exclusively activated by designer drugsdisabilityinsightinterstitialmalemimeticsneural circuitneuronal cell bodynew therapeutic targetnovelnovel therapeutic interventionpostsynapticpreclinical studyreceptorreconstitutionrepetitive behaviortherapeutic targettherapy developmenttooltransmission processubiquitin-protein ligase
项目摘要
PROJECT SUMMARY
Aggression is a frequent comorbidity in autism spectrum disorders (ASD). The problem is one of the
major reasons families seek medical therapy. Understanding the molecular basis and deciphering the neural
circuits that contribute to the development of this aggression comorbidity could inform novel targeted
therapeutics. Increased copies of maternal chromosome 15q11-13 region [interstitial duplication with a
single extra copy and extranumerary isodicentric chromosome 15q (Idic15) with two extra copies] are
frequent and strongly penetrant (Idic15) causes of ASD. We have recently established that extra copies
of Ube3a alone (15q11-13 gene expressed exclusively from maternal allele in neurons) are sufficient to
reproduce ASD-like deficits in mice (Smith et al. 2011). Interestingly, mice with extra copies of Ube3a
also show increased aggression. Taken together, these observations indicate that aberrant expression of
Ube3a underlies multiple ASD-associated behavioral problems. In this project we will dissect Ube3a's
role in controlling the aggression-comorbidity of ASD: 1) Identify specific neuronal cell types where
increased Ube3a gene dosage increase aggression and identify underlying transcriptional and
electrophysiological changes; and 2) Identify synaptic connections that are disrupted by increased Ube3a
gene dosage to increase aggression within those neuronal cell types. The project promotes the agency's
mission to further a deeper understanding of the neuronal cells, circuits, and genes involved in ASD via
genetic models. The novel molecular insights and genetic tools will facilitate development of treatments
for these life-long behavioral disabilities.
项目摘要
攻击性是自闭症谱系障碍(ASD)的常见合并症。问题在于
家庭寻求药物治疗的主要原因。了解分子基础并破译神经
有助于这种侵略性发展的电路科摩罗可以告知新的目标,
治疗学母体染色体15 q11 -13区域拷贝数增加[间质性重复伴a
单额外拷贝和具有两个额外拷贝的等二着丝粒染色体15 q(Idic 15)的数目
ASD的常见和强渗透性(Idic 15)原因。我们最近发现,
单独的Ube 3a(15 q11 -13基因在神经元中仅由母体等位基因表达)足以
在小鼠中重现ASD样缺陷(Smith et al. 2011)。有趣的是,有额外拷贝Ube 3a的小鼠
也表现出更强的攻击性。综上所述,这些观察结果表明,
Ube 3a是多种ASD相关行为问题的基础。在这个项目中,我们将剖析Ube 3a的
在控制ASD的侵袭性共病中的作用:1)鉴定特定的神经元细胞类型,
增加Ube 3a基因剂量增加攻击性,并确定潜在的转录和
电生理学变化; 2)识别被Ube 3a增加破坏的突触连接
基因剂量来增加这些神经元细胞类型内的攻击性。该项目促进了该机构的
使命是通过以下途径进一步深入了解ASD中涉及的神经元细胞、回路和基因
基因模型新的分子见解和遗传工具将促进治疗的发展
for these lifetime终身behavioral行为disabilities残疾.
项目成果
期刊论文数量(0)
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VTA VGluT2 Sociability Circuit in Genetic Autism
遗传性自闭症中的 VTA VGluT2 社交回路
- 批准号:
10091988 - 财政年份:2018
- 资助金额:
$ 43.25万 - 项目类别:
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