Postnatal mechanisms of cognitive development in mice
小鼠认知发展的产后机制
基本信息
- 批准号:10539977
- 负责人:
- 金额:$ 60.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-01-18 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:22q11.2AddressAdultAffectAnimalsAxonBirthBrain regionCapitalCell physiologyCellsChildhoodCognitionCognitiveCognitive deficitsCopy Number PolymorphismDataDevelopmentDiffusion Magnetic Resonance ImagingDimensionsDiseaseDoseElectron MicroscopyElectrophysiology (science)EmbryoEventExhibitsFiberFundingGene MutationGenesGeneticGoalsHeterozygoteHippocampus (Brain)HumanImpaired cognitionImpairmentIn VitroIndividualItalyKnowledgeLettersLinkMagnetic Resonance ImagingMemory impairmentMental disordersMolecularMusMutant Strains MiceMutationMyelinNatureNeonatalNeurodevelopmental DisorderNeuronsNomenclatureOligodendrogliaOutcomePathway interactionsPharmaceutical PreparationsPhysiologicalPlayProductionProgress ReportsProteinsPublishingResearchRodentRoleShort-Term MemorySignal TransductionSocial InteractionSolidSpeedTestingTextTherapeuticVariantWorkcognitive developmentcognitive functioncognitive taskdesignfimbriaflexibilitygenetic variantgranule cellhigh riskimprovedin vivomemory acquisitionmouse modelmyelinationnerve stem cellneurogenesisnovelnovel therapeuticsoligodendrocyte precursorpostnatalpostnatal periodprecursor cellsocial deficitsspatial memorystemstem cellssubventricular zonetherapeutic developmentwhite matter
项目摘要
Abstract
Cognitive deficits are major disabling impairments associated with neurodevelopmental disorders. Currently
available drugs have poor efficacy due to a limited understanding of the genetic and cellular mechanisms
underlying these deficits. Our project addresses this unmet need by exploring the mechanistic underpinnings of
cognitive deficits. Copy number variants (CNVs), such as a 1.5 Mb hemizygous deletion of 22q11.2, and variants
of single genes, such as heterozygous variants of Tbx1, a 22q11.2 gene, have been associated with a high risk
of cognitive deficits in humans and serve as promising mechanistic entry points. As many social, memory, and
cognitive deficits in individuals with these genetic variants manifest during childhood (i.e., a postnatal period after
birth and before full adulthood), our previous work focused on post-embryonic cellular events. We showed that
the heterozygosity of Tbx1 in early postnatal neural stem cells contribute to deficits in social interactions and that
altered postnatal myelination in the fimbria may represent a potential cellular substrate for impaired cognitive
speed. This proposed project will test the overarching hypothesis that alterations in postnatal myelination due to
dose alterations of genes implicated in neurodevelopmental disorders negatively impact cognitive speed. To
allow for the disambiguation of the relative roles of postnatal oligodendrogenesis and postnatal neurogenesis in
cognitive speed, we developed two conditional Tbx1 heterozygous mouse models: Ng2CreER;Tbx1flox/+ and
nesCreERT2;Tbx1flox/+ mice. To evaluate the relative roles played by Tbx1 and 22q11.2 CNV in cognitive speed,
we will include a mouse model of 22q11.2 hemizygous deletion. Aim 1 will evaluate the impacts on cognitive
speed of conditional heterozygous Tbx1 deletion from postnatal stem/progenitor cells of oligodendrocyte or
neuronal lineage in mice and determine the relative contributions to cognitive speed of Tbx1 deficiency
compared with global 22q11.2 hemizygosity. We will use rodent tasks for spatial memory, cognitive flexibility,
and working memory, as the speed of these cognitive dimensions are negatively impacted from childhood
among carriers of 22q11.2 hemizygosity. Aim 2 will identify regions with altered white matter integrity, assess
axonal myelination in affected brain regions, and evaluate the conductance speed of myelin-deficient pathways
using diffusion tensor imaging (DTI)-MRI, electron microscopy, and electrophysiological recordings, respectively,
in the three mouse models. Aim 3 will evaluate the in vivo functional roles of TBX1’s target genes in the
cognitive functions in mutant mice and establish the precise cellular processes associated with postnatal
oligodendrogenesis and myelin production in vivo and in vitro. The current proposal will reveal novel postnatal
cellular mechanisms associated with a distinct dimension of cognitive function, improving our understanding of
the cellular mechanisms contributing to altered cognitive dimensions that are severely impacted by 22q11.2
hemizygosity, Tbx1 and TBX1’s non-22q11.2 target genes, which will provide a mechanistic basis for the
development of therapeutic options.
摘要
认知缺陷是与神经发育障碍相关的主要致残性损伤。目前
由于对遗传和细胞机制的理解有限,
这些赤字的根源。我们的项目通过探索以下机制基础来解决这一未满足的需求:
认知缺陷拷贝数变异(CNVs),如22q11.2的1.5 Mb半合子缺失,以及变异
单个基因的突变,如22q11.2基因Tbx 1的杂合变异,与高风险相关。
人类认知缺陷的研究,并作为有希望的机械切入点。许多社交、记忆和
具有这些遗传变异的个体的认知缺陷在儿童期表现出来(即,产后一段时间后,
出生和完全成年之前),我们以前的工作集中在胚胎后细胞事件。我们发现
出生后早期神经干细胞中Tbx 1杂合性导致社会互动的缺陷,
海马伞中出生后髓鞘形成的改变可能是认知功能受损的潜在细胞基质,
速度这个项目将测试总体假设,即出生后髓鞘形成的改变,
与神经发育障碍有关的基因的剂量改变对认知速度产生负面影响。到
允许出生后少突神经发生和出生后神经发生的相对作用的歧义,
为了提高认知速度,我们开发了两种条件性Tbx 1杂合子小鼠模型:Ng 2CreER; Tbx 1flox/+和
nesCreERT 2; Tbxlflox/+小鼠。为了评估Tbx 1和22q11.2 CNV在认知速度中的相对作用,
我们将包括22q11.2半合子缺失的小鼠模型。目标1将评估对认知的影响
出生后少突胶质细胞干/祖细胞中条件性杂合Tbx 1缺失速度
神经元谱系,并确定Tbx 1缺陷对认知速度的相对贡献
与全球22q11.2半合子相比。我们将使用啮齿类动物的任务来测试空间记忆,认知灵活性,
和工作记忆,因为这些认知维度的速度从童年起就受到负面影响
22q11.2半合子携带者。目标2将识别白色物质完整性改变的区域,评估
在受影响的大脑区域的轴突髓鞘形成,并评估髓鞘缺乏途径的传导速度
分别使用扩散张量成像(DTI)-MRI、电子显微镜和电生理记录,
在三个小鼠模型中。目的3:研究TBX 1靶基因在肿瘤细胞中的作用。
突变小鼠的认知功能,并建立与出生后
体内和体外的少突神经发生和髓磷脂产生。目前的建议将揭示新的产后
细胞机制与认知功能的独特维度相关,提高了我们对
导致认知维度改变的细胞机制受到22q11.2的严重影响
半合子、TBX 1和TBX 1的非22q11.2靶基因,这将为Tbx 1和Tbx 1的非22q11.2靶基因的表达提供机制基础。
开发治疗方案。
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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Noboru Hiroi其他文献
Noboru Hiroi的其他文献
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{{ truncateString('Noboru Hiroi', 18)}}的其他基金
Predicting the developmental trajectories of cognitive and motor dimensions from preterm neonatal vocalizations
从早产儿发声预测认知和运动维度的发育轨迹
- 批准号:
10315460 - 财政年份:2021
- 资助金额:
$ 60.75万 - 项目类别:
Predicting the developmental trajectories of cognitive and motor dimensions from preterm neonatal vocalizations
从早产儿发声预测认知和运动维度的发育轨迹
- 批准号:
10463851 - 财政年份:2021
- 资助金额:
$ 60.75万 - 项目类别:
Structure and Function of Neonatal Social Communication in Genetic Mouse Models of Autism
自闭症遗传小鼠模型中新生儿社交沟通的结构和功能
- 批准号:
10220931 - 财政年份:2017
- 资助金额:
$ 60.75万 - 项目类别:
Structure and Function of Neonatal Social Communication in Genetic Mouse Models of Autism
自闭症遗传小鼠模型中新生儿社交沟通的结构和功能
- 批准号:
10005276 - 财政年份:2017
- 资助金额:
$ 60.75万 - 项目类别:
Postnatal mechanisms of cognitive development in mice
小鼠认知发展的产后机制
- 批准号:
10657796 - 财政年份:2013
- 资助金额:
$ 60.75万 - 项目类别:
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