Cortical Interneuron Dysfunction in Fragile X Syndrome
脆性 X 综合征中的皮质中间神经元功能障碍
基本信息
- 批准号:10418431
- 负责人:
- 金额:$ 51.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdaptive BehaviorsAddressAdultAffectAnimal ModelAnimalsApoptosisBehaviorBiological AssayBirthBrainBromodeoxyuridineCalciumCaspaseCell DeathCell DensityCellsCessation of lifeCharacteristicsChronicCollaborationsContractorDataDevelopmentExperimental DesignsFMR1Fragile X SyndromeFunctional disorderGangliaGenesGeneticGoalsGrantHypersensitivityImageImpairmentIn VitroIndividualIntellectual functioning disabilityInterneuronsKnock-outKnockout MiceLaboratoriesMapsMedialMusNeurodevelopmental DisorderNeurologic SymptomsNeuronsParvalbuminsPerceptual learningPharmaceutical PreparationsPhenocopyPhenotypePyramidal CellsQuality of lifeReportingRhodopsinSensorySliceSomatosensory CortexSomatostatinSymptomsTactileTestingTherapeuticTimeUniversitiesVibrissaeWorkautism spectrum disorderavoidance behaviorcell typecritical perioddensitydesigner receptors exclusively activated by designer drugshippocampal pyramidal neuronin vivoin vivo calcium imaginginterdisciplinary approachloss of functionmature animalmigrationmouse modelnerve stem cellneurogenesisnovelpatch clamppostnatalresponsesmall moleculetherapeutic targettooltranslational studytwo-photon
项目摘要
SUMMARY
Cortical circuit dysfunction is a primary pathophysiology that underlies prominent neurological symptoms of
Fragile X Syndrome (FXS). Yet the precise way in which circuit development in the cortex is altered in FXS
has not been fully elucidated. Recent work by us, and others, has established that local circuit interneurons
(INs) may be a key to understanding cortical circuits in FXS. We demonstrated that the density, maturity
and activity of parvalbumin (PV) cortical INs are all reduced in the Fmr1 knockout (KO) mouse model of
FXS. Here we propose to address outstanding questions in the field by determining how the birth, migration
and connectivity of PV INs are disrupted in Fmr1 KO mice, and how this leads to sensory hypersensitivity
and tactile defensiveness. We will incorporate a detailed analysis of PV INs using birth dating,
neuroanatomical and functional studies to define how the abnormal integration of PV INs into feedforward
circuits in the primary somatosensory cortex (S1) contributes to atypical sensory processing. In preliminary
studies, we demonstrate that, in response to repetitive whisker stimulation, Fmr1 KO mice display
maladaptive avoidance behaviors that correlate with a lack of neuronal adaptation of layer (L) 2/3 pyramidal
neurons in S1. We also show that PV INs and their precursors from the medial ganglionic eminence (MGE)
are hypoactive in S1 of Fmr1 KO mice by postnatal day (P) 6, and that increasing their activity for a few
days using excitatory DREADDs significantly increases their density by P15. We will now determine whether
similar early activity manipulations of MGE-derived INs, or later on in more mature PV INs, can restore the
loss of sensory adaptation of L2/3 neurons and ameliorate tactile defensiveness in Fmr1 KO mice. We will
address the following important questions: 1. What are the contributions of neurogenesis, migration,
connectivity and developmental apoptosis to the reduced density of PV INs in FXS? 2. How do MGE-derived
INs and pyramidal neurons interact during the early postnatal critical period and how is their ‘handshake’
different in FXS? 3. Is the hypoactivity of PV INs or their precursors causal to the circuit and behavior deficits
of Fmr1 KO mice? The mechanistic experimental design employs cell type-specific intersectional genetics,
in vivo calcium imaging, chemogenetics, and ex vivo circuit channel-rhodopsin connectivity mapping, among
others. An important goal of this grant is to identify whether targeting INs is a viable path for therapeutics in
FXS. As such a novel class of allosteric modulating drugs of Kv3.1 channels (responsible for fast-spiking
characteristics of PV INs) will be tested in Fmr1 KO mice. Overall, the collaboration between the laboratories
of Dr. Carlos Portera-Cailliau (co-PI, PL) at UCLA and Dr. Anis Contractor (co-PI) at Northwestern University
will enable a comprehensive approach to understanding the developmental and functional contributions of
INs to the pathophysiology of FXS.
总结
皮质回路功能障碍是一种主要的病理生理学,其是脑缺血的突出神经症状的基础。
脆性X综合征(FXS)。然而,在FXS中,大脑皮层回路发育的确切方式发生了改变,
尚未完全阐明。我们和其他人最近的工作已经确定,局部回路中间神经元
(INs)可能是理解FXS大脑皮层回路的关键我们证明了密度成熟度
小清蛋白(PV)皮质IN的活性在Fmr 1敲除(KO)小鼠模型中均降低,
FXS。在这里,我们提出解决悬而未决的问题,在该领域确定如何出生,迁移,
在Fmr 1 KO小鼠中,PV IN的连接和连接被破坏,以及这如何导致感觉超敏反应
和触觉防御。我们将使用出生日期对PV IN进行详细分析,
神经解剖学和功能研究,以确定PV IN如何异常整合到前馈
初级躯体感觉皮质(S1)中的回路有助于非典型的感觉处理。初步
研究中,我们证明,在响应重复的胡须刺激,Fmr 1基因敲除小鼠显示,
适应不良的回避行为与(L)2/3层锥体神经元适应性缺乏相关
S1神经元。我们还发现,内侧神经节隆起(MGE)的PV IN及其前体
在出生后第6天(P),Fmr 1 KO小鼠的S1中的活性低下,并且在少数情况下,
天使用兴奋性DREADD显着增加其密度P15。我们现在将决定
对MGE衍生的IN进行类似的早期活性操作,或在更成熟的PV IN中进行类似的早期活性操作,
L2/3神经元的感觉适应性丧失并改善Fmr 1 KO小鼠的触觉防御性。我们将
解决以下重要问题:1.神经发生,迁移,
连接和发育性细胞凋亡对FXS中PV IN密度降低的影响?2. MGE如何衍生
新生儿出生后早期关键期内神经元和锥体神经元的相互作用及其“握手”机制
在FXS中不同?3. PV IN或其前体的活动减退是否是回路和行为缺陷的原因
Fmr 1基因敲除小鼠机制实验设计采用细胞类型特异性交叉遗传学,
体内钙成像、化学遗传学和离体回路通道-视紫红质连接性作图,
他人这项资助的一个重要目标是确定靶向INs是否是一种可行的治疗方法,
FXS。因此,一类新型的Kv3.1通道(负责快速尖峰)的变构调节药物
将在Fmr 1 KO小鼠中检测PV IN的特征。总的来说,实验室之间的合作
加州大学洛杉矶分校的卡洛斯波特拉-卡里奥博士(共同PI,PL)和西北大学的阿尼斯承包商博士(共同PI)
将有助于采取全面的方法来理解发展和功能的贡献,
FXS的病理生理学研究。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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{{ item.author }}
{{ truncateString('Anis Contractor', 18)}}的其他基金
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10810245 - 财政年份:2022
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Cortical Interneuron Dysfunction in Fragile X Syndrome
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10599332 - 财政年份:2022
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