Determining the Impact of Callosal Connectivity on Visual Cortical Structure and Cortical Visual Impairment in Cdkl5 Deficiency Disorder
确定胼胝体连接对 Cdkl5 缺乏症患者视觉皮质结构和皮质视觉障碍的影响
基本信息
- 批准号:10641481
- 负责人:
- 金额:$ 7.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAnatomyAnimal BehaviorAxonBehavioralBostonCDKL5 disorderClinicCore FacilityCorpus CallosumDefectDepth PerceptionDeveloped CountriesDevelopmentDevelopmental Delay DisordersDiseaseElectrophysiology (science)ExhibitsEyeFutureHeadImageImpairmentIndividualKnock-outKnockout MiceLaboratoriesLifeMeasuresMentorshipMusMutant Strains MiceNervous System PhysiologyNeurodevelopmental DisorderNeurologicNeuronsParvalbuminsPediatric HospitalsPerceptionPhotic StimulationPhysiologicalPhysiologyPyramidal CellsQuality of lifeResearchResolutionRestRoleSeizuresSpeechStructureSynapsesTechniquesTestingThalamic structureTherapeuticTrainingVisionVisual AcuityVisual CortexVisual evoked cortical potentialVisual impairmentVisuospatialWalkingWorkarea striatacell typecomorbiditycortical visual impairmentdesigneffective therapyepileptic encephalopathiesexperienceexperimental studyhippocampal pyramidal neuronimprovedin vivoinhibitory neuroninnovationinsightmouse modelnervous system disordernovel therapeuticsoptogeneticsvisual dysfunctionvisual processing
项目摘要
PROJECT SUMMARY/ABSTRACT
One of the leading causes of visual dysfunction in developed countries is cortical visual impairment (CVI). CVI
is very commonly a comorbidity with neurological and neurodevelopmental disorders, and significantly
contributes to altered development. CVI occurs when deficits in the eyes alone cannot explain the defects in
perception, indicating that visual processing in the cortex is responsible for altered visual function. No
treatments or effective therapies are currently available. Elucidating the circuitry underlying CVI in
neurodevelopmental disorders will guide in designing targeted treatments not only for visual impairment, but
also to improve other core features of neurological functioning. One neurodevelopmental disorder with high
rates of CVI is CDKL5 deficiency disorder (CDD). CDD is an epileptic encephalopathy characterized by
seizures beginning in the first months of life, severe developmental delay, often including lack of speech and
independent walking. About 75% of individuals with CDD experience CVI and this impairment is also reflected
in mouse models of CDD which have been shown to have reduced visual evoked response and reduced visual
acuity. Although CVI is a prominent feature of CDD, we do not understand how CVI arises and the underlying
circuits. Recently, our laboratory discovered that CDD mouse models exhibit an increased functional callosal
connectivity across cortical hemispheres. Callosal interhemispheric connectivity is key for higher order
processing. In neurotypical development, callosal projection neurons (CPNs) prune their axons from layer 4
pyramidal neurons and refine selective synapses in superficial and deeper cortical layers allowing the
acquisition of adult visual function. Our hypothesis is that in the absence of CDKL5, callosal projections
fail to refine and to acquire proper mature function giving rise to CVI. By combining a multi-level
approach, I will test this working hypothesis in two aims. In aim one I will analyze anatomically the number, cell
type, and distribution of CPNs and their synaptic partners in Cdkl5 knockout mice. Training for this aim will be
provided by imaging core facilities and Dr. Michela Fagiolini who is an expert in visual cortical structure and
development. In aim two I will examine physiologically the neuronal activity and dynamics of visual cortical
circuits with and without modulation of CPNs in the visual cortex of freely behaving Cdkl5 knockout and
littermate WT mice. Training for this aim will be overseen by Dr. Michela Fagiolini, as well as the animal
behavior and physiology core. Additional mentorship will be provided by Dr. Heather Olson as the head of
CDKl5 clinic at Boston Children’s Hospital and by Dr. Bo Zhang on statistical technique and rigor. Together
these aims will provide critical insight into the role of interhemispheric connectivity in cortical visual impairment
in CDD opening the door to innovations in therapeutics.
项目摘要/摘要
在发达国家,导致视觉功能障碍的主要原因之一是皮质视觉障碍(CVI)。CVI
是神经和神经发育障碍的共病,而且显著
有助于改变发育。当仅有眼睛的缺陷不能解释眼睛的缺陷时,就会发生CVI
知觉,表明大脑皮层的视觉处理是导致视觉功能改变的原因。不是
目前已有治疗方法或有效的治疗方法。阐明CVI中潜在的电路
神经发育障碍将指导设计有针对性的治疗,不仅针对视力障碍,而且
也是为了改善神经功能的其他核心特征。一例神经发育障碍伴高
CVI发生率为CDKL5缺乏症(CDD)。CDD是一种癫痫性脑病,其特征是
从出生的头几个月开始癫痫发作,严重的发育迟缓,通常包括缺乏语言和
独立行走。大约75%的CDD患者经历了CVI,这种损害也反映了出来
在CDD的小鼠模型中,已被证明视觉诱发反应和视力下降
敏锐度。虽然CVI是CDD的一个显著特征,但我们不了解CVI是如何产生的,以及潜在的
电路。最近,我们的实验室发现,CDD小鼠模型表现出功能增强的膝盖骨
大脑皮层半球的连通性。颧骨半球间的连通性是更高阶数的关键
正在处理。在神经典型发育过程中,从第4层开始剪除它们的轴突
锥体神经元和提炼皮层浅层和深层的选择性突触,从而使
成人视觉功能的获得。我们的假设是,在缺乏CDKL5的情况下,膝盖骨投射
未能提炼和获得适当的成熟功能,导致CVI的产生。通过组合多个级别的
方法,我将在两个目标中检验这个工作假说。在目标一中,我将对细胞的数量进行解剖学分析
CDKL5基因敲除小鼠CPN及其突触伙伴的类型和分布。为实现这一目标进行的培训将是
由成像核心设施和Michela Fagiolini博士提供,Michela Fagiolini博士是视觉皮质结构和
发展。在第二个目标中,我将对视皮层的神经元活动和动力学进行生理学检查。
自由行为CDKL5基因敲除和非CDKL5基因敲除的视皮层中有和没有CPN调制的回路
产仔WT小鼠。这一目标的训练将由Michela Fagiolini博士和动物监督
行为和生理核心。其他导师将由希瑟·奥尔森博士担任
美国波士顿儿童医院的CDKL5临床医生和张波博士介绍了统计技术和严谨性。同舟共济
这些目标将为大脑半球间连通性在皮质视觉障碍中的作用提供关键的见解
在CDD中打开了治疗学创新的大门。
项目成果
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