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

• 批准号: 10641481
• 负责人: Elyza Kelly
• 金额: $ 7.2万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10641481
• 关键词: Adult; Anatomy; Animal Behavior; Axon; Behavioral; Boston; CDKL5 disorder; Clinic; Core Facility; Corpus Callosum; Defect; Depth Perception; Developed Countries; Development; Developmental Delay Disorders; Disease; Electrophysiology (science); Exhibits; Eye; Future; Head; Image; Impairment; Individual; Knock-out; Knockout Mice; Laboratories; Life; Measures; Mentorship; Mus; Mutant Strains Mice; Nervous System Physiology; Neurodevelopmental Disorder; Neurologic; Neurons; Parvalbumins; Pediatric Hospitals; Perception; Photic Stimulation; Physiological; Physiology; Pyramidal Cells; Quality of life; Research; Resolution; Rest; Role; Seizures; Speech; Structure; Synapses; Techniques; Testing; Thalamic structure; Therapeutic; Training; Vision; Visual Acuity; Visual Cortex; Visual evoked cortical potential; Visual impairment; Visuospatial; Walking; Work; area striata; cell type; comorbidity; cortical visual impairment; design; effective therapy; epileptic encephalopathies; experience; experimental study; hippocampal pyramidal neuron; improved; in vivo; inhibitory neuron; innovation; insight; mouse model; nervous system disorder; novel therapeutics; optogenetics; visual dysfunction; visual processing

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。