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 发达国家视觉功能障碍的主要原因之一是皮质损伤（CVI）。 与神经洛洛洛属和神经发育障碍非常合并症，并且显着 当眼睛中的缺陷无法解释缺陷时，会导致CVI的改变 感知，表明皮层中的视觉处理是改变视觉功能的响应x。 目前可以接受治疗或有效疗法。 神经发育障碍将指导设计针对性的治疗治疗，不仅是视觉上的，而且是 还可以改善神经功能的其他核心特征。 CVI的发生率是CDKL5缺乏症（CDD）。 癫痫发作从生命的头几个月开始，严重的发展延迟，通常包括言语不足和和和和 独立步行。 在CDD的鼠标模型中，已显示出减少视觉诱发的复发和降低的视觉 敏锐度。尽管CVI是CDD的重要特征 电路，我们的实验室发现CDD鼠标模型表现出不适 跨皮质半部的连通性。 加工。 锥体神经元和浅层皮质层中的选择性突触，使它们允许它们 获得成人视觉功能。我们的假设是没有CDKL5 无法完善并获得适当的成熟功能，从而通过组合多层次来产生CVI。 方法，我将以两个目标来检验这个工作假设。 CPN及其在CDKL5敲除小鼠中的类型和突触伙伴的分布。 由成像核心设施和视觉皮质结构专家Michela Fagiolini博士提供 在AIM中，我将在生理上检查视觉皮质的神经元活动和动力学 自由行为CDKL5敲除和 立立物WT小鼠将由Michela Fagiolini博士进行监督 Heather Olson博士将提供行为和生理核心 波士顿儿童医院的CDKL5诊所以及Bo Zhang博士的统计技术和严峻。 这些目标将提供皮质障碍中的批判性见解间跨性别的联系 在CDD中，打开了治疗剂创新的大门。