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视觉障碍（CVI）。 CVI 通常是与神经和神经发育障碍的合并症，并且显着 有助于改变的发展。 CVI发生时，仅在眼睛中定义无法解释缺陷 感知，表明皮层中的视觉处理负责改变视觉功能。不 目前可以接受治疗或有效疗法。阐明CVI的基础电路 神经发育障碍将指导设计针对性治疗的视觉障碍，还会指导有针对性的治疗方法 还可以改善神经功能功能的其他核心特征。一种神经发育障碍高 CVI的发生率是CDKL5缺乏障碍（CDD）。 CDD是一种以癫痫性脑病为特征 癫痫发作从生命的头几个月开始，严重的发育延迟，通常包括缺乏言语和 独立步行。约有75％的CDD经验CVI的人也反映了这种障碍 在CDD的鼠标模型中，已证明视觉诱发响应减少并减少了视觉 敏锐度。尽管CVI是CDD的重要特征，但我们不了解CVI是如何出现和基础的 界。最近，我们的实验室发现CDD鼠标模型暴露了增加的功能性callosos。 皮质半球的连通性。 callosal跨膜间连通性是高阶的关键 加工。在神经型发育中，Callosal投影神经元（CPN）从第4层修剪其轴突 锥体神经元和浅表和更深的皮质层中的选择性突触，使得 获得成人视觉功能。我们的假设是，在没有CDKL5的情况下 无法完善并获得适当的成熟功能，从而引起CVI。通过组合多层次 方法，我将以两个目标来检验这一工作假设。在目标中，我将在解剖学上分析数字，单元格 CPN及其突触伙伴在CDKL5敲除小鼠中的类型和分布。这个目标的培训将是 由Imaging核心设施和Michela Fagiolini博士提供 发展。在目标两个中，我将实际检查视觉皮质的神经元活性和动力学 在自由行为CDKL5敲除的视觉皮层中，有或没有调节CPN的电路 同窝型wt小鼠。该目标的培训将由Michela Fagiolini博士以及动物监督 行为和生理核心。希瑟·奥尔森（Heather Olson）博士将提供额外的精神制度 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。一起 这些目的将提供有关半球间连通性在皮质视觉障碍中的作用的批判性见解 在CDD中，打开了治疗创新的大门。