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.

项目总结/摘要 在发达国家，视觉功能障碍的主要原因之一是皮质性视觉障碍（CVI）。CVI 是一种非常常见的合并症与神经和神经发育障碍， 有助于改变发展。CVI发生时，缺陷的眼睛本身不能解释的缺陷， 这表明皮层中的视觉处理是导致视觉功能改变的原因。没有 治疗或有效的疗法目前是可用的。阐明CVI的电路基础， 神经发育障碍将指导设计有针对性的治疗方法，不仅对视力障碍， 也可以改善神经功能的其他核心特征。一种神经发育障碍， CDKL 5缺乏症（CDD）。CDD是一种癫痫性脑病， 在出生后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， 独立行走大约75%的CDD患者经历了CVI，这种损害也反映在 在已经显示具有降低的视觉诱发反应和降低的视觉刺激的CDD小鼠模型中， 敏锐度虽然CVI是CDD的一个突出特征，但我们不了解CVI是如何产生的，以及其背后的原因。 电路.最近，我们的实验室发现，CDD小鼠模型表现出增加的功能胼胝体 大脑皮层半球的连接胼胝体半球间的连接是高阶的关键 处理.在神经典型发育中，胼胝体投射神经元（CPNs）从第4层修剪其轴突 锥体神经元，并在表层和深层皮质层中细化选择性突触， 成人视觉功能的获得。我们的假设是，在缺乏CDKL 5的情况下，胼胝体投射 不能细化和获得适当的成熟功能，从而导致CVI。通过结合多层次 在这种方法中，我将在两个目标中测试这个工作假设。在目的一中，我将从解剖学上分析细胞的数量， 型和分布的CPNs和他们的突触伴侣在Cdkl 5敲除小鼠。为实现这一目标， 由成像核心设施和Michela Fagiolini博士提供，Michela Fagiolini博士是视觉皮层结构专家， 发展在目的二中，我将从生理学的角度研究视皮层神经元的活动和动力学 在自由行为Cdkl 5敲除的视觉皮层中有和没有CPNs调制的回路， 同窝WT小鼠。这一目标的训练将由Michela Fagiolini博士和动物监督。 行为和生理学核心。石楠奥尔森博士将提供额外的指导， CDK 15诊所在波士顿儿童医院和博士张波的统计技术和严谨性。一起 这些目标将为大脑半球间连接在皮层视觉损伤中的作用提供重要的见解 为治疗创新打开了大门。