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.

项目概要/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）。计算机视觉指数 是一种非常常见的神经系统和神经发育障碍的合并症，并且显着 有助于改变发展。当眼睛的缺陷无法单独解释眼睛的缺陷时，就会发生 CVI。 感知，表明皮层的视觉处理负责改变视觉功能。不 目前已有治疗或有效疗法。阐明 CVI 的底层电路 神经发育障碍将指导设计有针对性的治疗方法，不仅针对视力障碍，而且 还可以改善神经功能的其他核心特征。一种高度神经发育障碍 CVI 的发病率是 CDKL5 缺乏症 (CDD)。 CDD是一种癫痫性脑病，其特征是 癫痫发作在生命的最初几个月开始，严重的发育迟缓，通常包括缺乏言语和 独立行走。大约 75% 的 CDD 患者经历过 CVI，这种损害也反映出来 在 CDD 小鼠模型中，这些模型已被证明视觉诱发反应和视觉减弱 敏锐度。虽然CVI是CDD的一个显着特征，但我们并不了解CVI是如何产生的以及底层的原理。 电路。最近，我们实验室发现CDD小鼠模型表现出功能性胼胝体增加 跨皮质半球的连接。胼胝体半球间连接是高阶的关键 加工。在神经典型发育过程中，胼胝体投射神经元 (CPN) 从第 4 层修剪其轴突 锥体神经元并细化浅层和深层皮质层的选择性突触，从而允许 获得成人视觉功能。我们的假设是，在缺乏 CDKL5 的情况下，胼胝体投射 未能完善并获得适当的成熟功能，从而导致 CVI。通过结合多层次 方法，我将在两个目标上测试这个工作假设。在目标一中，我将从解剖学上分析数字、细胞 Cdkl5 敲除小鼠中 CPN 及其突触伙伴的类型和分布。为此目的而进行的培训将是 由成像核心设施和视觉皮层结构专家 Michela Fagiolini 博士提供 发展。在目标二中，我将从生理学角度检查视觉皮层的神经元活动和动力学 自由行为 Cdkl5 敲除和视觉皮层中具有和不具有 CPN 调制的电路 同窝WT小鼠。为此目的进行的训练将由 Michela Fagiolini 博士以及动物负责监督 行为和生理学核心。希瑟·奥尔森 (Heather Olson) 博士将作为该项目的负责人提供额外的指导。 波士顿儿童医院的 CDKl5 诊所，由张博博士介绍统计技术和严谨性。一起 这些目标将为大脑半球间连接在皮质视觉障碍中的作用提供重要的见解 CDD 为治疗创新打开了大门。