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/文摘