The role of Calbindin in developmental and transplant-reactivated cortical plasticity

钙结合蛋白在发育和移植再激活皮质可塑性中的作用

• 批准号: 10676102
• 负责人: taylor nakayama
• 金额: $ 4.32万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676102
• 关键词: Adolescent; Adult; Age; Amblyopia; Binding Sites; Bioinformatics; Biological; Calcium-Binding Proteins; Cell Transplantation; Cells; Cementation; Clinical; Communication; Complement; Data; Development; Educational process of instructing; England; Epilepsy; Functional Imaging; Functional disorder; Gene Expression Profile; Genes; Genetic Transcription; Goals; Immunohistochemistry; Injections; LoxP-flanked allele; Memory impairment; Molecular; Mus; Neurodevelopmental Disorder; Neurons; Ocular Dominance; Ontology; Parabiosis; Pathway Analysis; Pathway interactions; Population; Postdoctoral Fellow; Process; Rejuvenation; Resources; Role; Schizophrenia; Signal Pathway; Signal Transduction; Statistical Data Interpretation; Structure; Synaptic plasticity; Testing; Therapeutic; Time; Training; Transcript; Transplant Recipients; Transplantation; Up-Regulation; Viral; Vision; Visual; Visual Cortex; Work; brain repair; calbindin; cellular development; critical developmental period; critical period; developmental plasticity; differential expression; experience; genome-wide; graduate student; inhibitory neuron; insight; monocular deprivation; nerve stem cell; nervous system disorder; neural circuit; neuropsychiatric disorder; novel; novel therapeutics; optical imaging; outreach; overexpression; permissiveness; progenitor; protein protein interaction; repair strategy; repaired; sensory input; skills; stem; therapeutic development; transcription factor; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT Critical periods are restricted windows of heightened plasticity during which developing neural circuits are particularly sensitive to sensory input. Unlike the transient alterations that come with adult plasticity, changes occurring during developmental critical periods are lasting and cemented after closure. The transplantation of inhibitory progenitors into adult amblyopic mouse visual cortex has been shown to reactivate critical period plasticity and rescue visual deficits. Recent findings suggest that this reactivation stems from the transplant- induced developmental rejuvenation of host inhibitory neurons. The preliminary transcriptional profile of rejuvenated host inhibitory neurons identifies Calbindin (Calb1), an understudied plasticizing molecule, as a key upregulated factor. The long-term goal of this work is to investigate the role of Calb1 in the transplant- induced rejuvenation of host inhibitory neurons and subsequent reactivation of critical period plasticity. Aim 1a tests whether Calb1 is necessary for transplant-reactivated plasticity by virally-inactivating Calb1 function in recipient adults and using intrinsic signal optical imaging to assess for a shift in ocular dominance following monocular deprivation. To test whether Calb1 is necessary for developmental critical period plasticity, the same approach will be applied to non-transplanted juveniles. Aim 1b tests whether Calb1 is sufficient to reactivate plasticity, non-transplanted adults with virally-overexpressed Calb1 show shifts in ocular dominance post- monocular deprivation. Aim 2a utilizes weighted gene co-expression network analyses of the previously generated transcriptional data to identify the biological pathways underlying transplant-induced rejuvenation. Expression of identified pathway components will be validated and characterized in Aim 2b using immunohistochemistry. This work will yield novel insight into the cell and molecular mechanisms underlying inhibitory neuron transplantation, visual circuit development, and reveal new translatable targets for the development of neurotherapeutics. Brain repair strategies that catalyze endogenous cellular rejuvenation hold great clinical promise for a broad range of neurological and neuropsychiatric disease. The technical aspect of my training plan focuses on the acquisition of viral injection and functional imaging (Aim 1), and bioinformatic and statistical analysis skills (Aim 2). Aim 1 training will be carried out under sponsor and visual neurophysiologist Dr. Gandhi and postdoctoral fellow Dr. Figueroa-Velez, and Aim 2 training will be guided by co-sponsor and transcriptomics expert Dr. Spitale and bioinformatician Dr. England. Technical training will be complemented by a heavy emphasis on scientific communication, professional development, teaching, and outreach. UC Irvine is a rich, well-established training ground for successful graduate students and offers a breadth of resources, structured courses, and networking opportunities.

项目总结/文摘