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

项目总结/摘要 关键期是可塑性增强的受限窗口，在此期间，发育中的神经回路 对感官输入特别敏感。与成人可塑性带来的短暂改变不同， 在发育关键期发生的是持久的，并在关闭后得到巩固。移植 抑制祖细胞进入成年弱视小鼠视觉皮层已被证明重新激活关键期 可塑性和挽救视觉缺陷。最近的研究结果表明，这种重新激活源于移植- 诱导宿主抑制性神经元的发育复壮。初步转录谱 再生的宿主抑制性神经元识别出钙结合蛋白（Calb 1），一种研究不足的塑化分子， 上调因子。这项工作的长期目标是研究Calb 1在移植中的作用- 诱导宿主抑制性神经元的再生和随后的关键期可塑性的再激活。 目的1a通过病毒灭活Calb 1功能来测试Calb 1是否是移植再激活可塑性所必需的 并使用内在信号光学成像来评估眼优势的变化， 单眼剥夺为了测试Calb 1是否是发育关键期可塑性所必需的，同样， 将对未移植的青少年采用这种方法。目的1b测试Calb 1是否足以重新激活 可塑性，非移植的成年人与病毒过表达的Calb 1显示转移眼优势后， 单眼剥夺Aim 2a利用先前的加权基因共表达网络分析 产生的转录数据，以确定潜在的移植诱导返老还童的生物途径。 将在目标2b中使用 免疫组化这项工作将产生新的见解的细胞和分子机制的基础 抑制神经元移植，视觉回路的发展，并揭示新的翻译目标， 神经治疗学的发展。催化内源性细胞再生的脑修复策略 对广泛的神经系统和神经精神疾病具有巨大的临床前景。 我的培训计划的技术方面侧重于病毒注射和功能成像的获取（Aim 生物信息学和统计分析技能（目标2）。目标1培训将在赞助商和 视觉神经生理学家甘地博士和博士后研究员菲格罗亚-贝莱斯博士，和目标2培训将指导 由共同发起人和转录组学专家Spitale博士和生物信息学家England博士。技术培训将 辅之以高度重视科学交流，专业发展，教学， 外展加州大学欧文分校是一个丰富的，完善的培训基地，成功的研究生，并提供了一个 广泛的资源，结构化的课程和网络机会。

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.