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

项目摘要/摘要 关键时期是高度可塑性的有限窗口，在此期间发育的神经回路 对感官输入特别敏感。与成人可塑性带来的短暂变化不同，变化 在发育关键期发生的疾病在闭合后持续并被粘合。人类的移植 抑制前体细胞进入成年弱视小鼠的视皮层被证明是重新激活关键期 可塑性和挽救视力缺陷。最近的发现表明，这种重新激活源于移植- 诱导宿主抑制神经元的发育恢复。基因的初步转录图谱 恢复活力的宿主抑制神经元将Calbindin(Calb1)确定为关键，Calb1是一种未被研究的塑化分子 上调因子。这项工作的长期目标是研究Calb1在移植中的作用。 诱导宿主抑制神经元恢复活力，并随后重新激活关键期可塑性。 目的1a通过病毒灭活Calb1功能来测试Calb1是否是移植后再激活的可塑性所必需的 在接受治疗的成人中，使用固有的信号光学成像来评估术后眼部优势的改变 单眼剥夺。为了测试Calb1是否对发育关键期可塑性是必需的，同样 这种方法将适用于未移植的青少年。目标1b测试Calb1是否足以重新激活 可塑性，非移植的成年病毒过表达的Calb1在术后表现出眼睛优势的变化。 单眼剥夺。Aim 2a利用加权基因共表达网络分析以前的 生成了转录数据，以确定移植诱导的返老还童的生物途径。 识别的途径组件的表达将在AIM 2b中进行验证和表征 免疫组织化学。这项工作将对潜在的细胞和分子机制产生新的见解 抑制性神经元移植，视觉回路开发，并揭示了新的可翻译靶点 神经治疗学的发展。催化内源性细胞返老还童的脑修复策略 对广泛的神经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获取病毒注射和功能成像(AIM 1)以及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Figueroa-Velez博士以及Aim 2培训将得到指导 由联合发起人兼转录学专家斯皮塔尔博士和生物信息学家英格兰博士主持。技术培训将是 辅以对科学交流、专业发展、教学和 外展。加州大学欧文分校是为成功的研究生提供丰富、完善的培训基地，并提供 广泛的资源、结构化课程和网络机会。

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.