Aberrant parvalbumin-positive interneuron regulation of maternal behavior in a Rett Syndrome mouse model

雷特综合征小鼠模型中小白蛋白阳性中间神经元对母体行为的异常调节

• 批准号: 10537176
• 负责人: Alexa Pagliaro
• 金额: $ 3.24万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537176
• 关键词: Address; Auditory area; Behavior; Behavioral; Biological Assay; Birth; Brain; Calcium; Cells; Collaborations; Communication; Computer Models; Critical Thinking; Cues; Disease; Distress; Electrophysiology (science); Exhibits; Failure; Fellowship; Female; Fiber; Future; Genes; Goals; Growth; Histologic; Home; Hyperactivity; Impairment; Interneurons; Knowledge; Laboratories; Leadership; Learning; Light; Link; Maternal Behavior; Mediating; Mentors; Methyl-CpG-Binding Protein 2; Modeling; Monitor; Mus; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Neurosciences; Newborn Infant; Opsin; Parvalbumins; Patients; Performance; Perinatal; Photometry; Population; Process; Property; Regulation; Research; Retrieval; Rett Syndrome; Role; Scientist; Synaptic plasticity; Technical Expertise; Testing; Therapeutic Intervention; Time; Training; Ultrasonics; Visit; Work; auditory processing; base; behavioral impairment; career; career networking; collaborative environment; critical period; experience; insight; learned behavior; loss of function mutation; meetings; mouse model; novel; optogenetics; outreach; perinatal period; programs; pup; relating to nervous system; response; skill acquisition; social; therapeutic target; vocalization

PROJECT SUMMARY/ABSTRACT Rett Syndrome (RTT) is caused by heterozygous loss of function mutations to the gene that encodes methyl CpG-binding protein 2 (MeCP2). Amongst other deficits, RTT results in failure of the brain to activate plasticity programs during times that call for experience dependent learning. For instance, female mice in a RTT mouse model (MeCP2-hets) fail to learn a maternal behavior that relies on auditory processing of newborn pup vocalizations. Pups emit ultrasonic vocalizations when they are separated from the nest which cues maternal retrieval - a learned response to these distress cries. Over the course of that learning process, neural responses in the auditory cortex (AC) of maternally experienced females become more tuned to these newly-relevant, social cues. Not only do MeCP2-hets fail to learn this retrieval behavior, but they also exhibit parvalbumin (PV) inhibitory interneuron abnormalities in the AC specific to this period of experience-dependent plasticity. Prior characterizations of these PV aberrations point towards a hyperactive and hypermature AC PV network in the RTT model during this period, likely reflecting insufficient plasticity for the retrieval behavior to be successfully learned. However, technical limitations of these studies have only provided static snapshots of AC PV network properties at timepoints with relevance to the onset of maternal experience; this has impeded our understanding of the real-time AC PV network contributions to retrieval, and the direct behavioral consequences of its dysregulation in MeCP2-hets. Therefore, this project aims to determine the role of AC PV neurons in regulating maternal pup retrieval, and reveal how specific disruptions to the AC PV network impair this behavior in real time. Aim 1 will use fiber photometry and computational modeling to test the hypothesis that the AC PV network dynamically regulates retrieval, and network dysregulation in MeCP2-hets results in retrieval deficits. Aim 2 will employ optogenetics to test the hypothesis that suppressing the erroneously strengthened AC PV network in the RTT model will rescue performance of the retrieval behavior. Together, this work will reveal novel insight into the cellular and network-level bases of plasticity deficits that characterize many neurodevelopmental disorders, and validate a potential cellular therapeutic target for RTT patients. Cold Spring Harbor Laboratory (CSHL) is a world-renowned, vibrant, and collaborative environment to carry out the proposed research. Apart from being home to several highly respected neuroscience laboratories, the CSHL Meetings and Courses Program provides myriad opportunities to interact with world renowned scientists and trainees that regularly visit campus. This unparalleled exposure will strengthen my professional network and facilitate future collaborations in the next stages of my scientific career. Additionally, my comprehensive and diverse mentoring network will support my scientific growth in this fellowship through a training plan that emphasizes critical thinking and technical skill development, scientific communication, outreach and leadership.

项目摘要/摘要 Rett综合征(RTT)是由编码甲基的基因功能突变杂合性丢失引起的 CpG结合蛋白2(MeCP2)。在其他缺陷中，RTT导致大脑无法激活可塑性 在需要依赖经验学习的时代里的课程。例如，RTT小鼠中的雌性小鼠 模型(MeCP2-HETS)无法学习依赖新生幼崽听觉处理的母体行为 发声。当幼崽从巢中分离出来时，它们会发出超声波发声，这表明它们是母体 找回--对这些痛苦呼喊的习得反应。在学习过程中，神经反应 在经历过母性经历的女性的听觉皮质(AC)中，女性变得更适应这些新的相关的、社交的 暗示。MeCP2-HET不仅不能学习这种检索行为，而且还表现出对小白蛋白(PV)的抑制 AC中的神经元间异常是这一经验依赖性可塑性时期特有的。之前 这些PV像差的特征表明在大脑中存在一个过度活跃和过度成熟的AC PV网络。 这一时期的RTT模型，可能反映了成功提取行为的可塑性不足 学到了东西。然而，这些研究的技术限制仅提供了交流光伏网络的静态快照 与母性经历开始相关的时间点的性质；这阻碍了我们的理解 实时交流光伏网络对检索的贡献，以及其直接行为后果 MeCP2-HETS中的调节失调。因此，本项目旨在确定AC PV神经元在调节中的作用 母犬取回，并揭示交流光伏网络的特定中断如何真实地损害这一行为 时间到了。目标1将使用光纤光度学和计算建模来测试交流光伏网络的假设 动态调节提取，而MeCP2-HETS的网络失调导致提取缺陷。目标2将 利用光遗传学检验假设，抑制错误增强的交流光伏网络在 RTT模型会对检索行为的救援性能产生影响。总而言之，这项工作将揭示对 细胞和网络水平的可塑性缺陷基础，这是许多神经发育障碍的特征，以及 验证RTT患者潜在的细胞治疗靶点。 冷泉港实验室(CSHL)是世界知名的、充满活力和协作的环境 提出了这项研究。除了是几个备受尊敬的神经科学实验室的所在地外， CSHL会议和课程计划提供了无数与世界知名科学家互动的机会 以及定期访问校园的实习生。这次无与伦比的曝光将加强我的职业关系网和 在我科学生涯的下一个阶段促进未来的合作。此外，我的综合和 多样化的指导网络将通过一个培训计划来支持我在这个奖学金中的科学成长 强调批判性思维和技术技能发展、科学沟通、外展和领导力。