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.

项目总结/摘要 Rett综合征（RTT）是由编码甲基化的基因的杂合性功能缺失突变引起的。 CpG结合蛋白2（MeCP 2）。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期，例如，RTT小鼠中的雌性小鼠 模型（MeCP 2-hets）未能学习依赖于新生幼崽听觉处理的母性行为， 发声幼犬在离开巢穴时会发出超声波， 检索--对这些痛苦的呼喊的一种习得性反应。在学习过程中，神经反应 在有母性经验的女性的听觉皮层（AC）中， 线索MeCP 2-het不仅不能学习这种检索行为，而且还表现出小清蛋白（PV）抑制性。 这一时期的经验依赖性可塑性特定的AC中的中间神经元异常。之前 这些PV畸变的特征指向了一个过度活跃和过度成熟的AC PV网络， RTT模型在这一时期，可能反映了不足的可塑性检索行为，以成功地 学然而，这些研究的技术局限性仅提供了AC PV网络的静态快照 在与母体经验开始相关的时间点的属性;这阻碍了我们的理解 的实时交流光伏网络的贡献检索，其直接的行为后果 MeCP 2-hets中的失调。因此，本项目旨在确定AC PV神经元在调节 母亲的小狗检索，并揭示如何具体中断交流光伏网络损害这种行为在真实的 时间目标1将使用光纤测光和计算建模来测试假设，即交流光伏网络 动态调节检索，并且MeCP 2-hets中的网络失调导致检索缺陷。目标2将 采用光遗传学来测试抑制错误加强的AC PV网络的假设， RTT模型将拯救检索行为的性能。总之，这项工作将揭示新的洞察力， 可塑性缺陷的细胞和网络水平基础，是许多神经发育障碍的特征， 验证RTT患者的潜在细胞治疗靶点。 冷泉港实验室（CSHL）是一个世界知名的、充满活力的协作环境， 提出的研究。除了拥有几个备受尊敬的神经科学实验室外， CSHL会议和课程计划提供无数机会与世界知名科学家互动 以及定期访问校园的学员。这种无与伦比的曝光将加强我的专业网络， 在我科学生涯的下一个阶段促进未来的合作。此外，我的全面和 多样化的指导网络将通过培训计划支持我在该奖学金中的科学成长， 强调批判性思维和技术技能的发展，科学沟通，推广和领导。