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的杂合丧失功能突变引起的 CpG结合蛋白2（MECP2）。除其他缺陷外，RTT导致大脑失败无法激活可塑性 在呼吁经验依赖学习的时间的时间。例如，雌性小鼠在RTT鼠标中 模型（MECP2-HETS）无法学习依赖新生小狗听觉处理的母性行为 发声。幼崽与巢分开时会发出超声波发声 检索 - 对这些遇险哭声的渠道回应。在学习过程中，神经反应 在母亲经验的女性的听觉皮层（AC）中，人们对这些新的社会社会更加调整 提示。 MECP2-HET不仅无法学习这种检索行为，而且还表现出白细胞蛋白（PV）抑制作用 AC中特定于经验依赖性可塑性的AC中的中间神经元异常。事先的 这些PV畸变的表征指向在 在此期间的RTT模型，可能反映出成功的可塑性不足 学会了。但是，这些研究的技术局限性仅提供了AC PV网络的静态快照 与孕产妇经验的发作相关的时间点上的属性；这阻碍了我们的理解 实时AC PV网络对检索的贡献及其直接行为后果 MECP2-HETS中的失调。因此，该项目旨在确定AC PV神经元在调节中的作用 孕产妇检索，并揭示对AC PV网络的特定干扰如何实际损害这种行为 时间。 AIM 1将使用光纤光度法和计算建模来测试AC PV网络的假设 动态调节检索，MECP2-HETS中的网络失调会导致检索缺陷。 AIM 2意志 利用光遗传学来测试以下抑制错误加强AC PV网络的假设 RTT模型将挽救检索行为的性能。这项工作一起将揭示出对 可塑性缺陷的细胞和网络水平基础，这些缺陷是许多神经发育障碍的特征，并且 验证RTT患者的潜在细胞治疗靶点。 冷春港实验室（CSHL）是一个世界知名，充满活力和协作环境的环境 提出了拟议的研究。除了在家到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了与世界知名科学家互动的无数机会 和经常访问校园的学员。这种无与伦比的接触将加强我的专业网络， 在我的科学生涯的下一个阶段促进未来的合作。此外，我的全面 多样化的指导网络将通过培训计划来支持我在这项奖学金中的科学增长 强调批判性思维和技术技能发展，科学交流，外展和领导力。