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
基本信息
- 批准号:10537176
- 负责人:
- 金额:$ 3.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAuditory areaBehaviorBehavioralBiological AssayBirthBrainCalciumCellsCollaborationsCommunicationComputer ModelsCritical ThinkingCuesDiseaseDistressElectrophysiology (science)ExhibitsFailureFellowshipFemaleFiberFutureGenesGoalsGrowthHistologicHomeHyperactivityImpairmentInterneuronsKnowledgeLaboratoriesLeadershipLearningLightLinkMaternal BehaviorMediatingMentorsMethyl-CpG-Binding Protein 2ModelingMonitorMusNeurodevelopmental DisorderNeuronal PlasticityNeuronsNeurosciencesNewborn InfantOpsinParvalbuminsPatientsPerformancePerinatalPhotometryPopulationProcessPropertyRegulationResearchRetrievalRett SyndromeRoleScientistSynaptic plasticityTechnical ExpertiseTestingTherapeutic InterventionTimeTrainingUltrasonicsVisitWorkauditory processingbasebehavioral impairmentcareercareer networkingcollaborative environmentcritical periodexperienceinsightlearned behaviorloss of function mutationmeetingsmouse modelnoveloptogeneticsoutreachperinatal periodprogramspuprelating to nervous systemresponseskill acquisitionsocialtherapeutic targetvocalization
项目摘要
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.
项目概要/摘要
雷特综合征 (RTT) 是由编码甲基的基因杂合性功能缺失突变引起的
CpG 结合蛋白 2 (MeCP2)。除其他缺陷外,RTT 会导致大脑无法激活可塑性
在需要经验依赖学习的时期进行计划。例如,RTT 小鼠中的雌性小鼠
模型(MeCP2-hets)无法学习依赖新生幼犬听觉处理的母性行为
发声。当幼崽离开巢穴时,它们会发出超声波声音,向母亲发出信号
检索——对这些遇险呼喊的习得反应。在学习过程中,神经反应
有过母性经验的女性的听觉皮层(AC)变得更加适应这些新近相关的、社交的
提示。 MeCP2-hets 不仅无法学习这种检索行为,而且还表现出小清蛋白 (PV) 抑制作用
AC 中的中间神经元异常是这一时期经验依赖性可塑性特有的。事先的
这些光伏畸变的特征表明,交流光伏网络过于活跃和成熟
这一时期的 RTT 模型,可能反映了检索行为成功的可塑性不足
学到了。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
与孕产经历开始相关的时间点的特性;这阻碍了我们的理解
实时交流光伏网络对检索的贡献及其直接行为后果
MeCP2-hets 的失调。因此,本项目旨在确定 AC PV 神经元在调节中的作用
母体幼仔检索,并揭示交流光伏网络的特定中断如何实际损害这种行为
时间。目标 1 将使用光纤光度测量和计算模型来检验交流光伏网络的假设
MeCP2-hets 动态调节检索,而 MeCP2-hets 中的网络失调会导致检索缺陷。目标2将
利用光遗传学来检验抑制错误加强的交流光伏网络的假设
RTT模型将挽救检索行为的性能。总之,这项工作将揭示对
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,以及
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
提出拟议的研究。除了拥有几个备受推崇的神经科学实验室之外,
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
以及定期参观校园的学员。这种无与伦比的接触将加强我的专业网络和
促进我科学生涯下一阶段的未来合作。此外,我的全面和
多元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发展、科学沟通、外展和领导力。
项目成果
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