Functional dissection of a radial subdivision among hippocampal pyramidal cells

海马锥体细胞径向细分的功能解剖

• 批准号: 8835780
• 负责人: Nathan B Danielson
• 金额: $ 4.34万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835780
• 关键词: Alzheimer' s Disease; Animals; Area; Behavior; Behavioral; Brain; Calcium; Cataloging; Catalogs; Cells; Chronic; Code; Complex; Data; Development; Dissection; Distal; Dorsal; Environment; Event; Exhibits; Genetic; Goals; Head; Hippocampal Formation; Hippocampus (Brain); Image; Interneurons; Learning; Life; Light; Mediating; Memory; Methods; Monitor; Mus; Nature; Neurons; Operative Surgical Procedures; Output; Pathology; Patients; Pattern; Pharmacogenetics; Phase; Population; Preparation; Process; Property; Pyramidal Cells; Radial; Relative (related person); Research; Resolution; Retrieval; Rodent; Role; Schizophrenia; Societies; Structure; Testing; Time; Work; awake; base; cell type; conditioned fear; dentate gyrus; developmental genetics; flexibility; in vivo; information processing; learned behavior; lens; nervous system disorder; optical imaging; public health relevance; relating to nervous system; segregation; submicron; two-photon; way finding

 DESCRIPTION (provided by applicant): The capacity for memory is one of the most profound features of the mammalian brain, and the proper encoding and retrieval of information are the processes that form the basis of learning. The centrality of learning and memory to all aspects of mammalian life underscores the devastating nature of degenerative neurological disorders, such as Alzheimer's disease and schizophrenia that impair the hippocampus and compromise these processes. Although the hippocampal formation is one of the most extensively studied structures in the brain, the circuit mechanisms underlying its normal function remain elusive. Hippocampal principal cells form complex representations of the external environment, but in stark contrast to the diversity of inhibitory interneurons catalogued and despite the apparent need for functional segregation, they are largely considered a homogeneous population. The goal of this proposed research is to investigate functional segregation within the pyramidal cell population at the output node of the hippocampus, area CA1. In particular, given known developmental, genetic, and connectivity differences between superficial and deep cells in this region, we aim to explore the functional differences between these subpopulations and their relative contributions to learning and memory. This proposal implements numerous recent advances in optical imaging and genetic perturbation methods in the mouse, allowing us to longitudinally monitor and manipulate the activity of large populations of hippocampal neurons with submicron spatial resolution over days to weeks as the animal engages in various learning paradigms. In area CA1 principal cells form representations of the external world through their coordinated firing patterns. While spatial representations of static environments persist over long time periods, firing patterns in the CA1 principal cell population change dramatically over the course of learning. This proposal will test the hypothesis that superficial and deep CA1 principal cells demonstrate different coding dynamics during spatial navigation behaviors and learning tasks. Preliminary data from a head-fixed spatial navigation task suggests that spatial representations in the superficial CA1 pyramidal cell population are highly stable over many days, while firing patterns in the deep population are far more variable, suggesting a functional difference between these subpopulations and perhaps satisfying the need for both stability and flexibility in hippocampal codes. This proposal will also implement pharmacogenetic manipulations to test the hypothesis that coding differences between these subpopulations are the causal basis for differential contributions to learning and memory. In summary this work will use chronic head-fixed two- photon imaging of different subpopulations of CA1 pyramidal cells during learning in the awake rodent to further our understanding of functional subdivision in the hippocampal circuit.

 描述(申请人提供)：记忆能力是哺乳动物大脑最深刻的特征之一，正确的信息编码和检索是形成学习基础的过程。学习和记忆对哺乳动物生活的各个方面都至关重要，这突显了退行性神经疾病的破坏性，如阿尔茨海默病和精神分裂症，这些疾病损害了海马体，损害了这些过程。虽然海马体结构是大脑中研究最广泛的结构之一，但其正常功能背后的电路机制仍然难以捉摸。海马主细胞形成了外部环境的复杂表征，但与分类的抑制性中间神经元的多样性形成鲜明对比的是，尽管显然需要功能分离，但它们在很大程度上被认为是一个同质群体。这项拟议研究的目标是调查海马区CA1区输出节点锥体细胞群内的功能隔离。特别是，鉴于已知该地区浅层和深层细胞之间的发育、遗传和连通性差异，我们的目标是探索这些亚群之间的功能差异及其对学习和记忆的相对贡献。这一建议在小鼠身上实现了光学成像和遗传扰动方法的许多最新进展，使我们能够在动物参与各种学习范例的过程中，以亚微米空间分辨率纵向监测和操纵大量海马神经元的活动。在CA1区，主细胞通过其协调的放电模式形成对外部世界的表征。虽然静态环境的空间表示会持续很长一段时间，但在学习过程中，CA1主细胞群的放电模式会发生戏剧性的变化。这一建议将检验这一假设，即浅层和深层CA1主细胞在空间导航行为和学习任务中表现出不同的编码动态。来自头部固定空间导航任务的初步数据表明，浅层CA1锥体细胞群的空间表征在许多天内高度稳定，而深层群的放电模式则更加多变，这表明这些亚群之间存在功能差异，可能满足了海马区编码的稳定性和灵活性的需要。这一提议还将实施药物遗传学操作，以测试以下假设：这些亚群之间的编码差异是学习和记忆差异贡献的因果基础。综上所述，这项工作将利用清醒啮齿动物学习过程中不同亚群CA1锥体细胞的慢性头部固定双光子成像来加深我们对海马环路功能细分的理解。