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: 9129769
• 负责人: Nathan B Danielson
• 金额: $ 4.86万
• 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/9129769
• 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; Goals; Head; Health; 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; Research; Resolution; Retrieval; Rodent; Role; Schizophrenia; Societies; Structure; Testing; Time; Work; awake; base; cell type; conditioned fear; dentate gyrus; developmental genetics; flexibility; imaging genetics; in vivo; information processing; learned behavior; lens; nervous system disorder; optical imaging; 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（由申请人提供）：记忆能力是哺乳动物大脑最深刻的特征之一，信息的正确编码和检索是形成学习基础的过程。学习和记忆在哺乳动物生活的各个方面的中心地位强调了退行性神经系统疾病的破坏性，如阿尔茨海默病和精神分裂症，它们损害海马体并损害这些过程。虽然海马结构是大脑中研究最广泛的结构之一，但其正常功能的电路机制仍然难以捉摸。海马主细胞形成复杂的外部环境的代表，但在鲜明对比的多样性的抑制性interneurons编目，尽管明显需要功能隔离，他们在很大程度上被认为是一个同质的人口。本研究的目的是探讨海马CA1区输出节点锥体细胞群的功能分离。特别是，鉴于已知的发育，遗传和连接在该地区的表层和深层细胞之间的差异，我们的目标是探索这些亚群之间的功能差异和他们的相对贡献学习和记忆。 该提案在小鼠中实现了光学成像和遗传扰动方法的许多最新进展，使我们能够纵向监测和操纵大量海马神经元的活动，这些神经元具有亚微米空间分辨率，可以在几天到几周内进行各种学习模式。在CA1区，主细胞通过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征持续了很长一段时间，但CA1主细胞群的放电模式在学习过程中发生了巨大变化。该提案将测试的假设，表面和深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。从头部固定的空间导航任务的初步数据表明，在浅层CA1锥体细胞群的空间表示是非常稳定的许多天，而在深层人口的发射模式是更加多变，这表明这些亚群之间的功能差异，也许满足需要的稳定性和灵活性在海马代码。该提案还将实施药物遗传学操作，以检验这一假设，即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。总之，这项工作将使用清醒啮齿动物学习期间CA1锥体细胞不同亚群的慢性头部固定双光子成像，以进一步了解海马回路中的功能细分。