Linking Plasticity of Hippocampal Representation across the Single Neuron and Circuit Levels

将单个神经元和电路层面的海马表征的可塑性联系起来

• 批准号: 10437710
• 负责人: Jayeeta Basu
• 金额: $ 42.08万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437710
• 关键词: Acute; Affect; Alzheimer' s Disease; Animals; Axon; BRAIN initiative; Behavior; Behavioral; Biological Models; Brain; Cells; Code; Collaborations; Computer Models; Consultations; Data Analyses; Dendrites; Electrophysiology (science); Environment; Episodic memory; Event; Experimental Models; Glutamates; Grant; Head; Hippocampus (Brain); Image; Interneurons; Lateral; Learning; Link; Location; Maps; Medial; Modeling; Mus; Network-based; Neuronal Plasticity; Neurons; Output; Patients; Persons; Population Dynamics; Post-Traumatic Stress Disorders; Preparation; Process; Research Personnel; Resolution; Role; Sensory; Shapes; Slice; Synapses; Testing; Theoretical model; Transgenic Mice; Work; base; cell behavior; cell type; dentate gyrus; entorhinal cortex; environmental change; flexibility; hippocampal pyramidal neuron; in vivo two-photon imaging; information processing; innovation; integrated circuit; large scale data; network models; neuronal cell body; neuronal patterning; neuropsychiatric disorder; novel; optogenetics; prototype; response; tool; virtual; way finding

Functional interactions between the entorhinal cortex and hippocampus are critical for spatial navigation and episodic memories related to people, places, objects and events. Canonically, medial entorhinal cortex (MEC) processes spatial information while lateral entorhinal cortex (LEC) processes non-spatial contextual information. This ‘where’ and ‘what’ information is then projected to the hippocampus for formation of long-term representations associating the sensory and spatial features of the environment. Flexibility in hippocampal representations is critical for generating adaptive learnt behaviors and relies on plasticity. We propose a new role for entorhinal cortex in modulating hippocampal plasticity and spatial representations. To test this, we will dissociate the lesser known organization and function of long-range and local circuit dialogue between LEC vs. MEC and area CA3 of hippocampus during spatial coding. The PI (Basu) and co-PI (Clopath), both early stage investigators, are combining their complementary expertise in experimental and computational approaches to build an integrated circuit centric model of plasticity in the hippocampus across multiple levels. This study will test the hypothesis that beyond the classically biased role of LEC inputs in non-spatial coding, coordinated activity of glutamatergic and newly discovered GABAergic input (Basu et al., 2016) from both LEC and MEC is necessary for context-dependent plasticity of hippocampal place cells via gating of local excitation-inhibition dynamics and dendritic integration. To test this idea, we have established innovative set of tools on the experimental and computational fronts to examine place cell plasticity across multiple levels. We will perform intracellular electrophysiology from soma and dendrites of CA3 neurons in acute slices to functional map the LEC-CA3 circuit (Aim 1), and read out CA3 place cell behavior at sub-cellular resolution with in vivo two-photon imaging of CA3 soma and dendrites as well as LEC axons in behaving animals during a head-fixed context morphing spatial navigational task (Aim 2). In collaboration with Dr. Cliff Kentros, we will develop LEC cell type specific mouse lines for multiplexed optogenetic activation and silencing of glutamatergic and GABAergic inputs simultaneously or alternatingly and read-out how these manipulations impact CA3 plasticity. We are building a unique computational model of hippocampal place cell coding at single neuron (Aim 1) and network (Aim 2) levels incorporating modulation of dendritic excitation-inhibition and long-term plasticity (Bono and Clopath 2010). Drs. György Buzsáki and Dmitry Chklovskii will provide expert consultation on place cell and large-scale imaging data analysis. Our study will provide a unique perspective on long-range and local circuit dynamics that impart flexibility to otherwise stable neuronal representations of space based on environmental demands. This will help better identify circuits underlying maladaptive association of sensory contexts and their location, as seen in PTSD where CA3 is a major target, and in Alzheimer’s disease where entorhinal cortex is affected early on.

内嗅皮层和海马之间的功能相互作用对于空间导航至关重要 以及与人，地方，物体和事件有关的情节记忆。典型，内侧内hin 皮层（MEC）处理空间信息，而侧向内嗅皮层（LEC）处理非空间 上下文信息。然后将此“位置”和“什么”信息投射到海马 形成长期表示环境的感觉和空间特征的形成。 海马表示的灵活性对于产生自适应学习行为至关重要 可塑性。我们提出了肠道皮层调节海马可塑性和空间的新作用 表示。为了测试这一点，我们将分离久违的组织和远程组织的功能 在空间编码过程中，LEC和海马的CA3区域CA3之间的本地电路对话。 两个早期调查人员的PI（Basu）和Co-Pi（Clopath）正在结合其完整性 实验和计算方法的专业知识，以建立一个以综合电路模型为中心的模型 海马跨多个级别的可塑性。这项研究将检验以下假设 LEC输入在非空间编码，谷氨酸能和新的协调活动中的经典作用 从LEC和MEC发现的GABA能输入（Basu等，2016）对于上下文依赖性是必要的 海马放置细胞的可塑性通过局部兴奋性抑制动力学和树突融合的输入。 为了测试这个想法，我们已经在实验和计算方面建立了创新的工具集 检查跨多个级别的细胞可塑性。我们将从SOMA进行细胞内电生理学 急性切片中的Ca3神经元的树突形成功能图LEC-CA3电路（AIM 1），并读取CA3 将细胞行为放置在亚细胞分辨率下，用Ca3 soma和树突的体内两光子成像为 以及在头部固定上下文中表现动物的LEC轴突变形空间导航任务（AIM 2）。 与Cliff Kentros博士合作，我们将开发用于多路复用的LEC细胞类型的特定鼠标线 简单或 读出这些操作如何影响CA3可塑性。我们正在建立一个独特的计算模型 在单个神经元（AIM 1）和网络（AIM 2）级别的海马位置编码编码编码编码的调制 树突状兴奋和长期可塑性（Bono and Clopath 2010）。博士。 GyörgyBuzsáki和 Dmitry Chklovskii将就位置单元和大规模成像数据分析提供专家咨询。 我们的研究将为远程和本地电路动力学提供独特的视角，使灵活性赋予 否则，基于环境需求的空间的稳定神经元表示。这将有所帮助 如PTSD所示，确定感觉环境及其位置的不良适应性关联及其位置 其中CA3是主要靶标，而在阿尔茨海默氏病中，肠道皮质会很早就受到影响。

项目成果

The interplay between somatic and dendritic inhibition promotes the emergence and stabilization of place fields.

体细胞抑制和树突抑制之间的相互作用促进了位置场的出现和稳定。

• DOI: 10.1371/journal.pcbi.1007955
• 发表时间: 2020
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Pedrosa,Victor;Clopath,Claudia
• 通讯作者: Clopath,Claudia

Free recall scaling laws and short-term memory effects in a latching attractor network.

锁定吸引子网络中的自由回忆缩放定律和短期记忆效应。

• DOI: 10.1073/pnas.2026092118
• 发表时间: 2021
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Boboeva V

Coordinated hippocampal-thalamic-cortical communication crucial for engram dynamics underneath systems consolidation.

• DOI: 10.1038/s41467-022-28339-z
• 发表时间: 2022-02-11
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Tomé DF;Sadeh S;Clopath C
• 通讯作者: Clopath C