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

基本信息

批准号：
10202771
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
项目类别：
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/10202771
关键词：
Acute Affect Alzheimer&apos 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 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 large scale data network models neuronal cell body neuronal patterning neuropsychiatric disorder novel optogenetics prototype response tool virtual way finding

项目摘要

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.

内嗅皮层和海马体之间的功能相互作用对于空间导航至关重要以及与人、地点、物体和事件相关的情景记忆。皮质（MEC）处理空间信息，而外侧内嗅皮层（LEC）处理非空间信息然后，将“地点”和“内容”信息投射到海马体，以获取相关信息。形成与环境的感官和空间特征相关联的长期表征。海马表征的灵活性对于产生适应性学习行为至关重要，并且依赖于我们提出内嗅皮层在调节海马可塑性和空间方面的新作用。为了测试这一点，我们将分离出远程和远程的鲜为人知的组织和功能。空间编码期间 LEC 与 MEC 和海马 CA3 区之间的局部电路对话。 PI (Basu) 和 co-PI (Clopath) 都是早期研究人员，正在将他们的互补性结合起来实验和计算方法方面的专业知识，用于构建以集成电路为中心的模型这项研究将检验海马体在多个层面上的可塑性。 LEC 输入在非空间编码、谷氨酸能协调活动和新发现来自 LEC 和 MEC 的 GABAergic 输入（Basu et al., 2016）对于上下文相关是必要的通过局部兴奋抑制动力学和树突整合的门控海马位置细胞的可塑性。为了测试这个想法，我们在实验和计算方面建立了一套创新的工具我们将从胞体进行细胞内电生理学检查。和急性切片中 CA3 神经元的树突，以绘制 LEC-CA3 回路的功能图（目标 1），并读出 CA3 通过 CA3 胞体和树突的体内双光子成像将细胞行为置于亚细胞分辨率以及在头部固定环境变形空间导航任务期间行为动物的 LEC 轴突（目标 2）。我们将与 Cliff Kentros 博士合作，开发用于多重分析的 LEC 细胞类型特异性小鼠系同时或交替地光遗传学激活和沉默谷氨酸能和 GABA 能输入读出这些操作如何影响 CA3 可塑性。我们正在构建一个独特的计算模型。海马将细胞编码在单个神经元（目标 1）和网络（目标 2）水平，并结合调节树突激发抑制和长期可塑性（Bono 和 Clopath 2010）。 Dmitry Chklovskii 将提供位置细胞和大规模成像数据分析方面的专家咨询。我们的研究将为远程和局部电路动态提供独特的视角，从而赋予灵活性否则，基于环境需求的稳定的空间神经表征将有更好的帮助。识别感觉环境及其位置的适应不良关联背后的回路，如创伤后应激障碍 (PTSD) 中所见其中 CA3 是一个主要目标，而在阿尔茨海默病中，内嗅皮层很早就受到影响。