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: 9789069
• 负责人: Jayeeta Basu
• 金额: $ 49.51万
• 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/9789069
• 关键词: Acute; Affect; Alzheimer' s Disease; Animals; Axon; BRAIN initiative; Behavior; Behavioral; Biological Models; Brain; Cells; Code; Collaborations; Computer Simulation; 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; 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.

内嗅皮层和海马体之间的功能相互作用对空间导航至关重要