Connectivity and function of microcircuits in the superficial layers of the entorhinal cortex

内嗅皮层表层微电路的连接性和功能

• 批准号: 9316872
• 负责人: Stefan Leutgeb
• 金额: $ 48.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316872
• 关键词: Alpha Cell; Alzheimer' s Disease; Anatomy; Brain region; Cell Death; Cells; Code; Complement; Contralateral; Data; Discrimination; Disease; Enterochromaffin Cells; Environment; Generations; Head; Interneurons; Knowledge; Maps; Medial; Memory; Memory impairment; Methods; Modeling; Mus; Neurodegenerative Disorders; Optics; Pathology; Pattern; Phase; Population; Property; Pyramidal Cells; Recurrence; Role; Slice; Structure of molecular layer of cerebellar cortex; Supporting Cell; Symptoms; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Theoretical model; Viral; cell cortex; cell type; entorhinal cortex; functional restoration; memory process; nervous system disorder; neural circuit; neuron loss; optogenetics; patch clamp; spatial memory; stellate cell; tool

Project Summary Neuron loss and the reorganization of neural circuits in the superficial layers of entorhinal cortex are hallmarks of Alzheimer’s disease and temporal lobe epilepsy, and memory impairments are among the troubling symptoms of these diseases. Despite the knowledge that superficial entorhinal cell layers are selectively vulnerable in these diseases, the local connectivity of entorhinal circuits, how different functional cell types within these layers emerge, and how each cell type contributes to memory and spatial processing is only beginning to be revealed. The entorhinal cortex has extensive recurrent connectivity between its layers, and harbors many functional cell types such as grid cells, head-direction cells, border cells, context-selective cells, and other types of spatial and nonspatial cells. However, this functional diversity neither maps directly onto particular cell layers nor onto anatomically defined cell classes within layers. Each cell’s functional identity may therefore predominantly be determined by local microcircuits. The objective of this proposal is to examine whether functional cell identities in mEC, including grid cell firing and context-selective firing, emerge from circuit computations. We focus on local connectivity within the superficial layers and hypothesize that layer II pyramidal cells selectively contribute to rate coding in layer II stellate cells and that layer III inputs selectively contribute to spatial coding, including grid firing, in layer II stellate cells. This hypothesis will be tested in two specific aims. First, we will use viral tracing and patch clamp recordings with optical stimulation in entorhinal slices to determine the connectivity of mEC layer II pyramidal cells and layer III pyramidal cells and, for comparison, layer II stellate cells. Second, we will record from mEC cells in behaving mice while optogenetically stimulating or inhibiting entorhinal cell populations. In two separate subaims, we will examine (1) the effects of layer II pyramidal cell manipulations on the spatial and context-selective firing patterns of layer II stellate cells and layer III pyramidal cells and (2) the effects of layer III pyramidal cell manipulations on spatial and context- selective coding by layer II cells. Results from our aims will identify how local entorhinal circuits contribute to the generation of specialized entorhinal cell types, including grid cells and context-selective cells. This will not only fill gaps between theoretical models and experimental data, but also develop methods to selectively manipulate different functional cell types in mEC. Our results will therefore advance our understanding of the contribution of entorhinal cell types and cell layers to spatial and memory processing and thereby suggest strategies for restoring entorhinal circuit function and ameliorating the progression of neurodegenerative diseases.

项目摘要 内嗅觉皮质浅层神经元丢失和神经回路重组是其特征 阿尔茨海默氏症和颞叶癫痫，以及记忆障碍都是令人担忧的症状 这些疾病。尽管知道浅层内嗅细胞层在这些疾病中选择性地脆弱 疾病，内嗅路的局部连接，这些层内不同的功能细胞类型 每种类型的细胞如何对记忆和空间处理做出贡献才刚刚开始揭示。 内嗅皮层各层之间有广泛的经常性连接，并有许多功能细胞。 网格单元格、头部方向单元格、边界单元格、上下文选择单元格以及其他类型的空间和 非空间单元格。然而，这种功能多样性既不直接映射到特定的细胞层，也不映射到 各层内由解剖定义的细胞类。因此，每个细胞的功能标识可能主要是 由本地微电路确定。这项提议的目标是检查功能细胞的同一性 在MEC中，包括网格单元激发和上下文选择激发，产生于电路计算。我们专注于 浅层内的局部连接，并假设第二层锥体细胞选择性地 有助于在第二层星状小区中进行速率编码，并且第三层输入有选择地作出贡献 到空间编码，包括网格激发，在第二层星状细胞中。这一假设将分两个阶段进行检验。 明确的目标。首先，我们将使用病毒示踪和膜片钳记录对内嗅觉进行光刺激 切片以确定MEC第二层锥体细胞和第三层锥体细胞的连通性， 比较，第II层星状细胞。第二，我们将记录小鼠在光遗传过程中的MEC细胞 刺激或抑制内嗅细胞群。在两个不同的子目标中，我们将检查(1) 第II层锥体细胞对第II层星状细胞空间和上下文选择性放电模式的操纵 和第三层锥体细胞和(2)第三层锥体细胞操作对空间和背景的影响- 第二层细胞的选择性编码。我们AIMS的结果将确定局部内脏环路如何有助于 产生特殊的内嗅觉细胞类型，包括网格细胞和上下文选择细胞。这不会 不仅填补了理论模型和实验数据之间的空白，而且还开发了有选择地 在MEC中操纵不同功能细胞类型。因此，我们的结果将促进我们对 内嗅细胞类型和细胞层对空间和记忆加工的贡献 恢复内感神经回路功能和改善神经退行性变进展的策略 疾病。