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: 10159313
• 负责人: Stefan Leutgeb
• 金额: $ 39.88万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159313
• 关键词: 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 内嗅皮层浅层的神经元丢失和神经回路重组是其特征 老年痴呆症和颞叶癫痫症的症状，记忆障碍是令人不安的症状之一 这些疾病。尽管表面的内嗅细胞层在这些细胞中是选择性脆弱的， 疾病，内嗅回路的局部连通性，这些层中不同的功能细胞类型 出现，以及每种细胞类型如何有助于记忆和空间处理才刚刚开始被揭示。 内嗅皮层各层之间有广泛的循环连接，并含有许多功能细胞 类型，例如网格单元格、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 非空间细胞然而，这种功能多样性既不直接映射到特定的细胞层上，也不映射到 层内解剖学定义的细胞类别。因此，每个细胞的功能特性可能主要是 由本地微电路决定。这项建议的目的是检查功能细胞的身份是否 在mEC中，包括网格单元激发和上下文选择激发，从电路计算中出现。我们专注于 局部连接在浅层，并假设第二层锥体细胞选择性 有助于第二层星状细胞中的速率编码，第三层输入选择性地有助于 空间编码，包括网格发射，在第二层星状细胞。这一假设将在两个 具体目标。首先，我们将使用病毒示踪和膜片钳记录与光学刺激在内嗅 切片以确定mEC层II锥体细胞和层III锥体细胞的连接性， 比较，第二层星状细胞。第二，我们将记录行为小鼠中的mEC细胞， 刺激或抑制内嗅细胞群。在两个单独的子目标中，我们将研究（1） 第二层锥体细胞对第二层星状细胞空间和环境选择性放电模式的操纵 和第三层锥体细胞，以及（2）第三层锥体细胞操纵对空间和上下文的影响- 第二层细胞的选择性编码。我们的目标的结果将确定局部内嗅回路如何有助于 产生专门的内嗅细胞类型，包括网格细胞和环境选择细胞。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 操纵mEC中不同的功能细胞类型。因此，我们的研究结果将促进我们对 内嗅细胞类型和细胞层对空间和记忆处理的贡献，从而表明 恢复内嗅回路功能和改善神经退行性疾病进展的策略 疾病