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 神经元丧失和内嗅皮层表层层中神经回路的重组是标志 阿尔茨海默氏病和临时叶癫痫以及记忆力障碍是令人不安的症状之一 这些疾病。尽管知道浅表内嗅细胞层有选择地易受伤害 疾病，内嗅电路的局部连通性，这些层中不同的功能性细胞类型如何 出现，以及每种细胞类型如何促进记忆和空间处理。 enthernalin皮层在其层之间具有广泛的经常连接性，并且拥有许多功能性细胞 诸如网格细胞，头向细胞，边界细胞，上下文选择性细胞以及其他类型的空间和其他类型 非空间细胞。但是，这种功能多样性既不直接映射到特定的细胞层，也不会 层中的解剖学定义的单元格。因此，每个单元的功能身份可能主要是 由局部微电路确定。该建议的目的是检查功能细胞身份是否 在MEC中，包括网格电池射击和上下文选择性射击，从电路计算中出现。我们专注于 浅表层内的局部连通性，并假设II层锥体细胞有选择地 在第二层星细胞中有助于速率编码，该第三层输入选择性贡献 在第二层星状细胞中进行空间编码，包括电网射击。该假设将在两个中进行检验 具体目标。首先，我们将使用带有光学刺激的病毒追踪和斑块夹记录 切片以确定MEC II层锥体细胞和III层锥体细胞的连通性，以及 比较，第二层星状细胞。其次，我们将从MEC细胞中记录行为小鼠，而吻合均可记录 刺激或抑制亚肠地细胞群体。在两个单独的子iaM中，我们将研究（1） II层的锥体细胞操作在空间和上下文选择性点火模式上 和III层锥体细胞以及（2）III层锥体细胞操作对空间和上下文的影响 选择性编码划分II层。我们目标的结果将确定当地肠道电路如何贡献 专门的内嗅细胞类型的产生，包括网格细胞和上下文选择性细胞。这不会 仅填补理论模型和实验数据之间的空白，但也开发了选择性的方法 在MEC中操纵不同的功能细胞类型。因此，我们的结果将提高我们对 内嗅细胞类型和细胞层对空间和记忆处理的贡献，从而提出 恢复内嗅电路功能并改善神经退行性的进展的策略 疾病。