Entorhinal-hippocampal circuit dysfunction in AD mice

 描述（由申请人提供）：空间记忆障碍和定向障碍是与衰老相关的常见问题，通常是轻度认知障碍和阿尔茨海默病（AD）的首发症状之一。了解在具有早期AD病理学的小鼠模型中参与空间记忆形成的细胞的性质将增强我们对AD中认知衰退的最早形式的理解。已知在空间记忆中重要的细胞是海马的位置细胞（HPC）和内嗅皮层的网格和头方向细胞（EC）。我们将使用一种新的方法，同时记录网格和位置细胞的电生理特性，使用128通道电极记录从3个区域的内嗅皮层-海马（EC-HPC）电路在AD小鼠。然后，我们将分析大规模的电生理数据和测量突触可塑性使用尖峰定时依赖可塑性（STDP）模型。来自该模型的预测将用作指导以调整神经元中的尖峰定时，使用光遗传学调节来增强或抑制EC-HPC的受影响区域中的细胞群的突触强度。我们预计这将使我们能够纠正空间障碍缺陷。为了概括在早期AD患者中观察到的空间定向障碍，将应用小鼠中的行为等效任务，例如变形旷场、空间新物体识别任务和T-迷宫交替任务。这些任务被专门选择来研究在相关行为模式中被激活的EC-HPC回路神经元（CA 1，CA 3，齿状回，外侧和内侧内嗅皮层）的功能。 该提案汇集了不同的领域（电生理学，分子神经科学和计算神经科学），同时在多个大脑区域应用大规模记录技术，以开发分析和预测计算测试，以询问和恢复一个重要回路的功能， 在老年痴呆症中是不正常的

 DESCRIPTION (provided by applicant): Spatial memory impairment and disorientation are a common problem associated with aging and they are often one of the first symptoms of mild cognitive impairment and Alzheimer's disease (AD). Understanding the properties of cells involved in the formation of spatial memory in a mouse model with early AD pathology will enhance our understanding of the earliest forms of cognitive decline in AD. The cells known to be important in spatial memory are place cells of the hippocampus (HPC) and grid and head direction cells of the entorhinal cortex (EC). We will use a novel approach to simultaneously record the electrophysiological properties of grid and place cells using 128-channel electrode recordings from 3 regions of the entorhinal cortex-hippocampal (EC-HPC) circuit in AD mice. We will then analyze the large-scale electrophysiological data and measure synaptic plasticity using a spike-timing dependent plasticity (STDP) model. Predictions from this model will be used as a guide to adjust spike timing in neurons, either enhancing or suppressing the synaptic strength of cell populations in affected regions of the EC-HPC, using optogenetic modulation. We anticipate that this will allow us to correct the spatial impairment deficits. To recapitulate te spatial orientation impairments seen in early-stage AD patients, behaviorally equivalent tasks in mice such as morphing open fields, spatial novel object recognition task and T-maze alternation tasks will be applied. These tasks have been chosen specifically to study the functioning of EC-HPC circuit neurons (CA1, CA3, dentate gyrus, lateral and medial entorhinal cortex) that get activated in relevant behavioral modes. The proposal brings together diverse fields (electrophysiology, molecular neuroscience and computational neuroscience) applying large-scale recording techniques simultaneously across multiple brain regions to develop analytical and predictive computational tests to interrogate and restore function in an important circuit that is dysfunctional in Alzheimer's disease.