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。了解阿尔茨海默病早期病理模型中参与空间记忆形成的细胞的特性将增强我们对阿尔茨海默病认知衰退最早形式的理解。已知的在空间记忆中重要的细胞是海马区的位置细胞(HPC)和内嗅皮层的栅格和头部方向的细胞(EC)。我们将使用一种新的方法来同时记录AD小鼠内嗅皮层-海马区(EC-HPC)3个区域的128通道电极记录的栅格和放置细胞的电生理特性。然后，我们将分析大规模电生理数据，并使用峰时依赖可塑性(STDP)模型测量突触可塑性。这个模型的预测将被用来指导调整神经元的棘波计时，利用光遗传调节，增强或抑制EC-HPC受影响区域细胞群体的突触强度。我们预计，这将使我们能够纠正空间损伤赤字。为了概括早期AD患者的TE空间定向障碍，将应用小鼠的行为等同任务，如变形开阔场地、空间新对象识别任务和T迷宫交替任务。这些任务是专门用来研究EC-HPC回路神经元(CA1、CA3、齿状回、外侧和内侧嗅觉皮质)的功能，这些神经元在相关的行为模式中被激活。该计划汇集了不同的领域(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，以审问和恢复一个重要电路的功能， 在阿尔茨海默氏症中存在功能障碍。

 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.