Optogenetic dissection of hippocampal circuitry underlying Alzheimers disease

阿尔茨海默病海马回路的光遗传学解剖

• 批准号: 8917731
• 负责人: Christine Ann Denny
• 金额: $ 40.5万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8917731
• 关键词: APP-PS1; Activities of Daily Living; Acute; Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Behavior; Behavioral; Brain; Breeding; Bromodeoxyuridine; Cations; Cell Death; Cell Survival; Cell physiology; Cells; Chronic; Confocal Microscopy; Deep Brain Stimulation; Dementia; Disease Progression; Dissection; Electrophysiology (science); Environment; Exposure to; Functional disorder; Goals; Health; Hippocampus (Brain); Human; Immediate-Early Genes; Impairment; In Vitro; Individual; Label; Learning; Lesion; Light; Maps; Memory; Memory Disorders; Memory impairment; Modeling; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Output; Pathology; Patients; Population; Protocols documentation; Proton Pump; Recruitment Activity; Reporter; Retrieval; Rodent; Role; Senile Plaques; Staining method; Stains; Structure; Symptoms; Synapses; Techniques; Testing; Time Study; Transgenic Mice; Transgenic Organisms; Translations; Work; behavioral impairment; conditioned fear; design; experience; extracellular; hippocampal pyramidal neuron; improved; in vivo; long term memory; memory encoding; memory retrieval; mouse model; neural circuit; neuropsychiatry; novel; optogenetics; relating to nervous system; selective expression; tau Proteins; tau aggregation

DESCRIPTION (provided by applicant): It is of utmost importance to identify the circuits underlying learning and memory in order to understand not only the mechanisms of memory but also the how these mechanisms become dysregulated in memory disorders, such as Alzheimer's disease (AD). Human and rodent lesion studies have suggested a role for the hippocampus (HPC) in long-term memory, specifically the subregion CA1. CA1 is preferentially activated when a memory must be retained over a long period of time, and studies have shown that a large proportion of CA1 neurons are reactivated in repeated exposures to the same environment. However, no previous studies have been able to assess the long-term (> 1 month) involvement of individual CA1 neurons in learning and memory, or in AD, since all previous transgenic lines have lacked an indelible label. In this application, the contribution of individua CA1 neurons to the encoding of an experience and to the retrieval of a corresponding memory will be investigated by utilizing a transgenic line, the ArcCreERT2 mice. This mouse line allows for the indelible labeling of cells expressing the immediate early gene Arc/Arg3.1 and allows for a comparison between the cells that are activated during the encoding of an experience and those that are activated during the retrieval of the corresponding memory. In combination with optogenetic reporter lines, these studies will assess the long- term involvement of CA1 neurons in memory encoding and retrieval. To fully characterize the role of CA1 neurons in memory, we will selectively express the blue light activated cation channel channelrhodopsin-2 (ChR2) or the yellow light activated outward proton pump archaerhodopsin (Arch) in populations of CA1 neurons during encoding. Using optogenetics, we will then test the hypothesis that a subpopulation of CA1 neurons is sufficient and necessary for the retrieval of a corresponding long-term memory. Next, the role of CA1 in memory encoding and retrieval will be delineated in AD mice by utilizing a triple transgenic design in which CA1 neurons, initially labeled during encoding, can be optogenetically modulated in control and AD mice. In vivo, we will test the hypothesis that optogenetic stimulation or inhibition of CA1 pyramidal neurons during memory retrieval will improve expression of a memory in AD mice. Finally, optogenetic manipulations will be used in order to mimic a deep brain stimulation-like protocol in control and AD mice in order to improve overall cellular function, cell survival, and memory retrieval in AD mice.

描述（由申请人提供）：最重要的是识别学习和记忆的潜在回路，以便不仅理解记忆的机制，而且理解这些机制如何在记忆障碍如阿尔茨海默病（AD）中变得失调。人类和啮齿类动物损伤研究表明，海马（HPC）在长期记忆中的作用，特别是亚区CA 1。当记忆必须长时间保留时，CA 1优先被激活，研究表明，大部分CA 1神经元在重复暴露于相同环境中时被重新激活。然而，没有先前的研究能够评估单个CA 1神经元在学习和记忆中或在AD中的长期（> 1个月）参与，因为所有先前的转基因系都缺乏不可磨灭的标签。在本申请中，将通过利用转基因系ArcCreERT 2小鼠研究个体CA 1神经元对经验编码和相应记忆检索的贡献。该小鼠系允许对表达立即早期基因Arc/Arg3.1的细胞进行不可磨灭的标记，并允许在编码体验期间激活的细胞与在检索相应记忆期间激活的细胞之间进行比较。结合光遗传学报告细胞系，这些研究将评估CA 1神经元在记忆编码和检索中的长期参与。为了充分表征CA 1神经元在记忆中的作用，我们将在编码过程中选择性地在CA 1神经元群体中表达蓝光激活的阳离子通道channelrhodopsin-2（ChR 2）或黄光激活的外向质子泵archaerhodopsin（Arch）。使用光遗传学，我们将测试的假设，即CA 1神经元的亚群是足够的和必要的检索相应的长期记忆。接下来，CA 1在记忆编码和检索中的作用将通过利用三重转基因设计在AD小鼠中描绘，其中CA 1神经元，最初在编码期间标记，可以在对照和AD小鼠中进行光遗传学调节。在体内，我们将测试在记忆提取期间光遗传学刺激或抑制CA 1锥体神经元将改善AD小鼠中记忆的表达的假设。最后，将使用光遗传学操作来模拟对照和AD小鼠中的深部脑刺激样方案，以改善AD小鼠中的整体细胞功能、细胞存活和记忆恢复。