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: 9135544
• 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/9135544
• 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; 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; neuropsychiatric disorder; novel; novel therapeutics; 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）：识别学习和记忆背后的回路至关重要，以便不仅了解记忆机制，而且了解这些机制如何在记忆障碍（例如阿尔茨海默病（AD））中失调。人类和啮齿动物损伤研究表明海马体 (HPC) 在长期记忆中发挥着重要作用，特别是 CA1 分区。当记忆必须长期保留时，CA1会优先被激活，研究表明，在重复暴露于相同环境时，很大一部分CA1神经元会被重新激活。然而，之前的研究还没有能够评估单个 CA1 神经元对学习和记忆或 AD 的长期（> 1 个月）参与，因为所有之前的转基因品系都缺乏不可磨灭的标签。在此应用中，将通过利用转基因品系 ArcCreERT2 小鼠来研究个体 CA1 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，并允许对在编码经验期间激活的细胞和在检索相应记忆期间激活的细胞进行比较。结合光遗传学报告系，这些研究将评估 CA1 神经元在记忆编码和检索中的长期参与。为了充分表征 CA1 神经元在记忆中的作用，我们将在编码过程中选择性地在 CA1 神经元群体中表达蓝光激活的阳离子通道通道视紫红质-2 (ChR2) 或黄光激活的外向质子泵古视紫红质 (Arch)。然后，我们将使用光遗传学来检验这样的假设：CA1 神经元亚群对于检索相应的长期记忆来说是充分且必要的。接下来，将通过三重转基因设计在 AD 小鼠中描述 CA1 在记忆编码和检索中的作用，其中最初在编码过程中标记的 CA1 神经元可以在对照和 AD 小鼠中进行光遗传学调节。在体内，我们将测试以下假设：在记忆检索过程中光遗传学刺激或抑制 CA1 锥体神经元将改善 AD 小鼠的记忆表达。最后，将使用光遗传学操作在对照小鼠和 AD 小鼠中模拟类似深部脑刺激的方案，以改善 AD 小鼠的整体细胞功能、细胞存活和记忆恢复。