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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

基本信息

批准号：
9354198
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
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9354198
关键词：
Activities of Daily Living Acute Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Behavior Behavioral Brain 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 Hippocampus (Brain)Human Immediate-Early Genes Impairment In Vitro Individual Label Learning Lesion Light Memory Memory Disorders Memory impairment Modeling Mus Neurodegenerative Disorders Neurofibrillary Tangles Neurons Output Pathology Patients Peptides 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 abeta accumulation 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 public health relevance relating to nervous system selective expression tau Proteins tau aggregation

项目摘要

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）：为了了解记忆的机制，以及这些机制如何在记忆障碍（如阿尔茨海默病（AD））中变得失调，识别学习和记忆背后的电路至关重要。人类和啮齿动物的损伤研究表明，海马体（HPC）在长期记忆中起作用，特别是CA1亚区。当记忆必须长时间保留时，CA1优先被激活，研究表明，在重复暴露于相同的环境中，很大一部分CA1神经元被重新激活。然而，由于之前所有的转基因品系都缺乏不可磨灭的标记，因此没有先前的研究能够评估单个CA1神经元在学习和记忆或阿尔茨海默病中的长期参与（大约1 - 10个月）。在这项应用中，个体CA1神经元对经验编码和相应记忆检索的贡献将通过使用转基因系ArcCreERT2小鼠进行研究。该小鼠系允许对表达直接早期基因Arc/Arg3.1的细胞进行不可磨灭的标记，并允许在经历编码期间激活的细胞与在相应记忆检索期间激活的细胞之间进行比较。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表达蓝光激活的阳离子通道channelrhodopsin-2 （ChR2）或黄光激活的向外质子泵archaerhodopsin （Arch）在CA1神经元群体中。利用光遗传学，我们将测试CA1神经元亚群对于检索相应的长期记忆是足够和必要的假设。接下来，我们将利用三重转基因设计来描述CA1在AD小鼠记忆编码和检索中的作用，在这种设计中，CA1神经元在编码过程中被标记，可以在对照和AD小鼠中进行光遗传学调节。在体内，我们将验证在记忆检索过程中光遗传刺激或抑制CA1锥体神经元会改善AD小鼠记忆表达的假设。最后，光遗传学操作将用于在对照和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，细胞存活和记忆检索。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

From Engrams to Pathologies of the Brain.

DOI：
10.3389/fncir.2017.00023
发表时间：
2017
期刊：
Frontiers in neural circuits
影响因子：
3.5
作者：
Denny CA;Lebois E;Ramirez S
通讯作者：
Ramirez S

The participation of cortical amygdala in innate, odour-driven behaviour.

DOI：
10.1038/nature13897
发表时间：
2014-11-13
期刊：
NATURE
影响因子：
64.8
作者：
Root, Cory M.;Denny, Christine A.;Hen, Rene;Axel, Richard
通讯作者：
Axel, Richard

Optimization of immunolabeling and clearing techniques for indelibly labeled memory traces.

DOI：
10.1002/hipo.22951
发表时间：
2018-07
期刊：
Hippocampus
影响因子：
3.5
作者：
Pavlova IP;Shipley SC;Lanio M;Hen R;Denny CA
通讯作者：
Denny CA

Improved specificity of hippocampal memory trace labeling.

DOI：
10.1002/hipo.22556
发表时间：
2016-06
期刊：
Hippocampus
影响因子：
3.5
作者：
Cazzulino AS;Martinez R;Tomm NK;Denny CA
通讯作者：
Denny CA

Optogenetic stimulation of dentate gyrus engrams restores memory in Alzheimer's disease mice.

齿状回印迹的光遗传学刺激可恢复阿尔茨海默病小鼠的记忆。

DOI：
10.1002/hipo.22756
发表时间：
2017-10
期刊：
Hippocampus
影响因子：
3.5
作者：
Perusini JN;Cajigas SA;Cohensedgh O;Lim SC;Pavlova IP;Donaldson ZR;Denny CA
通讯作者：
Denny CA

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Christine Ann Denny其他文献

(R,S)-Ketamine is Antidepressant and Prophylactic Against Stress in Adolescent but Not Aged Mice

DOI：
10.1016/j.biopsych.2022.02.050
发表时间：
2022-05-01
期刊：
Conference abstract
影响因子：
作者：
Alessia Mastrodonato;Ina Pavlova;Noelle Kee;Josephine C. McGowan;Christine Ann Denny
通讯作者：
Christine Ann Denny