Glutamate receptor signaling pathways in the circuit integration of adult-born neurons

成人神经元电路整合中的谷氨酸受体信号通路

基本信息

批准号：
10393032
负责人：
Anis Contractor
金额：
$ 44.18万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10393032
关键词：
Ablation Adult Affect Affective Age-Related Memory Disorders Alzheimer&apos s Disease Animals Array tomography Behavior Birth Brain Cell Maturation Cells Chlorides Developmental Process Episodic memory Equilibrium Family Foundations Genes Genetic Recombination Glutamate Receptor Goals Head Hippocampus (Brain)Image Impairment Interneurons Kainic Acid Receptors Learning Link Maps Memory Microscope Modeling Molecular Molecular Profiling Mood Disorders Mus Neurodegenerative Disorders Neurons Pattern Phase Play Post-Traumatic Stress Disorders Process Property Receptor Signaling Resolution Retrieval Role Schizophrenia Signal Pathway Signal Transduction Space Perception Synapses Synaptic plasticity Testing adult neurogenesis base behavior measurement conditional knockout dentate gyrus experimental study gamma-Aminobutyric Acid granule cell in vivo insight memory process microendoscope nerve stem cell nervous system disorder neural circuit neural correlate neuropsychiatric disorder newborn neuron normal aging novel novel therapeutics optogenetics single cell analysis spatiotemporal symporter tool transcriptome transmission process

Ablation Adult Affect Affective Age-Related Memory Disorders Alzheimer&apos s Disease Animals Array tomography Behavior Birth Brain Cell Maturation Cells Chlorides Developmental Process Episodic memory Equilibrium Family Foundations Genes Genetic Recombination Glutamate Receptor Goals Head Hippocampus (Brain)Image Impairment Interneurons Kainic Acid Receptors Learning Link Maps Memory Microscope Modeling Molecular Molecular Profiling Mood Disorders Mus Neurodegenerative Disorders Neurons Pattern Phase Play Post-Traumatic Stress Disorders Process Property Receptor Signaling Resolution Retrieval Role Schizophrenia Signal Pathway Signal Transduction Space Perception Synapses Synaptic plasticity Testing adult neurogenesis base behavior measurement conditional knockout dentate gyrus experimental study gamma-Aminobutyric Acid granule cell in vivo insight memory process microendoscope nerve stem cell nervous system disorder neural circuit neural correlate neuropsychiatric disorder newborn neuron normal aging novel novel therapeutics optogenetics single cell analysis spatiotemporal symporter tool transcriptome transmission process

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项目摘要

Adult neurogenesis in the hippocampus occurs in the well-defined neurogenic niche in the subgranular zone of the dentate gyrus. Newborn neurons are continuously generated and mature over the course of weeks to integrate into the hippocampal circuit. Adult-born immature dentate gyrus cells (DGCs) have unique functional properties that give them a privileged role in circuits that define specific behaviors, and which are critical to episodic memory formation and retrieval. In particular these neurons play important roles in an animal’s ability to separate similar patterns and disambiguate overlapping memories, processes that become impaired during normal aging and in neurodegenerative and neuropsychiatric disorders. Therefore, mechanisms that regulate adult-born DGC maturation and integration are important in understanding diverse neurological disorders including Alzheimer’s disease, schizophrenia and post-traumatic stress disorders. Kainate receptors are a class of glutamate receptor whose contributions to heterogeneous synaptic processes are still not fully understood. The premise of these studies is built upon foundational studies in which we discovered that the maturation of adult-born DGCs is more rapid after ablation of kainate receptors. We found that this effect was likely through a disruption of intracellular Cl- gradient because of an effect on a neuronal Cl- transporter. We will fully describe the altered molecular, synaptic, and functional alterations after loss of kainate receptor signaling and will test whether GABA disruption is causal to the altered integration of maturating DGCs into the hippocampal circuit. We will determine how altered maturation of adult-born DGCs affects the animal’s ability to discriminate between similar patterns and temporal overlap of episodic memories and using in vivo microendoscope imaging correlate cellular activity to behavioral measurements in a pattern separation task. The goal of this project is to examine a new mechanism by which glutamate receptors affect adult-born DGC integration by modulating GABA signaling. These studies would define novel processes that regulate adult-born neurons that could underlie the known involvement of kainate receptor signaling in mechanisms of learning and memory.

海马中的成年神经发生发生在定义明确的神经源性生殖位齿状回。在数周的过程中，新生儿神经元连续产生并成熟集成到海马电路中。成人出生的未成熟齿状回细胞（DGC）具有独特的功能在定义特定行为的圈子中赋予他们特权角色，并且对情节记忆形成和检索。特别是这些神经元在动物的能力中起重要作用要分开类似模式并消除歧义的重叠记忆，在正常衰老以及神经退行性和神经精神疾病。因此，调节的机制成人出生的DGC成熟和整合对于理解潜水神经系统疾病很重要包括阿尔茨海默氏病，精神分裂症和创伤后应激障碍。 Kaiinate受体是对异质突触过程的贡献仍然不完全的谷氨酸受体理解。这些研究的前提建立在基础研究上，我们发现海谷酸酯接收器消融后，成人出生的DGC的成熟更快。我们发现这种效果是由于对神经元转运蛋白的影响，可能是通过破坏细胞内CL梯度的。我们将充分描述损失海谷酸盐接收器后的分子，突触和功能改变信号传导，并将测试GABA中断是否是由于成熟DGC整合到该的因果的原因海马电路。我们将确定成人出生的DGC的成熟如何影响动物的能力区分相似模式和情节记忆的暂时重叠并在体内使用微型内镜成像将细胞活性与模式分离任务中的行为测量相关联。该项目的目的是检查一种新机制，谷氨酸受体会影响成人出生的DGC 通过调节GABA信号传导进行集成。这些研究将定义调节成年神经元的新过程，这些神经元可能是海藻酸盐受体信号传导在机理中的已知参与的基础学习和记忆。