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

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.

海马体中的成体神经发生发生在颗粒下区明确的神经发生生态位中。新生的齿状回神经元在数周内不断生成并成熟。整合到海马回路中的成人出生的未成熟齿状回细胞（DGC）具有独特的功能。这些属性使它们在定义特定行为的电路中发挥特权作用，这对于尤其是情景记忆的形成和检索，这些神经元在动物的能力中发挥着重要作用。分离相似的模式并消除重叠的记忆和在过程中受损的过程的歧义因此，在正常衰老以及神经退行性和神经精神疾病中存在调节机制。成人出生的 DGC 成熟和整合对于理解多种神经系统疾病非常重要包括阿尔茨海默病、精神分裂症和创伤后应激障碍都是红藻氨酸受体。一类谷氨酸受体，其对异质突触过程的贡献尚未完全确定这些研究的前提是建立在我们发现的基础研究之上的。红藻氨酸受体消融后，成年 DGC 的成熟速度更快。可能是由于对神经元 Cl- 转运蛋白的影响而破坏了细胞内 Cl- 梯度。将全面描述红藻氨酸受体丢失后分子、突触和功能的改变信号传导，并将测试 GABA 破坏是否是导致成熟 DGC 整合改变的原因我们将确定成年 DGC 的成熟变化如何影响动物的能力。区分情景记忆的相似模式和时间重叠并在体内使用显微内窥镜成像将细胞活动与模式分离任务中的行为测量相关联。该项目的目标是研究谷氨酸受体影响成年 DGC 的新机制这些研究将定义调节成年神经元的新过程，这些过程可能是红藻氨酸受体信号传导参与机制的基础。学习和记忆。