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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.

海马的成年神经发生发生在海马颗粒下区的明确的神经发生龛中。齿状回新生神经元在数周内不断产生和成熟，整合到海马电路中。成年出生的未成熟齿状回细胞（DGC）具有独特的功能，在定义特定行为的电路中赋予它们特权角色的特性，以及对情景记忆的形成和提取特别是这些神经元在动物的能力中起着重要的作用为了分离相似的模式并消除重叠的记忆，正常衰老以及神经变性和神经精神障碍。因此，调控机制成人出生的DGC成熟和整合在理解各种神经系统疾病中很重要包括老年痴呆症、精神分裂症和创伤后应激障碍。红藻氨酸受体是一种一类谷氨酸受体，其对异质性突触过程的贡献仍不完全明白这些研究的前提是建立在基础研究的基础上，我们发现，在去除红藻氨酸受体后，成人出生的DGC的成熟更快。我们发现这种效应可能是由于对神经元Cl-转运体的影响而破坏细胞内Cl-梯度。我们将充分描述红藻氨酸受体丧失后分子、突触和功能的改变信号传导，并将测试GABA破坏是否是成熟DGC整合到细胞中的改变的原因。海马回路我们将确定成年DGC成熟的改变如何影响动物的能力，区分情节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性与模式分离任务中的行为测量相关联。本项目的目标是研究谷氨酸受体影响成人DGC的新机制通过调节GABA信号整合。这些研究将定义调节成年出生的神经元的新过程，这些过程可能是已知的红藻氨酸受体信号传导参与神经元凋亡机制的基础。学习和记忆。