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

• 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
• 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' 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

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.

成年神经发生在海马神经元颗粒下带中明确定义的神经源性壁龛中。 齿状回。新生神经元在几周的过程中不断生成和成熟 整合到海马体回路中。成体出生的未成熟齿状回细胞具有独特的功能 属性，这些属性使它们在定义特定行为的电路中具有特权角色，这些属性对 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扮演着重要的角色 为了分离相似的模式并消除重叠记忆的歧义，在 正常衰老，神经退行性和神经精神障碍。因此，监管的机制 成年出生的DGC的成熟和整合对于理解各种神经疾病很重要 包括阿尔茨海默氏症、精神分裂症和创伤后应激障碍。海人藻酸受体是一种 谷氨酸受体的一类，其对异质性突触过程的贡献仍不完全 明白了。这些研究的前提是建立在基础研究的基础上，在这些研究中，我们发现 去红藻氨酸受体后，成体出生的DGC成熟更快。我们发现，这种影响是 可能通过破坏细胞内的氯-梯度，因为对神经元的氯-转运体的影响。我们 将全面描述海人藻酸受体丢失后分子、突触和功能的改变 并将测试GABA中断是否导致成熟的DGC整合到 海马区回路。我们将确定成年出生的DGC的成熟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及其在活体中的应用 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出生的DGC的新机制。 通过调节GABA信号进行整合。这些研究将定义新的过程来调节成年出生的神经元，这可能是已知的参与海人酸受体信号转导机制的基础。 学习和记忆。