Elucidating the Role of Brain Extracellular Matrix in Hippocampal Learning and Memory

阐明脑细胞外基质在海马学习和记忆中的作用

• 批准号: 10749279
• 负责人: Ricardo Guajardo
• 金额: $ 3.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749279
• 关键词: Adult; Animals; Behavioral; Brain; Calcium; California; Chondroitin Sulfate Proteoglycan; Data; Dendrites; Deposition; Digestion; Discrimination; Disease; Dorsal; Endoscopy; Environment; Episodic memory; Extracellular Matrix; Fright; Functional disorder; Genes; Genetic; Genetic Recombination; Goals; Hippocampus; Hour; Hyaluronic Acid; Image; Immunofluorescence Immunologic; Impairment; In Situ Hybridization; Label; Learning; Logic; Measures; Mediating; Memory; Memory impairment; Mentors; Mentorship; Messenger RNA; Microscopy; Molecular; Mus; Nerve Degeneration; Nervous System; Neurons; Neurosciences Research; Output; Parahippocampal Gyrus; Pathogenesis; Pattern; Physicians; Physiological; Population; Process; Production; Property; Proteoglycan; Qualifying; Research; Retrieval; Role; San Francisco; Scientist; Source; Structure; Synapses; Synaptic plasticity; System; Technical Expertise; Testing; Therapeutic; Time; Training; Universities; Vertebral column; aggrecan; brain remodeling; career; clinical training; conditional knockout; conditioned fear; critical period; dentate gyrus; educational atmosphere; experimental study; extracellular; granule cell; insight; knockout animal; link protein; medical schools; memory acquisition; memory consolidation; memory process; neuropsychiatric disorder; novel; residence

PROJECT SUMMARY/ABSTRACT Composed of a latticework of proteoglycans and associated molecules, the brain extracellular matrix (ECM) is a medium for synaptic plasticity. The expression of chondroitin sulfate proteoglycans (CSPGs), most notably aggrecan (gene: Acan), has been shown to mediate the closure of critical periods of plasticity through the formation of perineuronal nets, structures thought to stabilize synaptic connections. Furthermore, enzymatic digestion of hippocampal ECM results in contextual learning deficits, suggesting that ECM may stabilize learning-related synaptic changes. The dentate gyrus of the hippocampus, a critical learning structure, has abundant aggrecan in its molecular layer, and dentate gyrus granule cells (DG GCs) continuously produce Acan mRNA in adulthood. Thus, aggrecan production by dentate gyrus neurons may underlie the stability of memory processes. Preliminary data presented here show that genetic deletion of Acan in dentate gyrus neurons results in remote contextual discrimination deficits. This proposal will test the hypothesis that activity-dependent aggrecan expression by DG GCs following learning is essential for DG ensemble separation and memory precision at retrieval. First, the effect of contextual fear learning on DG GC Acan expression and deposition will be characterized (Aim 1). Next, DG-specific Acan deletion will be used to test if aggrecan production is necessary for recent or remote contextual memory precision (Aim 2). Lastly, using microendoscopic calcium imaging, I will describe how aggrecan deletion changes DG GC ensemble properties (Aim 3). Altogether, this proposal aims to elucidate the extracellular matrix's role in mammalian learning and memory and the underlying molecular and network mechanisms. Furthermore, given that alterations to brain ECM are found in neurodegenerative and psychiatric conditions, understanding the physiologic properties of ECM may yield insights into disease pathophysiology and potential therapeutic avenues. These research goals will be realized in conjunction with a comprehensive training plan aimed at developing the applicant’s career as a physician-scientist. This training will include consistent, rigorous mentorship in conceptual and technical skills from two highly-qualified mentors, one of whom is a physician-scientist. The research and training proposed here will be carried out at the University of California, San Francisco, which offers both a world- class neuroscience research environment and an exceptional medical school for clinical training.

项目总结/摘要 脑细胞外基质（ECM）由蛋白多糖和相关分子的晶格组成， 突触可塑性的媒介。硫酸软骨素蛋白聚糖（CSPGs）的表达，最明显的是 聚集蛋白聚糖（基因：Acan），已被证明介导的关键时期的可塑性，通过关闭 神经元周围网络的形成，被认为是稳定突触连接的结构。此外，酶 海马ECM的消化导致背景学习缺陷，表明ECM可能稳定 学习相关的突触变化。海马体的齿状回是一个重要的学习结构， 齿状回颗粒细胞（DG GCs）在其分子层中含有丰富的聚集蛋白聚糖， 成年期Acan mRNA。因此，由齿状回神经元产生的聚集蛋白聚糖可能是海马神经元的稳定性的基础。 记忆过程 这里提出的初步数据表明，齿状回神经元中Acan的遗传缺失导致远程 背景歧视缺陷。这项提议将检验活性依赖性聚集蛋白可以 在学习之后，DG GC的表达对于DG系综分离和记忆精度至关重要， 检索首先，将研究情境恐惧学习对DG GC Acan表达和沉积的影响， 特征（目标1）。接下来，将使用DG特异性Acan缺失来测试聚集蛋白聚糖的产生是否是必要的 最近或遥远的上下文记忆精度（目标2）。最后，使用显微内镜钙成像，我 将描述聚集蛋白聚糖缺失如何改变DG GC系综性质（目的3）。总的来说，这项提案 目的是阐明细胞外基质在哺乳动物学习和记忆中的作用， 分子和网络机制。此外，考虑到脑细胞外基质的改变被发现在 神经退行性疾病和精神疾病，了解ECM的生理特性可能会产生 深入了解疾病的病理生理学和潜在的治疗途径。 这些研究目标将与一项全面的培训计划一起实现， 申请人的职业生涯作为一个物理学家，科学家。这种培训将包括在概念上的一致、严格的指导。 和技术技能从两个高素质的导师，其中一人是一个物理学家，科学家。研究与 这里提出的培训将在加州大学弗朗西斯科分校进行，该大学提供世界- 一流的神经科学研究环境和卓越的临床培训医学院。