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

项目摘要/摘要 脑细胞外基质(ECM)由蛋白多糖和相关分子组成的网状结构组成 突触可塑性的媒介。最引人注目的是硫酸软骨素蛋白多糖(CSPGs)的表达 Aggrecan(基因：Acan)，已被证明通过调节可塑性关键期的关闭。 神经周围网络的形成，这种结构被认为是稳定突触连接的结构。此外，酶制剂 海马区ECM的消化导致背景学习障碍，这表明ECM可能稳定下来 学习相关的突触改变。海马齿状回是一种重要的学习结构，具有 其分子层中含有丰富的聚集素，齿状回颗粒细胞(DG GC)持续产生 Acan基因在成年期的表达。因此，齿状回神经元产生的聚集素可能是 记忆过程。 这里提供的初步数据显示，齿状回神经元中Acan的基因缺失导致远端 背景歧视赤字。这一提议将检验依赖活动的aggrecan的假设 DG GCs在学习后的表达对于DG系综的分离和记忆的准确性是必不可少的 取回。首先，情境恐惧学习对DG GC Acan表达和沉积的影响将是 特征(目标1)。接下来，将使用特定于DG的Acan删除来测试是否需要生产aggrecan 对于最近或远程上下文记忆的精度(目标2)。最后，使用显微内窥镜下的钙成像，我 将描述aggrecan删除如何改变DG GC系综属性(目标3)。总之，这项提议 旨在阐明细胞外基质在哺乳动物学习和记忆中的作用及其潜在的 分子和网络机制。此外，鉴于脑细胞外基质的变化在 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 对疾病病理生理学和潜在治疗途径的洞察。 这些研究目标将与全面的培训计划一起实现，旨在开发 申请者的职业是内科科学家。此培训将包括在概念方面的一致、严格的指导 和来自两位高素质导师的技术技能，其中一位是内科科学家。该研究和 这里提议的培训将在加州大学旧金山分校进行，该校提供了一个世界- 一流的神经科学研究环境和一所特殊的临床培训医学院。

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.