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

项目概要/摘要 大脑细胞外基质 (ECM) 由蛋白聚糖和相关分子的网格组成 突触可塑性的媒介。硫酸软骨素蛋白多糖 (CSPG) 的表达，最显着的是 聚集蛋白聚糖（基因：Acan）已被证明可以通过 神经元周围网络的形成，这种结构被认为可以稳定突触连接。此外，酶促 海马 ECM 的消化导致情境学习缺陷，表明 ECM 可能会稳定下来 与学习相关的突触变化。海马体的齿状回是一个关键的学习结构，它具有 其分子层含有丰富的聚集蛋白聚糖，齿状回颗粒细胞（DG GC）不断产生 成年期的 Acan mRNA。因此，齿状回神经元产生的聚集蛋白聚糖可能是稳定的基础。 记忆过程。 这里提供的初步数据表明，齿状回神经元中 Acan 的基因缺失会导致远程 情境歧视缺陷。该提案将检验以下假设：活动依赖性聚集蛋白聚糖 学习后 DG GC 的表达对于 DG 集成分离和记忆精度至关重要 检索。首先，情景恐惧学习对 DG GC Acan 表达和沉积的影响将是 特征（目标 1）。接下来，将使用 DG 特异性 Acan 删除来测试是否需要生产聚集蛋白聚糖 最近或远程上下文记忆精度（目标 2）。最后，使用显微内窥镜钙成像，我 将描述聚集蛋白聚糖删除如何改变 DG GC 整体属性（目标 3）。总而言之，这个提案 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作用 分子和网络机制。此外，鉴于大脑 ECM 的改变被发现 神经退行性和精神疾病，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见解。 这些研究目标将与旨在发展 申请人作为医师科学家的职业生涯。该培训将包括概念方面一致、严格的指导 两位高素质导师的技术技能，其中一位是医师科学家。该研究和 这里提出的培训将在加州大学旧金山分校进行，该大学提供世界级的培训 一流的神经科学研究环境和出色的临床培训医学院。

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.