Subtype-specific rules of memory encoding and retrieval in dentate gyrus granule cells

记忆对日常生活至关重要，它决定了我们如何看待过去，塑造了我们如何应对未来。基于这一重要性，基础神经科学的基本目标之一就是了解大脑如何调节记忆。揭示特定细胞在记忆的各个阶段（从记忆的最初形成到随后的记忆提取）中所起的确切作用是实现这一目标的重要组成部分。 在这项拟议的研究中，我们将研究海马体中这些精确的细胞作用，海马体是一个对学习和记忆至关重要的大脑区域。具体来说，我们的研究将集中在这个大脑区域的输入细胞，即所谓的齿状回“颗粒细胞”。大量的研究表明，颗粒细胞在许多不同类型的记忆中发挥重要作用;然而，是否有特定亚型的成熟颗粒细胞在记忆中发挥精确的作用还没有研究。我们将寻求确定颗粒细胞的亚型特异性组织，提供关键的洞察到第一层的海马依赖性记忆。 利用实验和计算方面的多学科研究，我的实验室将通过将尖端神经科学技术与“大数据”分析相结合来研究颗粒细胞参与记忆的规则。开始，我们将在实验室环境中对那些经历过难忘经历的小鼠进行研究，研究相同的颗粒细胞用于记忆形成和随后的记忆提取的规则。为了补充这些实验，我们将测量小鼠基因组中数百个单个颗粒细胞中每个基因的表达，提供一个大数据框架来确定是否有特定的颗粒细胞亚型在记忆形成和检索中发挥不同的作用。最后，我们将在记忆形成过程中操纵已确定的颗粒细胞类型的亚型，并确定这种操纵是否会引起记忆提取后的不同行为。 这项工作将提供重要的洞察第一层的细胞处理在依赖于记忆的大脑，并有重要的影响，为各种学科。对于一般的神经科学界来说，了解大脑如何计算记忆是基础神经科学的核心目标。此外，澄清大脑中记忆的精确细胞类型特异性规则可能对认知神经科学，计算机科学和机器学习领域具有广泛的兴趣。

Memories are crucial for everyday life, determining how we view the past and shaping how we respond to the future. Stemming from this importance, one of the foundational goals of basic neuroscience lies in understanding how the brain mediates memory. Revealing the precise roles that specific cells play across the stages of memory from the initial formation of memory to subsequent memory retrieval is an essential component of accomplishing this goal. In this proposed research, we will study these precise cellular roles in the hippocampus, a brain region critical for learning and memory. Specifically, our research will focus on the input cells of this brain region, the so-called “granule cells” of the dentate gyrus. A rich collection of work has illustrated that granule cells can play important roles in many different types of memory; however, whether there are specific subtypes of mature granule cells that play precise roles in memory has not been investigated. We will seek to identify the subtype-specific organization of granule cells, providing critical insight into the first layer of hippocampal-dependent memory. Leveraging multidisciplinary research in both experiment and computation, my laboratory will examine the rules of granule cell participation in memory by combining cutting-edge neuroscience techniques with “Big Data” analysis. To begin, in mice that have gone through memorable experiences in a laboratory setting, we will examine the rules by which the same granule cells are used for both formation and subsequent retrieval of memories. To complement these experiments, we will measure the expression of every gene in the mouse genome for hundreds of individual granule cells, providing a Big Data framework to identify whether there are specific subtypes of granule cells that could play different roles in memory formation and retrieval. Finally, we will manipulate identified subtypes of granule cell types during memory formation, and identify whether this manipulation evokes different behaviours following memory retrieval. This work will provide essential insight into the first layer of cellular processing in hippocampal-dependent memory, and has important implications for a variety of disciplines. For the general neuroscientific community, understanding how the brain computes memory is a central goal of basic neuroscience. Moreover, clarifying the precise cell-type-specific rules of memory in the brain may be of broad interest to the fields of cognitive neuroscience, computer science, and machine learning.