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，塑造了我们对未来的反应。由于这一重要性，基础神经科学的基本目标之一在于了解大脑是如何调节记忆的。揭示特定细胞在从最初的记忆形成到随后的记忆提取的各个阶段所扮演的确切角色，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角色，海马体是大脑中对学习和记忆至关重要的区域。具体地说，我们的研究将集中在这一大脑区域的输入细胞，即所谓的齿状回的“颗粒细胞”。大量的研究表明，颗粒细胞可以在许多不同类型的记忆中发挥重要作用；然而，是否存在特定亚型的成熟颗粒细胞在记忆中扮演确切的角色尚未得到研究。我们将寻求确定颗粒细胞的亚型特异性组织，为海马依赖记忆的第一层提供关键的洞察力。 我的实验室利用实验和计算方面的多学科研究，将尖端神经科学技术与“大数据”分析相结合，研究颗粒细胞参与记忆的规律。首先，在实验室环境中经历了难忘经历的小鼠中，我们将检查相同的颗粒细胞用于形成和随后提取记忆的规则。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的每个基因的表达，提供一个大数据框架，以确定是否存在特定的颗粒细胞亚型，这些亚型可能在记忆形成和提取中扮演不同的角色。最后，我们将在记忆形成过程中操纵已识别的颗粒细胞类型的亚型，并确定这种操纵是否会在记忆提取后唤起不同的行为。 这项工作将提供对海马体依赖记忆中细胞处理的第一层的重要洞察，并对各种学科具有重要意义。对于普通神经科学界来说，了解大脑如何计算记忆是基础神经科学的中心目标。此外，阐明大脑中精确的特定细胞类型的记忆规则可能会引起认知神经科学、计算机科学和机器学习领域的广泛兴趣。

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.