Grid, border and head-direction circuits in the rodent Presubiculum.

神经元对外部环境的明确属性（动物的位置）做出反应的发现，为研究高端皮质的神经编码提供了突破性的途径，而复杂的认知和行为功能最有可能在高端皮质中实现。位置细胞、网格细胞、头部方向细胞和边界细胞的发现，以及它们在行为过程中的动态相互作用，无疑是理解大脑内部计算的一个里程碑。然而，尽管在过去的几十年里取得了巨大的进步，我们仍然远远没有对空间表征的机械理解。由于方法上的限制，我们对主细胞多样性与空间编码的关系知之甚少；在高端皮质中，空间表征（如网格、边界和头部方向）的细胞身份和回路在很大程度上仍未得到解决。在这里，我提出了一个新的研究议程来解决这个问题，并直接将神经元的功能特性（在体内行为期间评估）与细胞身份和电路联系起来。我们将重点关注下带前（PreS），这是一个高端的皮质区域，它对内侧内嗅皮层（MEC）起主要的输入作用，在那里发现了大多数网格细胞。作为第一步，我们将通过结合体外电生理学与逆行神经元示踪、分子分析和体内标记神经元的形态重建，系统地表征大鼠PreS中的主要神经元。为了解决不同细胞类型的空间放电相关性，我们将使用创新的细胞旁程序记录和标记自由行为动物的单个PreS神经元。特别关注MEC投射神经元：通过远程轴突填充，结合定量解剖分析，我们的目标是在亚细胞（单孔）分辨率上提供PreS和MEC之间的第一个功能接线图。初步数据证明了所提出方法的可行性，并为PreS电路中的结构-功能关系提供了强有力的指示。总之，这种方法学上独特的单细胞方法（从功能到结构）将阐明解剖学上识别的细胞和电路如何促进空间编码，从而为哺乳动物大脑中空间表征的细胞基础提供前所未有的见解。

The discovery of neurons which respond to a clear property of the external environment (the animal`s location) has provided groundbreaking access to neural coding in high-end cortices, where complex cognitive and behavioral functions are most likely to be implemented. The discovery of place cells, grid cells, head-direction cells and border cells, and their dynamic interactions during behavior, undoubtedly represents a milestone towards understanding internal brain computations. Yet, despite the immense progress over the past decades, we are still far from a mechanistic understanding of spatial representations. Due to methodological limitations, we still know very little about how principal cell diversity relates to spatial coding; in high end-cortices, the cell identity and circuits of spatial representations (e.g. grid, border and head-direction) have remained largely unresolved. Here I propose a novel research agenda to address this problem, and directly link neuronal functional properties (assessed in-vivo during behavior) to cell identity and circuits. We will focus on the Presubiculum (PreS) - a high-end cortical region which contributes a major input to Medial Entorhinal Cortex (MEC), where most grid cells have been found. As a first step, we will systematically characterize principal neurons in the rat PreS by combining in-vitro electrophysiology with retrograde neuronal tracing, molecular analysis and morphological reconstructions of in-vivo labeled neurons. To resolve the spatial firing correlates of the different cell types, we will record and label individual PreS neurons in freely behaving animals by using innovative juxtacellular procedures. Particular focus will be devoted to MEC-projecting neurons: by means of long-range axonal filling, in combination with quantitative anatomical analysis, we aim at providing the first functional wiring diagram between PreS and MEC at subcellular (sinlge-bouton) resolution. Preliminary data demonstrate the feasibility of the proposed approach, and provide strong indications for structure-function relationships within PreS circuits. In summary, this methodologically-unique single-cell approach (from function to structure) will elucidate how anatomically-identified cells and circuits contribute to spatial coding, and thus provide unprecedented insights into the cellular basis of space representations in the mammalian brain.