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

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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.