Slow synaptic plasticity from the hippocampus underlies gradual mapping and fragmentation of novel spaces by grid cells

Animals construct internal "cognitive maps" of the world during navigation in spatial and non-spatial domains, with grid cells in the medial entorhinal cortex (MEC) playing a key role. This requires associating internal position estimates with external cues to reduce spatial uncertainty over time. However, how grid cell representations evolve in novel spaces to support map formation is unclear. To address this question, we longitudinally record grid cells with two-photon calcium imaging over 10 days as mice learn operant tasks in novel virtual linear tracks. We observe that spatial tuning of grid cells is present immediately in novel tracks but evolves as a significant fraction of spatial fields shift backward on a run-by-run basis, within and across days. Backward shifts are more prevalent and persistent in successful learners. The fields gradually stabilize across days, anchored by landmarks, suggesting a slow plasticity mechanism that results in an increasingly fragmented and stable map. The backward shifts partially reset daily, reflecting a slower consolidation timescale. We show that though individual fields of a cell shift differentially, co-active fields of co-modular grid cells shift together, indicating their coupled dynamics keep them on the same two-dimensional torus during this plastic period. Next, we build a simple entorhinal-hippocampal model that explains the diverse phenomena - grid field shifts, fragmentation, and increasing fidelity of the spatial map - and predicts slow Hebbian plasticity in the return hippocampus-to-entorhinal pathway. Finally, using ex vivo slice electrophysiology, we show that plasticity in an indirect hippocampus-to-MEC pathway correlates with spatial learning performance and could account for the hypothesized slow plasticity of the model. Together, our study provides multifaceted evidence of slow plasticity in synapses from the hippocampus to the MEC, elucidating the formation of stable and fragmented maps that combine internal and cue-driven positional estimates in rich environments, elucidating cognitive map formation during spatial learning.动物在空间与非空间领域的导航过程中，会构建关于外部世界的内部“认知地图”，内侧内嗅皮层（medial entorhinal cortex, MEC）中的网格细胞（grid cells）在此过程中发挥关键作用。这一过程需要将内部位置估计与外部线索相关联，以随时间推移降低空间不确定性。然而，网格细胞的表征如何在全新环境中演变以支持认知地图的形成，目前尚不明确。 为解答这一问题，我们在小鼠于全新虚拟线性轨道中完成操作性任务的10天周期内，采用双光子钙成像（two-photon calcium imaging）技术对网格细胞进行纵向记录。我们观察到，网格细胞的空间调谐特性在全新轨道中即刻存在，但随着相当比例的空间野在单日及跨日的逐轮运行中向后偏移，其表征逐渐发生演变。向后偏移现象在任务成功完成的小鼠中更为普遍且持久。这些空间野随时间推移逐渐趋于稳定，并由地标锚定，这提示存在一种缓慢的可塑性机制，最终形成愈发碎片化且稳定的认知地图。向后偏移现象会在每日部分重置，这反映出更缓慢的巩固时间尺度。 我们发现，尽管单个神经元的空间野偏移存在差异，但共模块网格细胞的共激活空间野会同步偏移，这表明在该可塑性阶段，它们的耦合动态使其始终处于同一二维环面空间中。随后，我们构建了一个简单的内嗅皮层-海马模型，该模型可解释多种现象——包括网格细胞空间野偏移、地图碎片化以及空间地图保真度的提升——并预测了海马向内嗅皮层返回通路中缓慢的赫布可塑性（Hebbian plasticity）。最后，通过离体脑片电生理（ex vivo slice electrophysiology）实验，我们证实间接海马-MEC通路中的可塑性与空间学习成绩相关，且能够解释模型中假设的缓慢可塑性机制。 综上，本研究为海马至MEC的突触缓慢可塑性提供了多维度证据，阐明了在丰富环境中结合内部位置估计与线索驱动位置估计的稳定且碎片化认知地图的形成过程，揭示了空间学习期间认知地图的构建机制。