Grid cells in entorhinal cortex of freely-moving rats provide a strikingly periodic representation of self-location 1 which is suggestive of very specific computational mechanisms [2][3][4] . However, their existence in humans and distribution throughout the brain are unknown. Here we show that the preferred firing directions of directionally-modulated grid cells in rat entorhinal cortex are aligned with the grids, and that the spatial organization of grid cell firing is more strongly apparent at faster than slower running speeds. Since the grids are also aligned with each other 1,5 , we predicted a macroscopic signal visible to functional magnetic resonance imaging (fMRI) in humans. We then looked for this signal as participants explored a virtual reality environment, mimicking the rats' foraging task: fMRI activation and adaptation showing a speed-modulated 6-fold rotational symmetry in running direction. The signal was found in a network of entorhinal/subicular, posterior and medial parietal, lateral temporal and medial prefrontal areas. The effect was strongest in right entorhinal cortex, and the coherence of the directional signal across entorhinal cortex correlated with spatial memory performance. Our study illustrates the potential power of combining single unit electrophysiology with fMRI in systems neuroscience. Our results provide the first evidence for grid-cell-like representations in humans, and implicate a specific type of neural representation in a network of regions which support spatial cognition and also, intriguingly, autobiographical memory.Grid cells recorded in medial entorhinal cortex of freely moving rodents fire whenever the animal traverses the vertices of an equilateral triangular grid covering the environment (see Fig. 1a), and may provide a neural substrate for path integration [1][2][3]5,6 . However, it is not known whether or not grid cells exist in humans, or how widespread the network of neurons with grid-like firing is, although the pre-and para-subiculum 7 and posterior parietal cortex 8 have been implicated.Could grid cell firing be detected in the functional magnetic resonance imaging (fMRI) signal, which reflects changes in metabolic activity across thousands of individual neurons 9 ? The grid patterns of neighbouring cells are offset so as to 'tile' the environment 1 , makingCorrespondence and requests for materials should be addressed to C.F.D. (c.doeller@ucl.ac.uk), C.B. (caswell.barry@ucl.ac.uk) or N.B. (n.burgess@ucl.ac.uk).. Supplementary Information is linked to the online version of the paper at www.nature.com/nature. Author Contributions C.F.D., C.B. and N.B. jointly conceived and designed the experiments. C.F.D. performed the fMRI experiment and data analyses; C.B. performed the single-unit experiment and data analyses; N.B. gave direction on analyses; all authors discussed the analyses and results and contributed to the paper. (Fig. 1a-c). These first two factors will create systematic differences in neural population dynamics for runs aligned or misalig...
How the memory systems centered on the hippocampus and dorsal striatum interact to support behavior remains controversial. We used functional MRI while people learned the locations of objects by collecting and replacing them over multiple trials within a virtual environment comprising a landmark, a circular boundary, and distant cues for orientation. The relative location of landmark and boundary was occasionally changed, with specific objects paired with one or other cue, allowing dissociation of learning and performance relative to either cue. Right posterior hippocampal activation reflected learning and remembering of boundaryrelated locations, whereas right dorsal striatal activation reflected learning and remembering of landmark-related locations. Within the right hippocampus, anterior processing of environmental change (spatial novelty) was dissociated from posterior processing of location. Behavioral studies show that landmark-related learning obeys associative reinforcement, whereas boundary-related
Alzheimer's disease (AD) manifests with memory loss and spatial disorientation. AD pathology starts in the entorhinal cortex, making it likely that local neural correlates of spatial navigation, particularly grid cells, are impaired. Grid-cell-like representations in humans can be measured using functional magnetic resonance imaging. We found that young adults at genetic risk for AD (APOE-ε4 carriers) exhibit reduced grid-cell-like representations and altered navigational behavior in a virtual arena. Both changes were associated with impaired spatial memory performance. Reduced grid-cell-like representations were also related to increased hippocampal activity, potentially reflecting compensatory mechanisms that prevent overt spatial memory impairment in APOE-ε4 carriers. Our results provide evidence of behaviorally relevant entorhinal dysfunction in humans at genetic risk for AD, decades before potential disease onset.
The hippocampal formation has long been suggested to underlie both memory formation and spatial navigation. We discuss how neural mechanisms identified in spatial navigation research operate across information domains to support a wide spectrum of cognitive functions. In our framework, place and grid cell population codes provide a representational format to map variable dimensions of cognitive spaces. This highly dynamic mapping system enables rapid reorganization of codes through remapping between orthogonal representations across behavioral contexts, yielding a multitude of stable cognitive spaces at different resolutions and hierarchical levels. Action sequences result in trajectories through cognitive space, which can be simulated via sequential coding in the hippocampus. In this way, the spatial representational format of the hippocampal formation has the capacity to support flexible cognition and behavior.
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