Neuronal basis, functional role and pathological relevance of grid cell-like representations in the human brain

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Grid cells were initially discovered in the entorhinal cortex (EC) of rodents and are characterized by hexagonally arranged (i.e., six-fold rotationally symmetric) spatial firing fields. They have been hypothesized to support spatial navigation by implementing a mechanism for path integration (PI).In humans, grid cells could be identified via single-unit recordings in presurgical epilepsy patients during virtual spatial navigation. In addition, several fMRI studies found indirect evidence for “grid cell-like representations” (GCLRs), a putative network-level signature of grid cells in the EC with six-fold rotational symmetry. More recently, we conducted intracranial EEG (iEEG) recordings in the EC of epilepsy patients during the same spatial navigation task and observed GCLRs based on the power of theta (4-8Hz) oscillations. Until now, however, a direct link between grid cells and GCLRs could not be established. Additional open questions concern the exact functional role of GCLRs for PI and their clinical relevance for understanding Alzheimer’s disease (AD), because neurodegeneration in AD has been proposed to start in EC. Here, we propose two studies to address these issues. In the first study, we will use iEEG and single-unit recordings via combined micro-/macro-electrodes to simultaneously measure action potentials and iEEG oscillations in presurgical epilepsy patients. Patients will perform a PI task in an open-field virtual environment. This study will allow us to directly link the activity of single grid cells to GCLRs. In the second study, we will conduct fMRI recordings in healthy young participants. Half of the participants carry the ɛ4 allele of the Apolipoprotein E gene (APOE4), the most important genetic risk for sporadic AD, while the other half consists of control participants. The fMRI study is composed of two experiments across two consecutive days. On the first day, participants will conduct a same spatial navigation task in the scanner that has been used before to identify GCLRs. Experiment two consists of the same path integration task as in the iEEG/single unit experiment. We will quantify the stability of fMRI GCLRs across the two experiments and relate them to performance in the two experiments and to the APOE genotype. Together, the two studies will provide a better understanding of the neuronal mechanisms of GCLRs, their functional role for PI, and their possible impairment in genetic AD risk carriers.