Neural mechanisms, functional roles and pathophysiological relevance of human grid cell-like representations

ongoing

The entorhinal cortex contains grid cells, a major cell type underlying spatial navigation. At the same time, it is amongst the first areas of the brain to be affected by Alzheimer’s disease (AD). In humans, grid cell-like representations (GCLRs) have been proposed as a network-level signature of grid cells that can be recorded non-invasively via functional magnetic resonance imaging (fMRI). I have recently demonstrated that there is a disruption of GCLRs in genetic AD risk carriers at young age, and suggested GCLRs as a novel biomarker for early disease processes in AD. However, the relationship between GCLRs at a network level and grid cells measured at the single-neuron level is still unknown, as is the pathophysiological relevance of the impaired GCLRs and of compensatory hyperactivity in other navigational systems. In the translational research program proposed here, I aim to unravel the cellular mechanisms, functional relevance, and pathological impact of grid cell-like representations in humans. My specific objectives are to (1) provide the first validation of GCLRs, by directly relating GCLRs at the network level to single unit activity of individual neurons recorded via microelectrodes in epilepsy patients; (2) clarify the functional relevance of GCLRs and complementary navigational systems for spatial behavior via layer-resolved ultrahigh field (7T) fMRI; (3) determine whether impairments of GCLRs and compensatory recruitment of other navigational strategies are related to AD pathology, using tau- and amyloid-PET imaging in AD risk carriers; and (4) restore impaired GCLRs via a pharmacological intervention, which may constitute a novel therapeutic option for modifying early AD. These studies will provide the first detailed understanding of the neural mechanisms and functional role of grid cells in humans across several levels of brain organization and pave the way for novel diagnostic and therapeutic approaches to AD.