Cortisol treatment impairs path integration and alters grid-like representations in the male human entorhinal cortex

Acute stress triggers the release of cortisol, which broadly affects cognitive processes. Path integration, a specific navigational process, relies heavily on grid cells in the entorhinal cortex. The entorhinal cortex contains glucocorticoid receptors and is therefore likely to be influenced by cortisol, though little is known about this relationship. Given the role of the entorhinal cortex in neurological diseases such as Alzheimer's Disease, investigating the effects of cortisol on this brain region may offer insights into how stress affects these diseases. In this study, we examined the effects of cortisol on human path integration in 39 healthy men across two sessions. On each day, they received either 20 mg cortisol or a placebo and performed a virtual homing task during functional magnetic resonance imaging (fMRI). Cortisol markedly impaired path integration performance, independent of incoming distance or the presence of spatial cues, but did not affect navigational pattern as measured by proximity to the landmark. fMRI results showed that cortisol increased the activation of right caudate nucleus in the presence of landmarks. Using a representational similarity analysis, we observed grid-like representations in the right entorhinal cortex specifically on day one under placebo, but these were diminished by cortisol. Grid-like representations were associated with PI performance dependent on the availability of spatial cues and cortisol administration, suggesting that cortisol may interfere with the typical relationship of grid cells and PI. Overall, the study indicates that cortisol-induced disruption in grid cell function in the entorhinal cortex may underly stress effects on path integration.