Cortisol-related hippocampal-extrastriate functional connectivity explains the adverse effect of cortisol on visuospatial retrieval

Cortisol is known to affect visuospatial memory through its major binding site in the brain, the hippocampus. The synchronization of neural activity between the hippocampus, prefrontal cortex (PFC), and visual cortex is presumed to be essential for the formation of visuospatial memory because of their visuospatial learning-dependent neuroplasticity. However, it remains unclear how hippocampal connectivity with the PFC and visual cortex is involved in the relationship between cortisol and visuospatial memory in humans. We thus investigated whether functional connectivity (FC) of the hippocampus, specifically its rostral and caudal subdivisions, mediates the relationship between visuospatial memory and endogenous cortisol. One-hundred sixty-six healthy young adults underwent standard neuropsychological tests to assess visuospatial construction (a complex figure copying test) and retrieval (the corresponding recall test) and collected their saliva at 6-time points across 2 consecutive days for measurement of daily cortisol concentrations (dCOR). Ninety of them received resting-state fMRI scans. Greater dCOR was significantly associated with better figure copying performance, but contrastingly with poorer figure recall. In proportion to dCOR, the rostral hippocampus (rHC) showed significantly increased FC with the PFC (including its dorsolateral and medial parts) and the inferior lateral occipital cortex (iLOC), while the caudal hippocampus had increased FC with the anterior middle temporal cortex. Of the cortisol-related hippocampal connectivity, the rHC-iLOC FC was specifically correlated with figure recall and showed complete mediation for the negative relationship of dCOR with figure recall. These results suggest that cortisol might have enhancing effects on visuospatial encoding as well as impairing effects on visuospatial retrieval, possibly due to its occupancy patterns of corticosteroid receptors. Cortisol's adverse effects on visuospatial retrieval might be explained through cortisol-related rostral hippocampal connectivity with the iLOC, which is a part of the extrastriate cortex implicated in visuospatial perception. Thorough dissection of hippocampal-prefrontal-extrastriate connectivity might facilitate the understanding of neural mechanisms underlying cortisol's contrasting effects on encoding (or consolidation) and retrieval of visuospatial information.