Cortisol modulates hippocampus activation during semantic substitution in men

In the case of incomplete episodic memory retrieval, semantic knowledge may play a vital role compared to random memory errors in filling in memory gaps (semantic substitution). Stress impairs (episodic) memory retrieval via stress hormones (mainly cortisol) targeting the hippocampus. This preregistered neuroimaging study aimed to examine the neural mechanisms of the interplay between episodic memories and prior knowledge during the reconstruction of a past scenario under elevated cortisol levels in men. During encoding, sixty men prepared a virtual apartment for having guests over by using button presses to interact with household objects (e.g., toasting a slice of bread) that were placed congruently to semantic knowledge (e.g., a coffee machine in the kitchen) or incongruently (e.g., a toaster in the bathroom). One day later, participants received (order randomized, double-blind) either 20 mg of cortisol (n = 30) or a placebo (n = 30) before a recognition task. After identifying objects as old, we included a room recall using a forced-choice question in which room the objects were remembered. For incongruent objects this allowed us to differentiate the involvement of episodic, semantic, or random memory. Cortisol did not impair general recognition memory. The manipulation of stimuli during encoding, as being congruent and interactable (relevant to the goal) appears to be predictive of later accurate room recall. Semantic substitution in case of episodic memory failure was associated with anterior parahippocampal and gyrus rectus activation. Cortisol administration increased hippocampal activation during semantic substitution, suggesting a compensatory effect. The results characterized the neural correlates of semantic substitution and speak for an intertwined view of episodic memory and semantic knowledge, which is further shaped by the stress hormone cortisol.