REM sleep reduction leads to fear overgeneralization via negatively modulating prefrontal theta oscillations

Fear overgeneralization, defined as the excessive fear response to non-threatening stimuli, is a hallmark of anxiety-related disorders. Sleep has long been recognized as a critical factor in the consolidation and processing of fear memories, with research suggesting that different sleep phases, particularly rapid eye movement (REM) and non-rapid eye movement (NREM) sleep, may have distinct roles. However, how sleep influences fear generalization remains largely unknown. We systematically investigated the dynamic effects of sleep phases and their associated neural oscillations on fear generalization recently after sleep manipulation and remotely 1 week later.

In a randomized controlled between-subjects experiment, 126 participants were assigned to the four groups: total sleep deprivation (SD), early-night (dominated by NREM sleep) SD, late-night (dominated by REM sleep) SD, and total sleep. Participants completed the fear conditioning test before the sleep-manipulated night, the recent fear generalization test after sleep, and the remote fear generalization test 1 week later. Both neuroimaging data and behavioral data (subjective risk ratings and objective skin conductance responses) were collected synchronously to analyze brain functional changes during generalized stimuli processing.

Sleep, particularly REM sleep phase, inhibits fear generalization, whereas late-night SD, by reducing REM sleep, induces fear overgeneralization comparable to total SD. The percentage of REM sleep was negatively associated with the degree of fear generalization and positively correlated with dorsolateral prefrontal cortex BOLD activity during the recent generalization test. Notably, prefrontal theta oscillations mediated 44% of REM sleep's effects on fear generalization.

These findings demonstrate the essential role of post-conditioning REM sleep, particularly its reliance on theta oscillations in the frontal lobe, in mitigating fear overgeneralization.