Stimulus-specific enhancement of fear extinction during slow-wave sleep

Abstract

Sleep can strengthen memory for emotional information, but whether emotional memories can be specifically targeted and modified during sleep is unknown. In human subjects who underwent olfactory contextual fear conditioning, re-exposure to the odorant context in slow-wave sleep promoted stimulus-specific fear extinction, with parallel reductions of hippocampal activity and reorganization of amygdala ensemble patterns. Thus, fear extinction may be selectively enhanced during sleep, even without re-exposure to the feared stimulus itself.

Figure 1. Behavioral results

(a) During target odorant re-exposure, SCR decreased from the first half of re-exposure to the second half (compared to odorant-off control periods) for subjects in SWS (left). In comparison, SCR increased during this period for awake control subjects (right). *P≤0.05, one-tailed. Bar plots represent mean SCR activity (percentage-change units). Error bars, S.E.M. (adjusted for between-subjects differences; Online Methods). (b) From pre-sleep to post-sleep, mean SCR was selectively reduced for the target (sleep-reactivated) CS+ (tgCS+ vs. ntCS+). Negative values denote pre- to post-sleep reductions. *P≤0.05, one-tailed. Error bars, S.E.M. (c) Duration of contextual re-exposure in SWS predicted SCR reductions from pre- to post-sleep, r=−0.61, P=0.02 (tgCS+ vs. ntCS+, adjusted for CS− baselines). Each dot represents one subject. (d) In awake subjects, re-exposure duration predicted subsequent increases in SCR, r=0.53, P=0.04. Re-exposure duration was yoked between experimental sleep (c) and awake (d) groups.

Figure 2. Sleep-related modulatory effects of target odorant re-exposure on fMRI activity

(a) Activity evoked by tgCS+ (vs. ntCS+) was reduced from pre- to post-sleep in anterior hippocampus (t[14]=−4.65, **P<0.001; adjusted for CS− baselines). Activation maps are overlaid on a T1-weighted coronal section from a representative subject (display threshold, P<0.005). Box plots (right) indicate median (central line) and upper/lower quartiles (top/bottom of box) for each condition. Whiskers denote extent of data between 10^th and 90^th percentiles. (b) Post-sleep (vs. pre-sleep) activity in entorhinal cortex evoked by tgCS+ (vs. ntCS+) was negatively correlated with the duration of odorant re-exposure during SWS (r=−0.51, P=0.05, n=15). (c) (Left) Voxel-wise ensemble maps of left amygdala activity from one subject show that condition-specific patterns diverged more for tgCS+ (vs. ntCS+) from pre- to post-sleep. Each square represents signal intensity from a different voxel (n=75), arranged in columns from top left to bottom right, in ascending order for tgCS+ in the pre-sleep condition. (Right) Across all subjects, pre- and post-sleep pattern ensembles in amygdala became more distinct (less correlated) for tgCS+ compared to ntCS+ (t[14]=−2.66, *P=0.02; adjusted for CS− baselines; paired t test).