Figure 3

Impaired fear extinction in Y4 receptor knockout (KO) mice was rescued by repeated fasting episodes before extinction learning. (a) Y4KO mice and wild-type controls were subjected to fear acquisition, conditioned stimulus (CS) testing 24 h later, and to a total of four extinction sessions on days 2–6, followed by extinction recall on day 7. (b) No difference in fear acquisition and (c) fear recall, but (d) impaired extinction learning (note the apparent reduction of freezing levels in Y4KO mice during CS1 and 3, that was, however, due to jumping behavior, thus probably indicating an increased stress reaction) and (e) extinction recall in Y4KO mice compared with wild-type controls. (f) After fear acquisition, one group of Y4KO mice was subjected to repeated cycles of fasting before and during extinction learning followed by extinction recall under fed conditions. (g) Following fear acquisition, Y4KO mice were divided into two equal groups, one that was fasted before extinction training and one that was not, (h) no difference in fear expression between fasted and non-fasted Y4KO mice, (i) rescued fear extinction in fasted Y4KO mice compared with fed Y4KO controls, (j) successive reduction of freezing in extinction recall on testing days 3, 5, and 7 tested under fed conditions and reduced reinstatement on day 21 in Y4KO mice that were fasted before extinction training, suggesting permanent suppression of fear (repeated two-way analysis of variance (ANOVA) for acquisition and extinction learning, Student’s t-test for CS-induced freezing and extinction recall and reinstatement testing, *P<0.05, **P<0.01, ***P<0.001; WT vs Y4KO—WT: n=9, Y4KO: n=6 and Y4KO fasted vs non-fasted—Y4KO fasting: n=8, Y4KO food: n=8). KO, knock out.

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