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. 2022 Dec 22;19:67. doi: 10.1186/s12979-022-00323-7

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© The Author(s) 2022, corrected publication 2024

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 4 — HFD increases fear responses, particularly in aged mice. Aged HFD mice exhibit deficits in extinction learning (n = 10/group). (A) Fear conditioning paradigm. (B) Context test. Compared to baseline all mice displayed significant levels of freezing when returned to the training context on day 2 (3-way RM ANOVA; main effect of training F (1, 36) = 315.7; ₸, p < 0.0001). Freezing levels appeared to be modulated by diet (3-way RM ANOVA; main effect of diet F (1, 36) = 18.8; ‡, p < 0.0001) which was driven by the segregation of the two diet groups regardless of age at 24 h (1-way ANOVA F (3, 36) = 6.096, p = 0.0018). (C) Tone test. Mice were placed in a novel context and after a 180 s baseline period were exposed to the same tone used during training (the last 30 s of baseline and first 30 s of tone are presented. A 3-way repeated measures ANOVA revealed a main effect of training (F (1, 36) = 147.5 ₸, p < 0.0001). Freezing levels appeared to be modulated by diet (3-way RM ANOVA; main effect of diet F (1, 36) = 18.8; ‡, p < 0.0054) but this effect was not specific to group, although when freezing in response to tone was analyzed, there was a significant difference between mice in the Aged SD group and the Aged HFD group (1-way ANOVA F (3, 36) = 3.593,P = 0.0228 followed by Tukey post hoc comparison: adjusted p = 0.0141). (D) Extinction training. On days 2, 3 and 4 mice were returned to the original training context and freezing was measured for 30 min (presented here in 5 min bins). Across all three days there was a reduction in freezing in response to repeated context exposure (3-way RM ANOVA main effect of training: Day 2 F (1, 36) = 157.2, ₸, p < 0.0001; Day 3: F (1, 36) = 14.17; ₸, p = 0.0006; Day 4 F (1, 36) = 11.84; ₸, p = 0.0015) which was likely influenced by diet (3-way RM ANOVA main effect of diet: Day 2 F (1, 36) = 22.46, ₸, p < 0.0001; Day 3: F (1, 36) = 14.02; ₸, p = 0.0006; Day 4 F (1, 36) = 10.63; ₸, p = 0.0024) and age (3-way RM ANOVA main effect of age: Day 2 F (1, 36) = 4.963, ₸, p = 0.0322; Day 3: F (1, 36) = 6.750; ₸, p = 0.0135; Day 4 F (1, 36) = 16.03; ₸, p = 0.0003). This was especially evident on Day 2 where a training x diet x age interaction was observed (F (1, 36) = 4.963p = 0.0322). To more directly examine the effectiveness of extinction training a 1-way ANOVA was used to analyze freezing levels recorded in the final bin on each day. Across all three days there was a main effect of group (Day 2: F (3, 36) = 12.69, p < 0.0001; Day 3: F (3, 36) = 7.524, p = 0.0005; Day 4: F (3, 36) = 5.530 P = 0.0032). This effect appears to be a function of mice in the Aged HFD group which exhibited significantly more freezing as compared to the other 3 groups (Tukey’s multiple comparisons test *** p < 0.001, * p < 0.05). All data are presented as mean ± SEM