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. 2022 Oct 12;27(11):4485–4501. doi: 10.1038/s41380-022-01791-5

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© The Author(s) 2022

Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — A Experimental design, and timeline of the longitudinal protocol used involving social isolation. Wild-type (WT; n = 10) and Crtc1^−/− (n = 6) mice underwent a set of behavioral tests including an open-field test (OF; day 1), a forced swim test (FST; day 2) and a tail-suspension test (TST; day 3) followed by a ¹H-MRS scan on day 4. After this first set of experiments, animals were isolated at the age of 6 weeks and the whole procedure was repeated at 12 and 24 weeks of age. After the last ¹H-MRS scan, animals were sacrificed, and hippocampal and plasma samples were collected for analysis. B A switch in depressive-like behavior between Crtc1^−/− and wild-type mice occurs after 18 weeks of social isolation as revealed by the inversion in immobility time in TST (right panel; Interaction: F_2,28 = 5.16, p = 0.012), FST (center panel; Interaction: F_2,28 = 3.87, p = 0.035) and averaged z-score of TST and FST (left panel; Interaction: F_2,28 = 10.26, p = 0.0005). Two-way ANOVA, followed by Fisher LSD post hoc test; *p < 0.05, **p < 0.01. C Hippocampal neuroenergetic profile switches between Crtc1^−/− and wild-type mice at the end of 18 weeks of isolation as revealed by the inversion of lactate concentration (left panel; Interaction: F_2,28 = 7.32, p = 0.003), PCr/Cr ratio (center left panel; Interaction: F_2,28 = 2.79, p = 0.08) and PCr (center right panel; Interaction: F_2,28 = 4.78, p = 0.017). Hippocampal glucose levels increased in the Crtc1^−/− group only at the end of the 18 weeks of isolation (Time effect: F_2,28 = 3.43, p = 0.050). Two-way ANOVA, followed by Bonferroni’s post hoc test; *p < 0.05, **p < 0.01. D Correlative analysis between depressive-like behavior and hippocampal energy metabolite content. A significant negative correlation between Lac and behavior was found when results from FST and TST were considered together (R = −0.351, p = 0.013). Color code represents Pearson’s correlation coefficient and the analysis included all longitudinal age time points. Pearson’s Rs are shown for each correlation with associated p value (uncorrected for multiple comparisons); *p < 0.05, ***p < 0.0001. E At the end of 18 weeks of isolation, hippocampal levels of Pgc1α mRNA were higher while Glut4 levels were lower in Crtc1^−/− as compared to wild-type mice. Mitochondrial and cytoplasmic creatine kinases were not significantly different (n.s.) between the two groups. Unpaired Student’s t test, *p < 0.05. F Body weight of all animals increased significantly over time (Time effect: F_2,28 = 123.2, p < 0.0001) but increased more in the Crtc1^−/− group (Genotype effect: F_1,14 = 5.84, p = 0.030; Interaction: F_2,28 = 5.11, p = 0.013). Two-way ANOVA followed by Fisher LSD post hoc test *p < 0.05. G Plasma markers of metabolic syndrome (insulin, glucose and triglycerides) were high in both groups but not significantly different from each other (n.s.).