Learned Helplessness Reveals a Population at Risk for Depressive-Like Behaviour After Myocardial Infarction in Mice

Figures

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  Figure 1. Schematic representation of experimental design. One day after baseline echocardiography, myocardial infarction (MI) or sham operation was performed with a subsequent period of rest for 2 weeks. In the third week, behavioural testing was started with the open field test, followed by the dark–light box test. Afterwards, pain sensitivity was tested via the hotplate test with consecutive testing for depressive‐like behaviour in the Porsolt forced swim, the tail suspension, and the sucrose preference tests. The learned helplessness paradigm was conducted with 2 days of consecutive conditioning and testing for helplessness on the third day. One day later, follow‐up echocardiography was performed with subsequent sacrifice of experimental animals.

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  Figure 2. Heart failure (HF) following myocardial infarction (MI) is not a murine model of depressive‐like behaviour. MI induced a significant up‐regulation of high‐sensitive Troponin T (hs‐Troponin T) in plasma after 24 h when compared with sham‐operated animals (SHAM) (A). Left ventricular ejection fraction (EF) was significantly blunted 4 weeks after MI in HF mice (B), in line with the finding of a markedly up‐regulated heart weight/body weight ratio in HF mice (C). With respect to depressive‐like behaviour, we conducted testing of anhedonia via the sucrose preference test (D) and of despair, using the Porsolt forced swim test (E) and the tail suspension test (F). All three tests failed to reveal a significant increase in depressive‐like behaviour after MI. Data are presented as mean ± SEM. ***P < 0.0001 by Student's t‐test; n.s., not significant, n = 18–21 per group.

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  Figure 3. Heart failure (HF) after myocardial infarction does not affect motility, exploration, or anxiety‐like behaviour in mice. We observed no significant impact of HF regarding total distance travelled (A), mean speed (B), mean distance to center (C), and time in center (D) in the open field test. Furthermore, dark–light box testing (E–G) revealed no marked differences with respect to the total number of exits (E), the total amount of time exploring (F), or the latency to first exit (G). Data are presented as mean ± SEM; n.s., not significant by Student's t‐test (A, B, E–G) or Mann–Whitney U test (C) due to absence of normality, n = 12–21 per group.

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  Figure 4. Heart failure (HF) after myocardial infarction does not enhance learned helplessness (LH) per se. To evaluate a predisposition to despair, the learned helplessness paradigm was applied. The amount of shock avoidances (A), escapes (B), mean escape latency (C), and escape failures (D) revealed no marked differences between mice with HF or after sham operation (SHAM). Cluster analysis showed 32% of SHAM animals to be helpless as opposed to 38% of HF mice (E). Previous testing for foot pain sensitivity did not reveal any marked differences between groups (F). Data are presented as mean ± SEM; n.s., not significant by Student's t‐test, n = 19–21 per group.

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  Figure 5. Mice with heart failure (HF) after myocardial infarction contain a subpopulation at risk for learned helplessness (LH) with distinguished cardiac expression of nr4a1. Advanced cluster analysis reveals a large intermediate (IM) subpopulation, based on LH parameters, suggestive of an accumulating risk profile for depression in HF after myocardial infarction (A). This is mirrored by the number of escapes (B), the amount of escape failures (C), mean escape latency (D), and avoidances (E). Interestingly, this group features elevated left ventricular (LV) nuclear receptor 4a1 (nr4a1) expression when compared with RES and LH mice (H). Data are presented as mean ± SEM, *P < 0.05 by ANOVA (Bonferroni), n = 5–15 per group.

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  Figure 6. Proposed model of subclinical and multiple‐hit‐induced depression upon heart failure after myocardial infarction. Myocardial infarction with subsequent heart failure may facilitate subclinical depression. Multiple hits of subjectively perceived uncontrollable stress lead to an accumulating risk profile—with the potential of distinct myocardial signalling—ultimately translating to clinical depression.