Learned helplessness reveals a population at risk for depressive‐like behaviour after myocardial infarction in mice

Bruns, Bastian; Schmitz, Thomas; Diemert, Nathalie; Schwale, Chrysovalandis; Werhahn, Stefanie Maria; Weyrauther, Friederike; Gass, Peter; Vogt, Miriam A.; Katus, Hugo A.; Herzog, Wolfgang; Backs, Johannes; Schultz, Jobst‐Hendrik

doi:10.1002/ehf2.12440

Cited by 5 publications

(4 citation statements)

References 39 publications

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“…mice, while not affecting overall motility or anxiety-like behavior. In line with this, we have recently shown that HF upon MI causes a predisposition toward depressive-like behavior but not necessarily depressive-like behavior in mice [9]. Other publications have suggested experimental MI and HF as a trigger of depressive-like but not anxiety-like behavior [17,47,57].…”

Section: Ablation Of the Forebrain Mr/gr Exacerbates Depressive-like ...supporting

confidence: 78%

Forebrain corticosteroid receptors promote post-myocardial infarction depression and mortality

et al. 2022

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Myocardial infarction (MI) with subsequent depression is associated with increased cardiac mortality. Impaired central mineralocorticoid (MR) and glucocorticoid receptor (GR) equilibrium has been suggested as a key mechanism in the pathogenesis of human depression. Here, we investigate if deficient central MR/GR signaling is causative for a poor outcome after MI in mice. Mice with an inducible forebrain-specific MR/GR knockout (MR/GR-KO) underwent baseline and follow-up echocardiography every 2 weeks after MI or sham operation. Behavioral testing at 4 weeks confirmed significant depressive-like behavior and, strikingly, a higher mortality after MI, while cardiac function and myocardial damage remained unaffected. Telemetry revealed cardiac autonomic imbalance with marked bradycardia and ventricular tachycardia (VT) upon MI in MR/GR-KO. Mechanistically, we found a higher responsiveness to atropine, pointing to impaired parasympathetic tone of ‘depressive’ mice after MI. Serum corticosterone levels were increased but—in line with the higher vagal tone—plasma and cardiac catecholamines were decreased. MR/GR deficiency in the forebrain led to significant depressive-like behavior and a higher mortality after MI. This was accompanied by increased vagal tone, depleted catecholaminergic compensatory capacity and VTs. Thus, limbic MR/GR disequilibrium may contribute to the impaired outcome of depressive patients after MI and possibly explain the lack of anti-depressive treatment benefit.

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Section: Ablation Of the Forebrain Mr/gr Exacerbates Depressive-like ...supporting

confidence: 78%

Forebrain corticosteroid receptors promote post-myocardial infarction depression and mortality

et al. 2022

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“…It is interesting to note that HF has also been associated with depression, and several studies have addressed this issue for example in rodent models for MI. The corresponding data suggest, however, that MI can lead to either an acute or late onset of depressive‐like phenotypes (Frey et al , 2014; Bruns et al , 2019). In our experimental setting, neither CamkIIδc TG (unpaired t ‐test; P = 0.39, n = 7/group) nor MI mice (unpaired t ‐test; P = 0.1, n = 10 sham control group; n = 8, MI group) exhibited significantly altered depressive‐like behavior when tested in the porsolt forced swim test (Agís‐Balboa et al , 2017).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic gene expression links heart failure to memory impairment

et al. 2021

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In current clinical practice, care of diseased patients is often restricted to separated disciplines. However, such an organ‐centered approach is not always suitable. For example, cognitive dysfunction is a severe burden in heart failure patients. Moreover, these patients have an increased risk for age‐associated dementias. The underlying molecular mechanisms are presently unknown, and thus, corresponding therapeutic strategies to improve cognition in heart failure patients are missing. Using mice as model organisms, we show that heart failure leads to specific changes in hippocampal gene expression, a brain region intimately linked to cognition. These changes reflect increased cellular stress pathways which eventually lead to loss of neuronal euchromatin and reduced expression of a hippocampal gene cluster essential for cognition. Consequently, mice suffering from heart failure exhibit impaired memory function. These pathological changes are ameliorated via the administration of a drug that promotes neuronal euchromatin formation. Our study provides first insight to the molecular processes by which heart failure contributes to neuronal dysfunction and point to novel therapeutic avenues to treat cognitive defects in heart failure patients.

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“…In a recent publication, however, Bruns and coworkers analyzed the potential sequence of events with respect to different depression aspects upon heart failure in C57BL/6 mice [ 58 ]. Motility, exploration, and anxiety-like behavior were unaffected three weeks post-MI.…”

Section: Discussionmentioning

confidence: 99%

5-HTT Deficiency in Male Mice Affects Healing and Behavior after Myocardial Infarction

Popp

Schmitt-Böhrer

Langer

et al. 2021

JCM

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Anxiety disorders and depression are common comorbidities in cardiac patients. Mice lacking the serotonin transporter (5-HTT) exhibit increased anxiety-like behavior. However, the role of 5-HTT deficiency on cardiac aging, and on healing and remodeling processes after myocardial infarction (MI), remains unclear. Cardiological evaluation of experimentally naïve male mice revealed a mild cardiac dysfunction in ≥4-month-old 5-HTT knockout (−/−) animals. Following induction of chronic cardiac dysfunction (CCD) by MI vs. sham operation 5-HTT−/− mice with infarct sizes >30% experienced 100% mortality, while 50% of 5-HTT+/− and 37% of 5-HTT+/+ animals with large MI survived the 8-week observation period. Surviving (sham and MI <30%) 5-HTT−/− mutants displayed reduced exploratory activity and increased anxiety-like behavior in different approach-avoidance tasks. However, CCD failed to provoke a depressive-like behavioral response in either 5-Htt genotype. Mechanistic analyses were performed on mice 3 days post-MI. Electrocardiography, histology and FACS of inflammatory cells revealed no abnormalities. However, gene expression of inflammation-related cytokines (TGF-β, TNF-α, IL-6) and MMP-2, a protein involved in the breakdown of extracellular matrix, was significantly increased in 5-HTT−/− mice after MI. This study shows that 5-HTT deficiency leads to age-dependent cardiac dysfunction and disrupted early healing after MI probably due to alterations of inflammatory processes in mice.

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Learned helplessness reveals a population at risk for depressive‐like behaviour after myocardial infarction in mice

Cited by 5 publications

References 39 publications

Forebrain corticosteroid receptors promote post-myocardial infarction depression and mortality

Forebrain corticosteroid receptors promote post-myocardial infarction depression and mortality

Epigenetic gene expression links heart failure to memory impairment

5-HTT Deficiency in Male Mice Affects Healing and Behavior after Myocardial Infarction

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