Experimental heart failure causes depression-like behavior together with differential regulation of inflammatory and structural genes in the brain.
BACKGROUND
Depression and anxiety are common and independent outcome predictors in patients with chronic heart failure (CHF). However, it is unclear whether CHF causes depression. Thus, we investigated whether mice develop anxiety- and depression-like behavior after induction of ischemic CHF by myocardial infarction (MI).


RESULTS
In order to assess depression-like behavior, anhedonia was investigated by repeatedly testing sucrose preference for 8 weeks after coronary artery ligation or sham operation. Mice with large MI and increased left ventricular dimensions on echocardiography (termed CHF mice) showed reduced preference for sucrose, indicating depression-like behavior. 6 weeks after MI, mice were tested for exploratory activity, anxiety-like behavior and cognitive function using the elevated plus maze (EPM), light-dark box (LDB), open field (OF), and object recognition (OR) tests. In the EPM and OF, CHF mice exhibited diminished exploratory behavior and motivation despite similar movement capability. In the OR, CHF mice had reduced preference for novelty and impaired short-term memory. On histology, CHF mice had unaltered overall cerebral morphology. However, analysis of gene expression by RNA-sequencing in prefrontal cortical, hippocampal, and left ventricular tissue revealed changes in genes related to inflammation and cofactors of neuronal signal transduction in CHF mice, with Nr4a1 being dysregulated both in prefrontal cortex and myocardium after MI.


CONCLUSIONS
After induction of ischemic CHF, mice exhibited anhedonic behavior, decreased exploratory activity and interest in novelty, and cognitive impairment. Thus, ischemic CHF leads to distinct behavioral changes in mice analogous to symptoms observed in humans with CHF and comorbid depression.
Medical Clinic and Policlinic I, University Hospital of Würzburg Würzburg, Germany ; Comprehensive Heart Failure Center, University Hospital of Würzburg Würzburg, Germany.
Anna
A
Frey
Comprehensive Heart Failure Center, University Hospital of Würzburg Würzburg, Germany ; Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg Würzburg, Germany.
Sandy
S
Popp
Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg Würzburg, Germany.
Antonia
A
Post
Medical Clinic and Policlinic I, University Hospital of Würzburg Würzburg, Germany ; Comprehensive Heart Failure Center, University Hospital of Würzburg Würzburg, Germany.
Simon
S
Langer
Medical Clinic and Policlinic I, University Hospital of Würzburg Würzburg, Germany ; Comprehensive Heart Failure Center, University Hospital of Würzburg Würzburg, Germany.
Marc
M
Lehmann
Medical Clinic and Policlinic I, University Hospital of Würzburg Würzburg, Germany ; Interdisziplinäres Zentrum für Klinische Forschung, University Hospital of Würzburg Würzburg, Germany.
Ulrich
U
Hofmann
Department of Neurosurgery, University Hospital of Würzburg Würzburg, Germany.
Anna-Leena
AL
Sirén
Comprehensive Heart Failure Center, University Hospital of Würzburg Würzburg, Germany ; Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg Würzburg, Germany ; Interdisziplinäres Zentrum für Klinische Forschung, University Hospital of Würzburg Würzburg, Germany.
Leif
L
Hommers
Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg Würzburg, Germany.
Angelika
A
Schmitt
Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University Maastricht, Netherlands.
Tatyana
T
Strekalova
Medical Clinic and Policlinic I, University Hospital of Würzburg Würzburg, Germany ; Comprehensive Heart Failure Center, University Hospital of Würzburg Würzburg, Germany.
Georg
G
Ertl
Comprehensive Heart Failure Center, University Hospital of Würzburg Würzburg, Germany ; Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg Würzburg, Germany ; Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University Maastricht, Netherlands.
Klaus-Peter
KP
Lesch
Medical Clinic and Policlinic I, University Hospital of Würzburg Würzburg, Germany ; Comprehensive Heart Failure Center, University Hospital of Würzburg Würzburg, Germany.
Stefan
S
Frantz
anxiety; chronic heart failure; depression; mice; myocardial infarction