Patients with
heart failure (HF) have a high prevalence of depression associated with a worse prognosis, particularly in older women. The present study evaluated whether sex and
estrogens affect depression-like behavior and associated
neuroinflammation induced by
myocardial infarction (MI) in rats. MI was induced by occlusion of the left anterior descending artery in young adult male and female Wistar rats or in ovariectomized (OVX) female rats without and with
estrogen [17β-
estradiol (E2)] replacement. MI groups showed a comparable degree of cardiac dysfunction. Eight weeks post-MI, male rats with HF exhibited depression-like behaviors, including
anhedonia and higher immobility in the
sucrose preference and forced swim tests, which were not observed in female rats with HF. In the cued fear conditioning test, male but not female rats with HF froze more than
sham rats. After OVX, female
sham rats developed mild depression-like behaviors that were pronounced in OVX female rats post-MI and were largely prevented by E2 replacement.
Cytokine levels in the plasma and paraventricular nucleus increased in both sexes with HF, but only male rats with HF showed an increase in
cytokine levels in the prefrontal cortex. OVX alone did not affect
cytokine levels, but OVX-MI caused significant increases in the prefrontal cortex, which were shifted to an anti-inflammatory pattern by E2 replacement. These results suggest that
estrogens prevent depression-like behavior induced by HF post-MI in young adult female rats by inhibiting proinflammatory
cytokine production and actions in the prefrontal cortex. NEW & NOTEWORTHY In contrast to male rats, female rats with
heart failure after
myocardial infarction do not develop depression-like behavior or increases in prefrontal cortex
cytokines. However, after
ovariectomy, female rats exhibit similar changes, which are prevented by 17β-estradiol replacement.
Neuroinflammation in the prefrontal cortex in male subjects may contribute to depression-like behavior, whereas its
estrogen-dependent absence in female subjects may protect against depression.