Sex Differences in Depression-Like Behavior and Neuroinflammation in Rats Post MI: Role of Estrogens

Patients with heart failure (HF) have a high prevalence of depression associated with a worse prognosis, particularly in older women. This 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 that was not observed in female rats with HF. In the cued fear conditioning test, the 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 pro-inflammatory cytokines production and actions in the prefrontal cortex.