Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy

Abstract

Cardiovascular dysfunction is highly comorbid with mood disorders, such as anxiety and depression. However, the mechanisms linking cardiovascular dysfunction with the core behavioral features of mood disorder remain poorly understood. In this study, we usedmice bearing a knock-in sarcomeric mutation,which is exhibited in human hypertrophic cardiomyopathy (HCM), to investigate the influence of HCM over the development of anxiety and depression. We employed behavioral, MRI, and biochemical techniques in young (3-4 mo) and aged adult (7-8 mo) female mice to examine the effects of HCM on the development of anxiety- and depression-like behaviors.We focused on females because in both humans and rodents, they experience a 2-fold increase inmood disorder prevalence vs. males. Our results showed that young and aged HCM mice displayed echocardiographic characteristics of the heart disease condition, yet only aged HCM females displayed anxiety- and depression-like behaviors. Electrocardiographic parameters of sympathetic nervous systemactivation were increased in agedHCM females vs. controls and correlated with mood disorder-related symptoms. In addition, when compared with controls, agedHCMfemales exhibited adrenal gland hypertrophy, reduced volume inmood-related brain regions, and reduced hippocampal signaling proteins, such as brain-derived neurotrophic factor and its downstream targets vs. controls. In conclusion, prolonged systemic HCM stress can lead to development of mood disorders, possibly through inducing structural and functional brain changes, and thus,mood disorders in patients with heart disease should not be considered solely a psychologic or situational condition.