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 used mice 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 in mood 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 system activation were increased in aged HCM females vs. controls and correlated with mood disorder-related symptoms. In addition, when compared with controls, aged HCM females exhibited adrenal gland hypertrophy, reduced volume in mood-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.-Dossat, A. M., Sanchez-Gonzalez, M. A., Koutnik, A. P., Leitner, S., Ruiz, E. L., Griffin, B., Rosenberg, J. T., Grant, S. C., Fincham, F. D., Pinto, J. R. Kabbaj, M. Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy.

Keywords: adrenal gland; heart rate variability; mood disorder; sarcomeric protein; troponin.

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Figures

Figure 1.

Echo variables in HCM young adult and aged females. EF percentage (A), IVRT (B), MV A (C), and MV E/A (D) in young adult and aged adult control and HCM females. Data are means ± sem; n = 6–7/group young adult, n = 9–13/group aged adult. *P < 0.05, **P = 0.005 vs. control within same age group.

Figure 2.

Electrocardiographic variables in HCM aged females. The HF component of HRV (A), HRV (B), CV (C), and RMSSD (D) between heartbeats in young adult and aged adult control and HCM female mice. Data are means ± sem (n = 10–13/group). *P < 0.05 vs. control.

Figure 3.

Light–dark box test and FST reveal HCM-related mood disorder-like phenotype in aged female mice. A) Anxiety-like behavior in the light–dark box test. B) Number of transitions between the light and dark compartments. C) Depression-like behavior in the FST. Data are means ± sem; light–dark box test (n = 6–7/group, young adult; n = 12–14/group, aged adult; FST n = 8/group, young adult; n = 13–16/group, aged adult). *P < 0.05 vs. control.

Figure 4.

HCM induced adrenal gland hypertrophy in aged female mice: (adrenal gland weight/body weight) × 1000. Data are means ± sem (adrenal gland: n = 8/group, young; n = 10–14/group, aged). *P = 0.05 vs. control.

Figure 5.

Autonomic nervous system activity correlates significantly with behavioral indices of mood disorder in aged adult females. A) RMSSD and its correlation with anxiety-like behavior in the light–dark box test. B) RMSSD and its correlation with depression-like behavior in the FST. Data are means ± sem (n = 23 for light–dark box test; n = 22 for FST).

Figure 6.

Volumetric analysis of mood-related brain regions in aged adult HCM females. A1–A4) Sagittal section with 3-dimensional rendering of analyzed brain regions (A1), representative coronal sections depicting the PFC (A2), the CPu (A3), and the HPC (A4). B) Total brain volume in aged adult control and HCM mice. C–E) Indices of the PFC (C), CPu (D), and HPC of aged adult control and HCM females (E). Data are means ± sem (n = 4/group). *P < 0.05 vs. control.

Figure 7.

Markers of neurotrophic health and neuroplasticity are significantly downregulated in the HPC of aged adult HCM females. A) BNDF (14 kDa) levels over GAPDH (37 kDa). B) Levels of p-MAPK over MAPK (42/44 kDa). C) p-CaMKIIα over CaMKIIα (50 kDa) in young adult and aged mice. Data are means ± sem and expressed as a ratio of controls (within each respective age group) (n = 6–7/group). *P < 0.05 vs. control, aged adults. Insets: representative Western blots.

Figure 8.

Markers of neurotrophic health and neuroplasticity correlate with behavioral indices of mood disorder in aged adult females. A1–C1) Correlation between anxiety-like behavior in the light–dark box and BDNF/GAPDH (A1), p-MAPK/MAPK (B1), and p-CaMKIIα/CaMKIIα levels in aged adult control and HCM mice (C1). A2–C2)Correlation between depression-like behavior in the FST and BDNF/GAPH (A2), p-MAPK/MAPK (B2), and p-CaMKIIα/CaMKIIα levels in the HPC of aged adult control and HCM mice (C2). Data are means ± sem and are expressed as a ratio of aged controls (n = 13/group).