Sex Differences in bipolar disorder – lessons from patients and from a novel bipolar disorder-like mouse model

Introduction

Sex differences (SD) attract medical research attention, including multifactorial diseases, due to their impact on physiology, pathology, prevalence, and treatment outcomes. In bipolar disorder (BD), despite similar prevalence, the phenomenology and course are different, e.g. women’s onset occurs later than in men, they experience more depressive episodes, and more. Although understanding SD is crucial for developing tailored treatments and improving disease management, they have not received enough attention to guide recommendations. Technical and ethical constrains limit undertaking studies in humans, but animal models offer a powerful approach to investigating SD in experimental systems and disease models.

Objectives

Understanding SD impact on behavioral and neurochemical parameters in our own-designed BD-like mouse model.

Methods

Behavioral and neurochemical parameters of male and female mice exhibiting BD-like characteristics vs. naïve mice were compared. BD-like characteristics were induced by daily low-dose rotenone injections; males - 0.75 mg/kg/day rotenone induced manic- and depressive-like behaviors after 4 and 8 weeks, respectively; females - a higher dose (1.5 mg/kg/day) but a shorter timeframe - after 2 and 4 weeks, respectively.

Results

Rotenone induced mild mitochondrial dysfunction as robustly reported in BD patients. The bipolar-like behavior was accompanied by neurochemical alterations (neuroinflammation, mitochondrial respiration, metabolomics) in both sexes. Female responses were strongly estrous-cycle dependent - both manic- and depressive-like effects predominantly observed during metestrus. Lithium attenuated the rotenone-induced behavioral alterations in both sexes.

Conclusions

Achieving the goal to design a female bipolar-like mouse model enabled our comparative study showing sex-specific behavioral and neurochemical phenotypes.