Estrogen signaling in the medial amygdala decreases emotional stress responses and obesity in ovariectomized rats

Declining estradiol (E2), as occurs during menopause, increases risk for obesity and psychopathology (i.e., depression, anxiety). E2 modulates mood and energy homeostasis via binding to estrogen receptors (ER) in the brain. The often comorbid and bidirectional relationship between mood and metabolic disorders suggests shared hormonal and/or brain networks. The medial amygdala (MeA) is abundant in ERs and regulates mood, endocrine, and metabolic stress responses; therefore we tested the hypothesis that E2 in the MeA mitigates emotional and metabolic dysfunction in a rodent model of surgical menopause. Adult female rats were ovariectomized (OVX) and received bilateral implants of E2 or cholesterol micropellets aimed at the MeA. E2-MeA decreased anxiety-like (center entries, center time) and depression-like (immobility) behaviors in the open field and forced swim tests (FST), respectively in ovariectomized rats. E2-MeA also prevented hyperphagia, body weight gain, increased visceral adiposity, and glucose intolerance in ovariectomized rats. E2-MeA decreased caloric efficiency, suggestive of increased energy expenditure. E2-MeA also modulated c-Fos neural activity in amygdalar (central and medial) and hypothalamic (paraventricular and arcuate) brain regions that regulate mood and energy homeostasis in response to the FST, a physically demanding task. Given the shared neural circuitry between mood and body weight regulation, c-Fos expression in discrete brain regions in response to the FST may be due to the psychologically stressful and/or metabolic demands of the task. Together, these findings suggest that the MeA is a critical node for mediating estrogenic effects on mood and energy homeostasis. •Estradiol administered in the medial amygdala (E2-MeA) decreases anxiety-like behavior in OVX'd rats.•E2-MeA decreases depressive-like behavior in OVX'd rats.•E2-MeA decreases body weight and adiposity in OVX'd rats.•E2-MeA decreases caloric efficiency in OVX'd rats.•E2-MeA improves glucose tolerance in OVX'd rats.