17β Estradiol increases resilience and improves hippocampal synaptic function in helpless ovariectomized rats

Abstract

Summary Memory impairment is the most commonly reported cognitive symptom associated with major depressive disorder. Decreased hippocampal volume and neurogenesis in depression link hippocampal dysfunction with deficits in memory. Stress decreases hippocampal dendritic spine density and long-term potentiation (LTP) at glutamate synapses, a cellular correlate of learning and memory. However, elevated plasma levels of 17β estradiol (E2) during proestrus increase hippocampal structure and function, directly opposing the negative consequences of stress. In women, significant fluctuations in ovarian hormones likely increase vulnerability of hippocampal circuits to stress, potentially contributing to the greater incidence of depression compared to men. Using the learned helplessness model of depression and ovariectomized female rats, we investigated whether acquisition of helplessness and hippocampal synaptic dysfunction is differentially impacted by the presence or absence of plasma E2. We find that inescapable shock induces a greater incidence of helplessness in vehicle- versus E2-treated OVX rats. In the vehicle-treated group, LTP was absent at CA3-CA1 synapses in slices only from helpless rats, and CA1 spine density was decreased compared to resilient rats. In contrast, significant LTP was observed in slices from E2-treated helpless rats; importantly, spine density was not different between E2-treated helpless and resilient rats, dissociating spine density from the LTP magnitude. We also find that E2 replacement can reverse previously established helpless behavior. Thus, our results show that E2 replacement in OVX rats increases resilience and improves hippocampal plasticity, suggesting that E2 therapy may increase resilience to stress and preserve hippocampal function in women experiencing large fluctuations in plasma estrogen levels.

Ovarian hormones modify anxiety behavior and glucocorticoid receptors after chronic social isolation stress

“…Our results show a decrease in anxiety for the mid-levels of estrogen (estrus) instead of in the peak in the gonadal hormones (proestrus). This result was surprising since high levels of estrogen appear to be protective in terms of cognition, brain plasticity, and behavior [42,43]. A previous study by Sayin et al [44] found that high levels of estrogen exert an anxiolytic effect.…”

Estradiol levels modulate brain activity and negative responses to psychosocial stress across the menstrual cycle

“…This interpretation is further supported by the location of estradiol receptors in the central nervous system; the hippocampus is rich in both estradiol and glucocorticoid receptors, making it an important area of interaction between these hormones. In animal models, estrogen appears to support neuroplasticity at the hippocampus (Gould et al, 1990; Woolley et al, 1990) and to be protective against the negative effects of stress (Bredemann and McMahon, 2014). High estradiol levels during the periovulatory phase of the menstrual cycle may support hippocampal function in part through these protective mechanisms.…”

“…Animal models suggest that female rodents do not gain the same beneficial effect of acute stress on hippocampally-mediated or prefrontal tasks as male animals, and that high estrogen levels enhance the negative effects of stress in these areas(Shansky et al, 2004; Shors and Leuner, 2003). In contrast studies in ovariectomized female rats indicate that estrogen replacement increases resilience to stress in earned helplessness models and support hippocampal plasticity(Bredemann and McMahon, 2014; Smith et al, 2010). The modulation of stress effects on brain activity and function remain unclear and likely depend on the type of stress and measure of function(Shansky, 2009).…”

El papel del ácido gamma-aminobutírico en la depresión de la mujer

“…Como ya hemos mencionado, existen diversos trabajos que reportan los efectos de las hormonas gonadales femeninas en el estado de ánimo. Claros ejemplos son el impacto de la regulación que ejerce el estradiol sobre la actividad cerebral y la plasticidad del mismo, los numerosos estudios en modelos animales que sustentan el efecto del estradiol como antidepresivo en modelos animales con menopausia [72][73][74] y los trabajos sobre población clínica que demuestran los efectos benéficos que los estrógenos tienen sobre el ánimo [75][76][77] . De igual forma, se han encontrado efectos antidepresivos en la dehidroepiandrosterona 78 y la progesterona con su metabolito 5α-reducido, alopregnanolona, que producen efectos antidepresivos 79 , al parecer a través de su unión con el receptor GABA A 80 .…”