Anxiolytic Effects and Neuroanatomical Targets of Estrogen Receptor-β (ERβ) Activation by a Selective ERβ Agonist in Female Mice

Abstract

The dichotomous anxiogenic and anxiolytic properties of estrogens have been reported to be mediated by two distinct neural estrogen receptors (ER), ERα and ERβ, respectively. Using a combination of pharmacological and genetic approaches, we confirmed that the anxiolytic actions of estradiol are mediated by ERβ and extended and these observations to demonstrate the neuroanatomical targets involved in ERβ activation in these behavioral responses. We examined the effects of the biologically active S-enantiomer of diarylpropionitrile (S-DPN) on anxiety-related behavioral measures, the corresponding stress hormonal response to hypothalamo-pituitary-adrenal axis reactivity, and potential sites of neuronal activation in mutant female mice carrying a null mutation for ERβ gene (βERKO). S-DPN administration significantly reduced anxiety-like behaviors in the open field, light-dark exploration, and the elevated plus maze (EPM) in ovariectomized wild-type (WT) mice, but not in their βERKO littermates. Stress-induced corticosterone (CORT) and ACTH were also attenuated by S-DPN in the WT mice but not in the βERKO mice. Using c-fos induction after elevated plus maze, as a marker of stress-induced neuronal activation, we identified the anterodorsal medial amygdala and bed nucleus of the stria terminalis as the neuronal targets of S-DPN action. Both areas showed elevated c-fos mRNA expression with S-DPN treatment in the WT but not βERKO females. These studies provide compelling evidence for anxiolytic effects mediated by ERβ, and its neuroanatomical targets, that send or receive projections to/from the paraventricular nucleus, providing potential indirect mode of action for the control of hypothalamo-pituitary-adrenal axis function and behaviors.

Regulation of the Mouse Medial Prefrontal Cortical Synapses by Endogenous Estradiol

“…Our studies revealed an estrous cycle-dependent modulation of the IL-mPFC glutamatergic synapses. Consistent with the high expression of estrogen receptor-b (ERb) in cortical areas including the mPFC and the beneficial effects of ERb activation on anxiety behaviors and fear extinction (Kritzer, 2002;Milner et al, 2010;Oyola et al, 2012;Shughrue et al, 1997;Walf et al, 2008;Zeidan et al, 2011), ERb agonist restored the ability of the IL-mPFC glutamatergic synapses to undergo potentiation in diestrus mice.…”

17β-Estradiol Differentially Regulates Stress Circuitry Activity in Healthy and Depressed Women

“…Additional analysis of HPG axis hormones revealed that women with a faster rate of change in follicle-stimulating hormone (FSH) levels (suggesting a faster transition to menopause) had the lowest risk (Freeman et al, 2014). Further, some randomized control trials have found antidepressant effects of shortterm estradiol administration in perimenopausal women Soares et al, 2001; but see Morrison et al, 2004), which parallels animal studies demonstrating potent anxiolytic effects of ERb agonists in ovariectomized female rodents (Weiser et al, 2010, Oyola et al, 2012. Further, population studies suggest that ovarian dysfunction precedes MDD onset (Nemeroff et al, 1984;Harlow et al, 2003).…”

Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice

“…Binge-like eating behavior was confirmed in the "intermittent" HDF group in the second week. At 11:00 am on Monday of the third week (the same time when mice would be tested for binge-like eating behavior), these mice were subjected to the light-dark tests using published protocol (46). Briefly, the test consisted of a polypropylene chamber (44 × 21 × 21 cm) unequally divided into a larger, brightly illuminated open compartment (clear polypropylene) and a smaller, dark compartment (in dark polypropylene), connected by a small opening.…”

“…At 11:00 am on Tuesday of the third week, these mice were subjected to the EPM using published protocol (46). The EPM was con- Forced swim tests.…”