Rapid effects of estrogens on behavior: environmental modulation and molecular mechanisms.

Estradiol can modulate neural activity and behavior via both genomic and nongenomic mechanisms. Environmental cues have a major impact on the relative importance of these signaling pathways with significant consequences for behavior. First we consider how photoperiod modulates nongenomic estrogen signaling on behavior. Intriguingly, short days permit rapid effects of estrogens on aggression in both rodents and song sparrows. This highlights the importance of considering photoperiod as a variable in laboratory research. Next we review evidence for rapid effects of estradiol on ecologically-relevant behaviors including aggression, copulation, communication, and learning. We also address the impact of endocrine disruptors on estrogen signaling, such as those found in corncob bedding used in rodent research. Finally, we examine the biochemical mechanisms that may mediate rapid estrogen action on behavior in males and females. A common theme across these topics is that the effects of estrogens on social behaviors vary across different environmental conditions.

Nongenomic effects of estradiol on aggression under short day photoperiods.

In several vertebrate species, the effects of estrogens on male aggressive behavior can be modulated by environmental cues. In song sparrows and rodents, estrogens modulate aggression in the nonbreeding season or winter-like short days, respectively. The behavioral effects of estrogens are rapid, which generally is considered indicative of nongenomic processes. The current study further examined the hypothesis that estradiol acts nongenomically under short days by utilizing a protein synthesis inhibitor, cycloheximide (CX). Mice were housed in either short or long day photoperiods, and treated with an aromatase inhibitor. One hour before resident-intruder testing mice were injected with either CX or saline vehicle, and 30 min later were treated orally with either cyclodextrin conjugated estradiol or vehicle. Under short days, mice treated with estradiol showed a rapid decrease in aggressive behavior, independent of CX administration. CX alone had no effect on aggression. These results show that protein synthesis is not required for the rapid effects of estradiol on aggression, strongly suggesting that these effects are mediated by nongenomic processes. We also showed that estradiol suppressed c-fos immunoreactivity in the caudal bed nucleus of the stria terminalis under short days. No effects of estradiol on behavior or c-fos expression were observed in mice housed under long days. Previously we had also demonstrated that cage bedding influenced the directional effects of estrogens on aggression. Here, we show that the phenomenon of rapid action of estradiol on aggression under short days is a robust result that generalizes to different bedding conditions.

Corncob bedding alters the effects of estrogens on aggressive behavior and reduces estrogen receptor-α expression in the brain.

There is growing appreciation that estrogen signaling pathways can be modulated by naturally occurring environmental compounds such as phytoestrogens and the more recently discovered xenoestrogens. Many researchers studying the effects of estrogens on brain function or behavior in animal models choose to use phytoestrogen-free food for this reason. Corncob bedding is commonly used in animal facilities across the United States and has been shown to inhibit estrogen-dependent reproductive behavior in rats. The mechanism for this effect was unclear, because the components of corncob bedding mediating this effect did not bind estrogen receptors. Here, we show in the California mouse (Peromyscus californicus) that estrogens decrease aggression when cardboard-based bedding is used but that this effect is absent when corncob bedding is used. California mice housed on corncob bedding also had fewer estrogen receptor-α-positive cells in the bed nucleus of the stria terminalis and ventromedial hypothalamus compared with mice housed on cardboard-based bedding. In addition, corncob bedding suppressed the expression of phosphorylated ERK in these brain regions as well as in the medial amygdala and medial preoptic area. Previous reports of the effects of corncob bedding on reproductive behavior are not widely appreciated. Our observations on the effects of corncob bedding on behavior and brain function should draw attention to the importance that cage bedding can exert on neuroendocrine research.

Sex differences in social interaction behavior following social defeat stress in the monogamous California mouse (Peromyscus californicus).

Stressful life experiences are known to be a precipitating factor for many mental disorders. The social defeat model induces behavioral responses in rodents (e.g. reduced social interaction) that are similar to behavioral patterns associated with mood disorders. The model has contributed to the discovery of novel mechanisms regulating behavioral responses to stress, but its utility has been largely limited to males. This is disadvantageous because most mood disorders have a higher incidence in women versus men. Male and female California mice (Peromyscus californicus) aggressively defend territories, which allowed us to observe the effects of social defeat in both sexes. In two experiments, mice were exposed to three social defeat or control episodes. Mice were then behaviorally phenotyped, and indirect markers of brain activity and corticosterone responses to a novel social stimulus were assessed. Sex differences in behavioral responses to social stress were long lasting (4 wks). Social defeat reduced social interaction responses in females but not males. In females, social defeat induced an increase in the number of phosphorylated CREB positive cells in the nucleus accumbens shell after exposure to a novel social stimulus. This effect of defeat was not observed in males. The effects of defeat in females were limited to social contexts, as there were no differences in exploratory behavior in the open field or light-dark box test. These data suggest that California mice could be a useful model for studying sex differences in behavioral responses to stress, particularly in neurobiological mechanisms that are involved with the regulation of social behavior.