Review
Estrogens and non-reproductive behaviors related to activity and fear

https://doi.org/10.1016/j.neubiorev.2003.11.017Get rights and content

Abstract

Estrogens affect a variety of behaviors in addition to sexual responses, some of them related to motor activity and emotional reactivity. This is true in experimental animals and in humans. The literatures on these subjects are confusing because not all of the experimental results point in the same direction. Here we propose the following theoretical suggestion, hoping to account for the variety of reports extant: following the generally arousing effects of estrogens, their hormonal actions on motor activity and fear depend on context. In a safe environment, estrogen treatment causes increased activity. But in a novel environment or in contexts otherwise perceived as threatening, activity is reduced by estrogen, due to the hormone's arousing action, which heightens fear. Many hormone-dependent neural circuits involving several neuropeptides could provide mechanisms for this dynamic. We suggest a causal route could involve the activation of corticotropin releasing hormone gene expression in the brain. In sum, estrogenic effects on arousal states, as manifest differently according to details of the environmental context during behavioral test, could account for some of the discrepancies in the literature.

Introduction

Estrogens are known to affect a variety of behaviors related to emotions, activity levels, and mood. Both the human and animal literatures suggest that the influences of estrogens on non-reproductive processes are variable in both their amplitude and direction; their effects may depend on the current state of the organism and the context in which it is engaged. Despite a long history of examining the role of estrogens in non-reproductive behaviors, its influences are still ambiguous. The goal of this essay is to touch on some of what is already known about estrogens' non-reproductive functions, primarily in rodent models, looking at fear and activity levels in different contexts, and to suggest a perspective on estrogenic functions in order to understand a variety of findings in the literature.

In humans, the influences of estrogens on affect, activity, and mood are certain but unclear. Estrogens are known to have considerable regulatory influence on systems mediating anxiety and mood (for discussion, see Refs. [1], [2]). Females become more susceptible to mood disorders starting at puberty; they are twice as likely as males to develop various anxiety [2] and depressive [3], [4] disorders. Cycling reproductive hormones are most likely influential (for discussion, see Ref. [5]). Low or dropping levels of estrogens, as found during various stages in the menstrual and reproductive cycles, can be associated with depression, irritability, panic, and anxiety [3], [4], [6], [7]. Relatively high levels of estrogens, such as seen during the preovulatory estrogen surge, can produce increased feelings of well being [8] as well as anxiety and increased nervous energy [6], [9]. Estrogen replacement therapy (ERT) has been associated with improved mood, increased energy levels, and feelings of general well being [7], [10], though others have found no significant changes following ERT [11], [12], [13]. Thus, within the normal cycle of female estrogen levels, and during ERT, the effects of estrogens can range from improved mood to anxiety, from increased energy levels to increased nervous energy. This demonstrates that these hormonal effects are not uniform in their amplitude or direction. Further, estrogens cannot be seen simply as ‘nature's psychoprotectant’ that they commonly are believed to be.

The animal literature concerning the influence of estrogens on affect and activity levels points to estrogens as having generally stimulating effects on activity levels ([14], [15], [16], [17], [18], [19], [20], [21]; for review, see Refs. [22], [23], [24]). However, as with humans, estrogenic effects in animals on emotional responses are varied, with elevations in estrogens producing a range of responses on tests of anxiety and fear [25], [26], [27], [28], [29], [30], [31], [32] (and see below).

The purpose of this review is to highlight some of the differences among results and to propose theoretical explanations for some of them. Clearly, the precise details of environmental context for the experiment must be considered, because in our own work [16], [17], estrogen administered to ovariectomized (OVX) mice produced diametrically opposite behaviors depending on the experimental setup. Estrogen-treated mice demonstrated increased activity in the safety of the home cage (e.g. running wheel (RW), home cage activity), but also increased fear in novel or threatening contexts (displayed, in part, as reduced activity in standard tests of rodent fear). These divergent responses suggest that estrogens can produce behavioral outcomes that depend, in part, upon the context in which the behavioral assay takes place. Other major contributing factors include the differences in functional roles between two separate gene products coding for estrogen receptors, Estrogen Receptor-alpha (ER-alpha), versus Estrogen Receptor-beta (ER-beta). In rodent brains ER-alpha is expressed strongly in hypothalamic neuronal groups closely related to reproductive physiology, and also in the brainstem at pontine and medullary levels [33]. The distribution is relatively restricted. In contrast, ER-beta is much less expressed in reproductive neuroendocrine cell groups, but is widely expressed in the forebrain—even in neocortex as well as in limbic forebrain cell groups—and in the dorsal raphe [34]. Clearly these separate distributions of the two ERs will have different relationships to the brain regions known to be affecting the behaviors in question. For example, estrogen-dependent locomotor activity (driven from preoptic neurons which in turn project to the mesencephalic locomotor region) depends on a different combination of brain regions than fear (reported to be mediated through basolateral amygdala). A full description of all the neuronal systems participating in voluntary motor activity, fear and anxiety is beyond the scope of this paper, but it is obvious that the two different ER-alpha and -beta distributions must intersect them differently. The experiments anticipated by this paper for the future must go beyond gene knockouts. The interpretative difficulties brought out by genetic manipulations which are permanent in the life of the animal and present across the entire brain are now recognized. Therefore, manipulation of mRNA function in a manner specific neuroanatomically and temporally, for example, by new moieties of antisense DNA (morpholinos, locked nucleic acids, or peptide-antisense) will help by interrupting estrogen signaling in a brain region specifically chosen to be relevant for one of the behaviors in question but not another. Short of those experiments for the future, we review the large literature already available.

Section snippets

Theory of estrogens and arousal

Estrogens undoubtedly heighten arousal in female rats [35]. This is demonstrated in sexually receptive females, in part, by heightened muscular tension throughout their bodies, rapid alternating movements, and rapid locomotion.

How might theory and data about general arousal help to address the differences in the effects of estrogens on activity and fear/anxiety? Historically, the arousal concept was seen as necessary to neurophysiology and behavior, but was plagued by the same type of

Activity versus fear

Estrogens and activity levels. Motor activity in rodents has commonly been measured in the RW or an open field test (OF) [24], though OF is now frequently used as a measure of fear. RW activity has consistently been shown to be increased in the presence of estrogens in rats, whether during proestrus and estrus versus metestrus and diestrus, or in OVX females receiving estrogens [14], [15], [18], [19], [20], [21], [40] (for review see Ref. [22]). Females are more active than males [24] both in

Estrogens and learned fear

Fear learning obviously has a strong emotional component, though results of such studies may be interpreted in terms of their learning component as well. Increased acquisition or retention of fear learning, such as in classical conditioning or passive avoidance, is typically considered a positive indicator of fear [63], [64]. Two-way active avoidance is an exception, with poorer performance considered a measure of increased fear, and with benzodiazepines improving performance [27], [47], [65].

Outlook

Estrogens affect a variety of behaviors related to arousal, emotions, and mood in animals and humans. But these hormonal effects are not uniform in their amplitude or direction. Looking forward, at least two theoretical ideas need to be tested systematically, in order to explain the variety of findings in the literature. As emphasized in the manuscript, hormone effects on behavior can depend upon the context in which the behavior takes place. This point has also been asserted in reviews of

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