Roles of oestrogen receptors alpha and beta in behavioural neuroendocrinology: beyond Yin/Yang

Abstract

Oestrogen receptor beta (ERbeta) was discovered more than 10 years ago. It is widely distributed in the brain. In some areas, such as the entorhinal cortex, it is present as the only ER, whereas in other regions, such as the bed nucleus of the stria terminalis and preoptic area, it can be found co-expressed with ERalpha, often within the same neurones. These ERs share ligands, and there are several complex relationships between the two receptors. Initially, the relationship between them was labelled as 'yin/yang', meaning that the actions of each complemented those of the other, but now, years later, other relationships have been described. Based on evidence from neuroendocrine and behavioural studies, three types of interactions between the two oestrogen receptors are described in this review. The first relationship is antagonistic; this is evident from studies on the role of oestrogen in spatial learning. When oestradiol is given in a high, chronic dose, spatial learning is impaired. This action of oestradiol requires ERalpha, and when ERbeta is not functional, lower doses of oestradiol have this negative effect on behaviour. The second relationship between the two receptors is one that is synergistic, and this is illustrated in the combined effects of the two receptors on the production of the neuropeptide oxytocin and its receptor. The third relationship is sequential; separate actions of the two receptors are postulated in activation and organisation of sexually dimorphic reproductive behaviours. Future studies on all of these topics will inform us about how ER selective ligands might affect oestrogen functions at the organismal level.

Fig. 1

This cartoon illustrates the antagonistic relationship between the two oestrogen receptors (ERs). The white diamond represents ERβ, the black diamond represents ERα, and the grey triangle is oestradiol activating the receptors. An ERβ-specific agonist is represented by the off-grey pentagon. (A) The example shows the impact of excess oestradiol on the two ERs and the resulting behaviour. (B) The relationship is shown when an ERβ agonist is used.

Fig. 2

This cartoon figure illustrates the synergistic relationship between the two oestrogen receptors (ERs). The white diamond represents ERβ, the black diamond represents ERα, and the grey triangle is oestradiol activating the receptors. Below each receptor is the oxytocin gene that it affects.

Fig. 3

This cartoon illustrates a sequential relationship between the two oestrogen receptors (ERs) during development. The white diamond represents ERβ, the black diamond represents ERα, and the grey triangle is oestradiol activating the receptors. (A) An illustration of the roles of ERβ activation in neonatal males followed by activation of the ERα in adult males. The end result of the two actions is defeminisation of adult male behaviour. (B) An illustration of the situation in a normal female. Here, the lack of ERβ activation in the neonatal period is responsible for the adult activational effect of oestradiol on lordosis.