Oxytocin and Estrogen Receptor β in the Brain: An Overview

Abstract

Oxytocin (OT) is a neuropeptide synthesized primarily by neurons of the paraventricular and supraoptic nuclei of the hypothalamus. These neurons have axons that project into the posterior pituitary and release OT into the bloodstream to promote labor and lactation; however, OT neurons also project to other brain areas where it plays a role in numerous brain functions. OT binds to the widely expressed OT receptor (OTR), and, in doing so, it regulates homeostatic processes, social recognition, and fear conditioning. In addition to these functions, OT decreases neuroendocrine stress signaling and anxiety-related and depression-like behaviors. Steroid hormones differentially modulate stress responses and alter OTR expression. In particular, estrogen receptor β activation has been found to both reduce anxiety-related behaviors and increase OT peptide transcription, suggesting a role for OT in this estrogen receptor β-mediated anxiolytic effect. Further research is needed to identify modulators of OT signaling and the pathways utilized and to elucidate molecular mechanisms controlling OT expression to allow better therapeutic manipulations of this system in patient populations.

Keywords: adrenal; anxiety; behavior; estradiol; hypothalamus; oxytocin; pituitary.

Figure 1

Overview of estrogen receptor β (ERβ) action in oxytocin neurons of the paraventricular nucleus (PVN) and oxytocin signaling. (A) ERβ signaling in PVN oxytocinergic neurons. (1) Estrogen enters the cell and binds to inactive ERβ. In its inactive form, ERβ is bound to a complex of chaperone proteins. (2) Upon binding its ligand, ERβ dimerizes. (3) The dimerized receptor binds to the composite hormone response element (cHRE) of the oxytocin promoter. Co-activators, such are SRC-1 and CBP, are recruited along with the transcription machinery to promote transcription. (4) Ultimately, the oxytocin peptide is produced. (B) Oxytocin signaling in the brain. Oxytocin is produced in neurons of the PVN and supraoptic nucleus (SON). Oxytocin neurons from both regions project to the posterior pituitary (P Pit). In addition to this release, the PVN also sends oxytocin projections throughout the brain (5). ERβ is expressed in approximately 85% of neurons in the rodent PVN but not in the SON (72). This suggests that ERβ could play a role in increasing oxytocin production in regions important in responding to stress and can subsequently influence brain areas that express oxytocin receptors [shown in blue; (8, 13)]. BNST, bed nucleus of the stria terminalis; DR, dorsal raphe nucleus; LS, lateral septum; MnR, median raphe nucleus; PFC, prefrontal cortex.