Distribution and chemical composition of estrogen receptor β neurons in the paraventricular nucleus of the female and male mouse hypothalamus

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First described in 1996 (Kuiper, Enmark, Pelto‐Huikko, Nilsson, & Gustafsson, 1996), the beta form of estrogen receptor (ERβ) has been linked to an array of neurophysiological functions like learning and memory (Rissman, Heck, Leonard, Shupnik, & Gustafsson, 2002; Jacome et al., 2010), anxiety‐related disorders (Lund, Rovis, Chung, & Handa, 2005; Oyola et al., 2011) and hypothalamic–pituitary–adrenal (HPA) axis response to stress (Weiser, Wu, & Handa, 2009). Determining the neurobiological participation of ERβ in these systems will not only require a precise understanding of ERβ's neuroanatomical organization in the brain, but also require deciphering the protein partners of ERβ, shedding light on molecular pathways that might impact ERβ's physiological effects.
Much of what we currently know of the distribution of ERβ in the brain and hypothalamus comes from studies in the rat using in situ hybridization (Laflamme, Nappi, Drolet, Labrie, & Rivest, 1998), immunohistochemistry (Shughrue & Merchenthaler, 2001), and PCR (Kuiper et al., 1997), and in the human hypothalamus using immunohistochemistry (Kruijver, Balesar, Espila, Unmehopa, & Swaab, 2003). Nonetheless, the expression pattern of ERβ protein in the brain has been somewhat controversial, mainly due to the current lack of specific antisera to directly label this nuclear receptor (Snyder, Smejkalova, Forlano, & Woolley, 2010). Nevertheless, most reports agree on one finding, across all species examined, there is a dense presence of ERβ expressing neurons in the paraventricular nucleus of the hypothalamus (PVN). This has led us to believe that this localization pattern should play a key role in the function of this nucleus.
Estrogen's biological actions are mediated by two nuclear receptors: ERα and ERβ. Estradiol has been shown to play a key role in the regulation of the HPA axis, acting through ERα and ERβ. For example, Lund et al. (2005) studied the activation of the HPA axis in ovariectomized rats using selective ERα and ERβ agonists. While ERα agonists caused hyperreactivity of the HPA axis, ERβ agonists decreased the corticosterone and adrenocorticotropic hormone (ACTH) response to stress (Lund et al., 2005). The distribution of these receptors differs across brain regions, with ERβ mRNA (Shughrue, Komm, & Merchenthaler, 1996; Laflamme et al., 1998) and protein (Li, Schwartz, & Rissman, 1997; Shughrue & Merchenthaler, 2001) expression predominating in the PVN, perhaps indicating a dominant role of PVN ERβ‐mediated actions of estradiol on the activity of the HPA axis. These results in rats lead us to inquire whether these two receptors are localized in a similar fashion in the mouse PVN.
The neurons of the PVN play a central role in the control of the HPA axis. Integration of numerous signals is required to maintain effective control of this axis, which is crucial for homeostasis. Although the PVN is composed of a heterogeneous population of neurons, the main neuroendocrine players involved in the regulation of the HPA axis and shown to interact with ERβ, are those that express oxytocin (OT), arginine vasopressin (AVP), and corticotropin‐releasing hormone (CRH) (Handa & Weiser, 2014). These peptide hormones are critical for the proper activation and termination of HPA activity, the end result being the elevation and eventual inhibition of circulating corticosteroids.
Recent studies have pointed out anatomic similarities and dissimilarities in cyto‐ and chemo‐architecture between rats and mice, particularly in the PVN, (Swanson & Sawchenko, 1980; Biag et al., 2012). In this study, we dissected the chemical and cytological distribution of ERβ neurons within the mouse PVN utilizing a transgenic mouse model. This ERβ‐EGFP mouse model was previously described by Milner et al.
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