Estradiol-Dependent and -Independent Stimulation of Kiss1 Expression in the Amygdala, BNST, and Lateral Septum of Mice

Abstract

Kisspeptin, encoded by Kiss1, activates reproduction by stimulating GnRH neurons. Although most Kiss1 neurons are located in the hypothalamus, smaller Kiss1 populations also reside in the medial amygdala (MeA), bed nucleus of the stria terminalis (BnST), and lateral septum (LS). However, very little is known about the regulation and function of these extra-hypothalamic Kiss1 neurons. This study focused on the roles and interactions of two signaling factors, estradiol (E2) and GABA, known to stimulate and inhibit, respectively, extra-hypothalamic Kiss1 expression. First, using estrogen receptor (ER)α knockout (KO) and βERKO mice, we demonstrated that Kiss1 in both the BnST and LS is stimulated by E2, as occurs in the MeA, and that this E2 upregulation occurs via ERα, but not ERβ. Second, using GABABR KO and wild-type mice, we determined that whereas E2 normally increases extra-hypothalamic Kiss1 levels, such upregulation by E2 is further enhanced by the concurrent absence of GABABR signaling in the MeA and LS, but not the BnST. Third, we demonstrated that when GABABR signaling is absent, the additional removal of gonadal sex steroids does not abolish Kiss1 expression in the MeA and BnST, and in some cases the LS. Thus, Kiss1 expression in these extra-hypothalamic regions is not solely dependent on E2 stimulation. Finally, we demonstrated a significant positive correlation between Kiss1 levels in the MeA, BnST, and LS, but not between these regions and the hypothalamus (anteroventral periventricular nucleus/periventricular nucleus). Collectively, our findings indicate that both E2 and GABA independently regulate all three extra-hypothalamic Kiss1 populations, but their regulatory interactions may vary by brain region and additional yet-to-be-identified factors are likely involved.

Unraveling the connection between GABA and kisspeptin in the control of reproduction

“…These findings suggested that GABABR signaling may normally inhibit Kiss1 expression in the MeA of adult mice (Di Giorgio et al 2014). Our findings also indicate that both E2 and GABA, through GABABRs, independently regulate extra-hypothalamic Kiss1 cell populations (Stephens et al 2018). As GABAB1KO females have impaired reproduction, a marked increase in MeA kisspeptin input may participate in the alterations observed.…”

The Roles of the Amygdala Kisspeptin System

“…43 A recent study explored the interaction between estradiol and GABA using GABA B R KO mice revealing that although estradiol normally increases MeA kisspeptin levels, expression was further upregulated by estradiol treatment in GABA B R KO mice. 44 This suggests that stimulatory estradiol and inhibitory GABA B R signaling are able to independently regulate kisspeptin expression in the MeA. Furthermore, removal of circulating gonadal sex steroids by gonadectomy in these mice did not abolish kisspeptin expression signifying that it is not exclusively dependent on estradiol stimulation, but also on additional as yet unknown factors.…”

“…Furthermore, removal of circulating gonadal sex steroids by gonadectomy in these mice did not abolish kisspeptin expression signifying that it is not exclusively dependent on estradiol stimulation, but also on additional as yet unknown factors. 44 Collectively, these studies provide new advances in our understanding of the mechanisms which modulate the amygdala kisspeptin system. How changes in kisspeptin expression affect resultant sexually differentiated behaviors remains to be fully studied.…”

The Role of the Brain in the Pathogenesis and Physiology of Polycystic Ovary Syndrome (PCOS)

“…Within the brain, kisspeptin is primarily expressed in the hypothalamic arcuate nucleus (ARN) and the anteroventral periventricular nucleus and periventricular nucleus continuum (AVPV/PeN), regions implicated in the regulation of GnRH secretion [65,73]. Lower degrees of kisspeptin expression occur in the medial amygdala [74], bed nucleus of the solitary tract (BNST), and lateral septum [75], but the roles of these extra-hypothalamic kisspeptin neurons remains unknown. The two hypothalamic kisspeptin populations are thought to serve different roles, with the ARN cells being involved in stimulating GnRH/LH pulses in both females and males [52], while the AVPV/PeN cells regulate the preovulatory GnRH/LH surge in females [65].…”