Estrogen Stimulation of Kiss1 Expression in the Medial Amygdala Involves Estrogen Receptor-α But Not Estrogen Receptor-β

Abstract

The neuropeptide kisspeptin, encoded by Kiss1, regulates reproduction by stimulating GnRH secretion. Neurons synthesizing kisspeptin are predominantly located in the hypothalamic anteroventral periventricular (AVPV) and arcuate nuclei, but smaller kisspeptin neuronal populations also reside in extrahypothalamic brain regions, such as the medial amygdala (MeA). In adult rodents, estradiol (E) increases Kiss1 expression in the MeA, as in the AVPV. However, unlike AVPV and arcuate nuclei kisspeptin neurons, little else is currently known about the development, regulation, and function of MeA Kiss1 neurons. We first assessed the developmental onset of MeA Kiss1 expression in males and found that MeA Kiss1 expression is absent at juvenile ages but significantly increases during the late pubertal period, around postnatal day 35, coincident with increases in circulating sex steroids. We next tested whether developmental MeA Kiss1 expression could be induced early by E exposure prior to puberty. We found that juvenile mice given short-term E had greatly increased MeA Kiss1 expression at postnatal day 18. Although MeA Kiss1 neurons are known to be E up-regulated, the specific estrogen receptor (ER) pathway(s) mediating this stimulation are unknown. Using adult ERα knockout and ERβ knockout mice, we next determined that ERα, but not ERβ, is required for maximal E-induced MeA Kiss1 expression in both sexes. These results delineate both the developmental time course of MeA Kiss1 expression and the specific ER signaling pathway required for E-induced up-regulation of Kiss1 in this extrahypothalamic brain region. These findings will help drive future studies ascertaining the potential functions of this understudied kisspeptin population.

Multiple failures in the lutenising hormone surge generating system in GABAB1KO female mice

“…Whether these alterations in LH secretion are also influenced by the massive increase in Kiss1 mRNA expression in extra‐hypothalamic sites, such as the amygdala, BNST and lateral septum that we have previously reported in GABAB1KO mice, and which are also regulated by Esr1 similar to Kiss1 neurones in the AVPV/PeN remains to be determined. Interestingly, Pineda et al have very recently demonstrated that amygdala kisspeptin neurones innervate GnRH neurones in the preoptic area and Adekunbi et al have shown that antagonism of medial amygdala kisspeptin delayed puberty onset, disrupted oestrous cyclicity and reduced the incidence of LH surges, giving support to this hypothesis.…”

Aging and estradiol effects on gene expression in the medial preoptic area, bed nucleus of the stria terminalis, and posterodorsal medial amygdala of male rats

“…The kisspeptin receptor, encoded by Kiss1r , was also identified. The kisspeptin system has been studied in the amygdala in the context of estrogen signaling in males (Stephens et al, 2016) and in sexual behavior (Gresham et al, 2016). Another gene, Thra , to our knowledge has not bee studied in the BnST of males, but knockout mice exhibit increased anxiety, as well as facilitated sexual behavior, with decreased mount and intromission latencies (Vasudevan et al, 2013).…”

Expanding the role of tachykinins in the neuroendocrine control of reproduction

“…However, if this constitutes a sex difference in the expression of SP or it is a mere reflection of different levels of sex steroids remains to be elucidated. In this context, an earlier report documents greater SP immunoreactivity in the medial amygdala of male compared to female rats (Micevych et al 1988), an area which is also known for a greater Kiss1 population of cells in males vs females (Stephens et al 2016). However, the interaction between these two systems (SP and Kiss1 in the medial amygdala) has not yet been explored.…”