Characterization of KNDy Neuronal Activity in Gilts: Distribution and Effect of A Progestin

Abstract

Puberty is a process that incorporates a large array of both external factors and internal signals. The endocrinology of puberty has been studied in a number of mammalian species and typically depends upon an increase in hypothalamic secretion of gonadotropin releasing hormone (GnRH). Neural inputs regulating GnRH secretion during the pubertal process are not completely understood. In the past decade, attention has focused on the role for a particular set of neurons located in the arcuate nucleus (ARC) of the hypothalamus. They have been named KNDy neurons because they coexpress kisspeptin, neurokinin B (NKB) and dynorphin and have been shown to stimulate (kisspeptin, NKB) or inhibit (dynorphin) GnRH and luteinizing hormone (LH) secretion. While KNDy neurons have been studied extensively in primates, rodents, and sheep, almost nothing is known about this system in porcine, a species of significant agricultural importance. Our studies describe an initial foray into characterizing this system in the porcine hypothalamus. We first determined that, similar to other species, kisspeptin was expressed in the ARC and that NKB and kisspeptin were coexpressed in this region to a very high extent. We then examined the distribution of receptors for NKB (NK3R) and found them to be expressed in the preoptic area (POA) and several areas of the hypothalamus, including the paraventricular nucleus (PVN) and retrochiasmatic area (RCh). However, there was no evidence of NK3R expression in the ARC. The NK3R-positive cells found in the POA did not co-localize with GnRH but expressed close contacts with GnRH neurons. We then used gilts that were ovariectomized (OVX) or OVX and treated with Altrenogest (OVXA), a progestin, to test the hypothesis that Altrenogest would suppress kisspeptin and NKB immunopositive cell numbers in the ARC and NK3R-positive cell numbers throughout the hypothalamus. Surprisingly, kisspeptin containing cell numbers tended to be increased (p = 0.09) in in OVXA gilts (n = 6) compared to their OVX, untreated counterparts (n = 6). In addition, there was no significant change in NKBpositive cell numbers in response to Altrenogest. Subsequent analysis determined a tendency (p = 0.08) for a decrease in the percentage of kisspeptin neurons expressing c-Fos, a marker of neural activation, in OVXA versus OVX gilts. There was no effect of Altrenogest on NK3Rpositive cell numbers in any area. These studies mark one of the first investigations into the KNDy system in swine. Many of the characteristics examined here are similar to that previously reported for other mammalian species, with the notable exception of an absence of NK3R expression within the ARC. Treatment with a progestin did not suppress kisspeptin or NKB expression but did tend to reduce activity of kisspeptin neurons. These results suggest that, similar to other species, KNDy neurons likely play an important role in regulating reproduction in swine. v

Neurokinin 1/3 receptor antagonists for menopausal women: A current systematic review and insights into the investigational non-hormonal therapy

“…[60,105,106] While these neuronal and genetic changes have been restored with conventional estrogen replacement therapy, NK3R has emphasized that the NKB/NK3R signally pathway can lower plasma LH and estradiol levels among castrated nonhuman primates. [107,108] The reduction of pulsing in LH, basal LH, and estradiol levels is of note when administered to healthy women in the follicular phase. [80,108] The changes in hormone levels with NK pathways may also aid women with polycystic ovary syndrome whom hyper secrete LH by decreasing the pulsing frequency and by reducing basal LH and testosterone levels.…”

“…[107,108] The reduction of pulsing in LH, basal LH, and estradiol levels is of note when administered to healthy women in the follicular phase. [80,108] The changes in hormone levels with NK pathways may also aid women with polycystic ovary syndrome whom hyper secrete LH by decreasing the pulsing frequency and by reducing basal LH and testosterone levels. [87] The rapid onset among healthy male volunteers in reducing testosterone also modulates interventions for women in need of reproductive axis modulators.…”

The neuroendocrine pathways and mechanisms for the control of the reproduction in female pigs

“…Similarly, studies in pig ARC have shown that virtually all Kisspeptin neurons in co-express NKB ( Lents et al, 2020 ). Because the roles of NKB and its receptor in regulating GnRH of the pig are not presently understood, the expression of TAC3R has recently been localized throughout several areas of the hypothalamus in ovariectomized (OVX) gilts ( Lindo 2018 ). Many of the hypothalamic regions that display TAC3R immunostaining in the pig also contain GnRH neurons.…”

“…Furthermore, the greatest number of TAC3R expressing cells are the dbB and the PVN, followed by the POA and SCN. The PeV and RCh have evidence of TAC3R immunostaining ( Lindo 2018 ). Although about 40% of GnRH neurons occurred in close apposition to TAC3R containing cells, close contacts were few, suggesting that the TAC3R containing cells in the porcine hypothalamus do not directly regulate GnRH neurons in pigs.…”