Regulation of Gonadotropin Releasing Hormone Release by Neuropeptide Y at the Median Eminence during the Preovulatory Period in Ewes

Abstract

The median eminence (ME) of the hypothalamus is known to be an important brain site where hypophysiotropic release might be regulated by excitatory and inhibitory signals impinging on their neuronal terminals. Since a role for neuropeptide Y (NPY) on preovulatory luteinizing hormone (LH) release has been suggested, we hypothesized that NPY might act at the ME to control preovulatory gonadotropin-releasing hormone (GnRH) release and thus the onset of the preovulatory surge of LH. To examine this possibility, we used the ewe as an animal model to determine: (a) immunocytochemical distribution of GnRH and NPY in the ewe ME; (b) changes in in vivo release of NPY and GnRH using ME push-pull cannula (PPC) perfusate samples, as well as in plasma LH, during the luteal, follicular and preovulatory phases of a synchronized estrous cycle, and (c) effects of ME perfusion of NPY or a Y1-NPY antagonist, or an NPY antiserum on in vivo release of ME-GnRH and plasma LH during a synchronized follicular phase. Immunolocalization reveals a dense plexus of beaded GnRH-containing neurites in the arcuate nucleus and in its vicinity, the pituitary stalk and the palisade. In contrast, a dense plexus of NPY-containing neurites occurs in the internal layer, with occasional fibers found in the intermediate and lateral external zone of the ME. In the area between the lateral internal and lateral external layers, both NPY and GnRH-containing processes were found, thus providing opportunities for synaptic and/or paracrine interactions between NPY- and GnRH-containing neurons. Hormonal analysis indicated that a synchronized preovulatory surge of LH is elicited within a 2-hour window by the sequential implantation and removal of silastic-encased estradiol (E2) or progesterone (P4) implants. In this paradigm, there was a parallel increase in ME release of both NPY and GnRH preceding the synchronized LH surge. The onset of this synchronized LH surge was advanced by ME perfusion of exogenous NPY and was both delayed and blunted by ME perfusion with the NPY antagonist (both were perfused through the PPC probe for 2 h, starting 2–3 h before the expected onset of the LH surge). In addition, NPY perfusion in the ME increases, while perfusion of the Y1-NPY antagonist or of the NPY antiserum decreases ME-PPC GnRH content and plasma levels of LH in early follicular ewes. Finally, perfusion of NPY antiserum during an ongoing LH surge disrupted LH release. These results suggest that interactions between NPY and GnRH neurons are important in controlling the timing, magnitude and maintenance of the preovulatory LH surge.

Negative Correlation between Neuropeptide Y Profile in the Cerebrospinal Fluid and Growth Hormone Pulses in the Peripheral Circulation in Goats

“…Direct measurement of NPY secretion in the periventricular nucleus of rats using a push-pull cannula also revealed that NPY was secreted in discrete episodes [42]. In ruminants, it has been reported that NPY neurons are located in the arcuate and periventricular nuclei, and that their axons project to many brain regions including the median eminence [43,44,45,46]. While the target of NPY released in episodic fashion is also still unclear, one possibility is that NPY activates SRIH neurons to inhibit GH secretion.…”

Kisspeptin Directly Regulates Neuropeptide Y Synthesis and Secretion via the ERK1/2 and p38 Mitogen-Activated Protein Kinase Signaling Pathways in NPY-Secreting Hypothalamic Neurons

“…NPY neurons in the arcuate nucleus of the hypothalamus have been found to project to GnRH neurons (18,19), and morphological evidence indicates colocalization of NPY receptors and GnRH neurons (18). Both in vivo and in vitro studies have demonstrated that NPY stimulates GnRH secretion (20 -26), because NPY infusion into the third ventricle of ewes significantly elevated GnRH levels in the median eminence (23), and exposure of NPY to GT1-7 cells significantly increases GnRH secretion (24). Although the stimulatory effect of NPY on GnRH neurons has been well-documented, NPY can also have an inhibitory action on GnRH release, which is associated with changes in steroidal environment, stage of development, and species (27)(28)(29)(30)(31)(32).…”

Hypothalamic arcuate neuropeptide Y-neurons decrease periventricular somatostatin-neuronal activity before puberty in the female lamb: Morphological arguments

“…In the preoptic area of adult sheep direct connections between NPY and GnRH have been demonstrated (Tillet et al, 1989;Norgren and Lehman, 1989). In addition, during the breeding season, infusion of NPY in the median eminence induces an advance of the onset of LH surge (Advis et al, 2003) but when infused during anoestrus season NPY has no effect (Wó jcik- Gładysz et al, 2003). According to these data in adults, we cannot exclude a direct effect of NPY onto GnRH neurons during puberty; however as far as we know, such physiological effect was never demonstrated and in adult, NPY seems to play a role during the oestrus cycle only when GnRH neurons are active, not during anoestrus season when they are quiescent.…”

“…It is distributed in numerous neuronal populations, especially in the hypothalamus of several species, including sheep (Antonopoulos et al, 1989;Chaillou et al, 2002). It is involved in many neuroendocrine functions such as the control of food intake (Chaillou et al, 2002;Barker-Gibb and Clarke, 1996;Ober and Malven, 1992;Adam et al, 1997;Polkowska and Gladysz, 2001) or reproduction (Barker-Gibb et al, 1995;Malven et al, 1995;Wó jcik-Gładysz et al, 2003;Advis et al, 2003;Estrada et al, 2003). Neuropeptide Y is also involved in the regulation of GH, and it stimulates GH secretion in the adult sheep (Morrison et al, 2003;McMahon et al, 1999), whereas in rats it suppresses GH release by stimulating somatostatin discharge (Rettori et al, 1990).…”