In spontaneously ovulating rodents, the preovulatory LH surge is initiated on the day of proestrus by a timed, stimulatory signal originating from the circadian clock in the suprachiasmatic nucleus (SCN). The present studies explored whether kisspeptin is part of the essential neural circuit linking the SCN to the GnRH system to stimulate ovulation in Syrian hamsters (Mesocricetus auratus). Kisspeptin neurons exhibit an estrogen-dependent, daily pattern of cellular activity consistent with a role in the circadian control of the LH surge. The SCN targets kisspeptin neurons via vasopressinergic (AVP), but not vasoactive intestinal polypeptide-ergic, projections. Because AVP administration can only stimulate the LH surge during a restricted time of day, we examined the possibility that the response to AVP is gated at the level of kisspeptin and/or GnRH neurons. Kisspeptin and GnRH activation were assessed after the administration of AVP during the morning (when AVP is incapable of initiating the LH surge) and the afternoon (when AVP injections stimulate the LH surge). Kisspeptin, but not GnRH, cellular activity was up-regulated after morning injections of AVP, suggesting that time-dependent sensitivity to SCN signaling is gated within GnRH but not kisspeptin neurons. In support of this possibility, we found that the GnRH system exhibits pronounced daily changes in sensitivity to kisspeptin stimulation, with maximal sensitivity in the afternoon. Together these studies reveal a novel mechanism of ovulatory control with interactions among the circadian system, kisspeptin signaling, and a GnRH gating mechanism of control.
Long days (LDs) stimulate and short days (SDs) inhibit reproduction in photoperiodic rodents by modifying nocturnal pineal melatonin secretion. In LD Turkish hamsters, unlike other rodents, pinealectomy induces reproductive quiescence comparable to that produced by SDs. We assessed whether SDs and pinealectomy induce similar or different patterns of kisspeptin and gonadotropin-inhibitory hormone (also known as RFamide-related peptide-3 [RFRP-3] in mammals) expression, important mediators of seasonal reproductive changes in other species. Brains were harvested from sham-operated female Turkish hamsters maintained in LDs and SDs and LD-pealectomized (pinx) females, all housed in their respective photoperiods for 12 weeks. Uterine weights were substantially higher in LD-sham than in LD-pinx and SD-sham females. RFRP-3-immunoreactive(-ir) cells in the dorsomedial hypothalamic nucleus were greater in number and size in the reproductively competent LD-sham hamsters than in both reproductively suppressed SD-sham and LD-pinx hamsters. LD-sham hamsters had more kisspeptin-ir cells in the anteroventral periventricular nucleus than did LD-pinx hamsters. Reproductive quiescence, whether induced by short-day lengths or pinealectomy, was generally accompanied by comparable changes in RFRP-3 and kisspeptin, suggesting that long-duration melatonin signaling and withdrawal of melatonin by pinealectomy may act through the same neural substrates to induce gonadal quiescence.
The dorsomedial nucleus (DMN) of the hypothalamus, the only site within the mediobasal hypothalamus of Syrian hamsters that both binds melatonin and has abundant concentrations of androgen receptors, has been proposed as a target tissue for induction of seasonal changes in brain sensitivity to steroid negative feedback. We tested whether DMN ablation, which does not interfere with pineal gland secretion of melatonin in short day lengths, prevents testicular regression by altering sensitivity to steroid negative feedback. Hamsters with DMN lesions, unlike control hamsters, failed to undergo testicular regression after transfer from a long (14 h light/day) to a short day length (8 h light/day); however, increased negative-feedback inhibition of follicle-stimulating hormone by testosterone was not compromised by ablation of the DMN, indicating that this tissue is not an essential mediator of seasonal changes in feedback sensitivity. We propose a redundant neural network comprised of multiple structures, each of which contributes to neuroendocrine mechanisms, that determines the effect of short days on gonadal function.
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