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Recent advances in the hypothalamic control of reproduction
Reproduction is driven by the gonadotropin releasing hormone (GnRH) cells of the brain, but the pulsatile secretion of GnRH into the hypophysial portal blood is controlled by kisspeptin cells. In the sheep, as in other species, the kisspeptin cells form two major populations in the brain, one in the arcuate nucleus and the other in the preoptic area. The former appear to mediate the negative feedback effects of sex steroids as well as being initiators of the ‘positive feedback’ effect that elicits the GnRH surge to cause ovulation in the female. The latter facilitate the positive feedback effect. The arcuate nucleus population of kisspeptin cells also produce neurokinin B and dynorphin, leading to their designation as KNDY cells. Kisspeptin expression in the KNDY cells is reduced in the non-breeding season, further re-inforcing the fundamental role these cells play in control of reproduction. In addition, these KNDY cells appear to be involved in the response to altered bodyweight. This is achieved via the signalling of leptin to the KNDY cells either directly or indirectly – kisspeptin gene expression is lower in lean animals, but this can be reversed by administration of leptin. KNDY cells are interconnected to the cells of the arcuate nucleus that produce anorexigenic melanocortins and those that produce the orexigen, neuropeptide Y. This provides a bi-directional interface between metabolic circuits and reproductive circuits. Thus, melanocortins and neuropeptide Y may regulate reproduction independently or via control of kisspeptin cells, providing a way that metabolic function and reproduction are inter-linked.
Recent data provide strong evidence that KNDY cells are most likely to be the cells that drive the pulsatile secretion of GnRH. Thus, c-Fos labelling in KNDY cells is seen at the time of ram-induced LH secretion (proxy for GnRH pulses) in anestrous ewes. In addition, KNDY cells in brains of animals sampled within 30 min of an endogenous pulse of LH displayed increased c-Fos labelling, compared to cells from animals that were not experiencing an LH pulse at the time of brain collection. Most interestingly, the means by which KNDY cells cause GnRH secretion appears to be due to action on the GnRH terminals within the median eminence. Accordingly, direct application of kisspeptin to the median eminence in vitro causes GnRH secretion. This novel mechanism has forced a revision of the model for neuroendocrine control of reproduction.
Keywords: GnRH