Successful reproduction requires maintenance of the reproductive axis within fine operating limits through negative feedback actions of sex steroids. Despite the importance of this homeostatic process, our understanding of the neural loci, pathways, and neurochemicals responsible remain incomplete. Here, we reveal a neuropeptidergic pathway that directly links gonadal steroid actions to regulation of the reproductive system. An RFamide (Arg-Phe-NH 2) peptide that inhibits gonadotropin release from quail pituitary was recently identified and named gonadotropin-inhibitory hormone (GnIH). Birds are known to have specialized adaptations associated with gonadotropin-releasing hormone (GnRH) regulation to optimize reproduction (e.g., encephalic photoreceptors), and the existence of a hypothalamic peptide inhibiting gonadotropins may or may not be another such specialization. To determine whether GnIH serves as a signaling pathway for sex steroid regulation of the reproductive axis, we used immunohistochemistry and in situ hybridization to characterize the distribution and functional role of this peptide in hamsters, rats, and mice. GnIH-immunoreactive (GnIH-ir) cell bodies are clustered in the mediobasal hypothalamus with pronounced projections and terminals throughout the CNS. In vivo GnIH administration rapidly inhibits luteinizing hormone secretion. Additionally, GnIH-ir neurons form close appositions with GnRH cells, suggesting a direct means of GnRH modulation. Finally, GnIH-ir cells express estrogen receptor-␣ and exhibit robust immediate early gene expression after gonadal hormone stimulation. Taken together, the distribution of GnIH efferents to neural sites regulating reproductive behavior and neuroendocrine secretions, expression of steroid receptors in GnIH-ir nuclei, and GnIH inhibition of luteinizing hormone secretion indicate the discovery of a system regulating the mammalian reproductive axis.luteinizing ͉ mating ͉ reproduction T he final common pathway in the neural regulation of reproduction is the gonadotropin-releasing hormone (GnRH) neuronal system. Neurons that synthesize and secrete GnRH occupy a midventral continuum from the diagonal band of Broca to the mediobasal hypothalamus (1). GnRH neurons regulating gonadotropin secretion project to the median eminence to control synthesis and secretion of the pituitary gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) (2-4).In both males and females, gonadal steroids act through negative feedback to maintain the reproductive axis within the favorable operating limits necessary for fertility and successful mating. Negative feedback control of the GnRH system could be accomplished by sex hormones acting on either cognate receptors expressed in GnRH neurons or on gonadal-steroid-responsive systems upstream of GnRH. Although early evidence before this millennium suggested only the latter (5-11), more recent evidence suggests that both of these mechanisms act in concert to regulate precisely the reproductive axis in females (12-1...

The mammalian suprachiasmatic nuclei (SCN) transmit signals to the rest of the brain, organizing circadian rhythms throughout the body. Transplants of the SCN restore circadian activity rhythms to animals whose own SCN have been ablated. The nature of the coupling signal from the grafted SCN to the host brain is not known, although it has been presumed that functional recovery requires re-establishment of appropriate synaptic connections. We have isolated SCN tissue from hamsters within a semipermeable polymeric capsule before transplantation, thereby preventing neural outgrowth but allowing diffusion of humoral signals. Here we show that the transplanted SCN, like neural pacemakers of Drosophila and silkmoths, can sustain circadian activity rhythms by means of a diffusible signal.

No abstract

It is well established that overt circadian rhythms are permanently disrupted following lesions of the hamster hypothalamic suprachiasmatic nucleus (SCN). In the present study, we show that implantations of brain grafts containing the fetal SCN reestablish circadian rhythms of locomotor activity in adult hamsters previously made arrhythmic by SCN lesions. The restoration of free-running rhythms in conditions of constant darkness is correlated with the presence in the graft of neuropeptides normally present in the SCN of unlesioned hamsters, including vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), and vasopressin (VP). In several recipients, grafts were found to receive retinal input, and appeared to send efferents into the host brain. Not all functions of the SCN were reinstated by the graft: animals with restored locomotor rhythms did not show gonadal regression in the absence of light, and failed to synchronize (entrain) to light intensities to which SCN-intact animals responded.