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Simple Summary: An increase in the pulsatile release of gonadotropin-releasing hormone (GnRH) is essential for the onset of puberty. However, the mechanisms controlling pubertal increases in GnRH release are still unclear. In primates the GnRH neurosecretory system is active during the neonatal period but subsequently enters a dormant state in the juvenile period. The present study examined developmental changes in the gonadotropin inhibitory hormone (GnIH) neuronal system, an inhibitory neuropeptidergic system upstream of GnRH neurons, and the relationship among changes that were observed in GnRH and kisspeptin (Kiss1) gene expression during puberty. A significant inverse age-related relationship between GnRH, Kiss1, and GnIH was observed, suggesting GnIH's potential role in reproductive suppression prior to puberty, with this theoretical 'brake' during the pubertal transition. These findings underscore the need for further research on the role that is played by GnIH in reproductive transition to aid in the development of potential GnIH-based drugs to treat pubertal disorders and adult fertility. Modulation of pulsatile gonadotropin-releasing hormone (GnRH) secretion across postnatal development in higher primates is not fully understood. While gonadotropin-inhibitory hormone (GnIH) is reported to suppress reproductive axis activity in birds and rodents, little is known about the developmental trajectory of GnIH expression in rhesus monkeys throughout the pubertal transition. This study was aimed at examining the variation in GnIH immunoreactivity (-ir) and associated changes among GnIH, GnRH, and Kiss1 mRNA expression in the hypothalamus of infant, juvenile, prepubertal, and adult male rhesus monkeys. The brains from rhesus macaques were collected from infancy until adulthood and were examined using immunofluorescence and RT-qPCR. The mean GnIH-ir was found to be significantly higher in prepubertal animals (p < 0.01) compared to infants, and significantly reduced in adults (p < 0.001). Significantly higher (p < 0.001) GnRH and Kiss1 mRNA expression was noted in adults while GnIH mRNA expression was the highest at the prepubertal stage (p < 0.001). Significant negative correlations were seen between GnIH-GnRH (p < 0.01) and GnIH-Kiss1 (p < 0.001) expression. Our findings suggest a role for GnIH in the prepubertal suppression of the reproductive axis, with disinhibition of the adult reproductive axis occurring through decreases in GnIH. This pattern of expression suggests that GnIH may be a viable target for the development of novel therapeutics and contraceptives for humans. [ABSTRACT FROM AUTHOR]

Kisspeptin is involved in the hypothalamic pituitary gonadal-axis' seasonal regulation in rodents and sheep. Studies of kisspeptin signaling in regulating the transition between breeding and nonbreeding seasons have focused on kisspeptin expression, myelin basic protein (MBP) expression around kisspeptin-ir cells, and quantifying the synaptic connections between kisspeptin and gonadotropin-releasing hormone (GnRH) neurons in various animal models; however, the role of kisspeptin in regulating the seasonal breeding of primates has not been explored yet. This study investigated changes in kisspeptin signaling during breeding and a non-breeding season in a non-human primate model, the rhesus monkey. Three adult male monkeys (n = 3) from the breeding season and two monkeys (n = 2) from the non-breeding season were used in this study. After measuring the testicular volume and collecting a single blood sample, all animals were humanely euthanized under controlled conditions, and their hypothalami were collected and processed. Two 20 µm thick hypothalamic sections (mediobasal hypothalamus) from each animal were processed for kisspeptin-MBP and kisspeptin-GnRH immunohistochemistry (IHC). One section from each animal was used as a primary antibody omitted control to check the nonspecific binding in each IHC. Compared to the non-breeding season, plasma testosterone levels and testicular volumes were significantly higher in monkeys during the breeding season. Furthermore, compared to the non-breeding season, increased kisspeptin expression and a higher number of synaptic contacts between kisspeptin fibers and GnRH cell bodies were observed in the arcuate nucleus of the breeding season monkeys. In contrast, enlarged kisspeptin soma and higher MBP expression were observed in non-breeding monkeys. Our results indicated enhanced kisspeptin signaling in primate hypothalamus during the breeding season. These findings support the idea that kisspeptin acts as a mediator for the seasonal regulation of the reproductive axis in higher primates. [ABSTRACT FROM AUTHOR]

Propose: The mechanism that underpins how RFRP‐3 and kisspeptin interacts are not fully understood in higher primates. This study therefore set out to assess RFRP‐3 and kisspeptin expression and their morphological interactions in the breeding, and in the non‐breeding period in monkey hypothalamus. Methods: Eight mature male macaques (Macaca mulatta) in the breeding season (February; n = 4) and non‐breeding season (June; n = 4) were used. To reveal the expression and co‐localization of RFRP‐3 and kisspeptin, double‐labeled immunohistochemistry was performed. Testicular volume, sperm count, and plasma testosterone level were also measured to validate the breeding and non‐breeding paradigms. Results: Testicular volume, plasma testosterone level, and sperm count showed a significant reduction during non‐breeding season. The number of kisspeptin‐positive cells was significantly increased during the breeding season (p < 0.05), whereas more RFRP‐3‐positive cell bodies were seen in the non‐breeding season (p < 0.01). Close contacts of RFRP‐3 fibers with kisspeptin cells showed no significant difference (p > 0.05) across seasons. However, co‐localization of RFRP‐3‐ir cell bodies onto kisspeptin IR cell bodies showed a statistical increase (p < 0.01) in non‐breeding season. Conclusion: In higher primates, RFRP‐3 decreases kisspeptin drives from the same cells to GnRH neurons in an autocrine manner causing suppression of the reproductive axis during the non‐breeding period.We evaluated the co‐localization of RFRP‐3 and kisspeptin in the monkey hypothalamus. Kisspeptin stimulates the GnRH secretion which in turn activate the reproductive axis, initiate puberty and regulates seasonal reproduction. Whereas, RFRP‐3 shows inhibitory effect on GnRH secretion halting reproductive axis activity in various conditions likely in non‐breeding season, low metabolic status and stress. In our study we found that some cells of arcuate nucleus in primates co‐express both RFRP‐3 and kisspeptin providing evidence that RFRP‐3 suppresses the kisspeptin within the same cells causing the inhibition of reproduction in the non‐breeding season. Thus, in future we can use kisspeptin as therapeutic tool for infertility along with antagonizing the effect of RFRP‐3. [ABSTRACT FROM AUTHOR]

Irisin, encoded by the FNDC5 gene, is a recently discovered endocrine factor mainly secreted as a myokine and adipokine. However, irisin/FNDC5 expression has also been reported in different other organs including components of the r eproductive axis. Yet, there is the scarcity of data on FNDC5/irisin expression, regulation and its reproductive effects, particularly in primates. Here, we report the expressio n of FNDC5/irisin, along with PGC1A (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) and ERRA (estrogen-related receptor alpha), in components of the reproductive axis of marmoset monkeys. Hypothalamic FNDC5 and ERRA transcript levels are developmentally regulated in both male and female. We further uncovered sex-spe cific differences in FNDC5, ERRA and PGC1A expression in muscle and the reproductive axis. Moreover, irisin and ERRa co-localize in the marmoset hypothalamus. Additionally, in the arcuate nucleus of rhesus monkeys, the number of irisin+ cells was significantly increased in short-term fasted monkeys as compared to ad libitum-fed monkeys. More importantly, we observed putative interaction of irisin-immunoreactive fibers and few GnR H-immunoreactive cell bodies in the mediobasal hypothalamus of the rhesus monkeys. Functionally, we noted a stimulatory effect of irisin on GnRH synthesis and release in mouse hypothalamic neuronal GT1-7 cells. In summary, our findings show that FNDC5 and irisin are developmentally, metabolic-status dependently and sex-specifically expressed in the primate hypothalamic-pituitary-gonadal axis and exert a stimulatory effect on GnRH expression and release in mouse hypothalamic cells. Further studies are required to confirm the reproductive effects of irisin in vivo and to illuminate the mechanisms of its regulation. [ABSTRACT FROM AUTHOR]

Regeneration refers to regrowth of tissue in the central nervous system. It includes generation of new neurons, glia, myelin, and synapses, as well as the regaining of essential functions: sensory, motor, emotional and cognitive abilities. Unfortunately, regeneration within the nervous system is very slow compared to other body systems. This relative slowness is attributed to increased vulnerability to irreversible cellular insults and the loss of function due to the very long lifespan of neurons, the stretch of cells and cytoplasm over several dozens of inches throughout the body, insufficiency of the tissue-level waste removal system, and minimal neural cell proliferation/self-renewal capacity. In this context, the current review summarized the most common features of major neurodegenerative disorders; their causes and consequences and proposed novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

The present study was designed to assess the responsiveness of hypothalamic–pituitary–gonadal axis to kisspeptin administration with increasing age in men. Human kisspeptin‐10 was administered in single iv bolus dose (1 µg/kg BW) to healthy adult, middle and advanced age men. Serial blood samples were collected for 30 min pre‐ and 120 min post‐kisspeptin injection periods at 30‐min interval. Analysis of plasma LH by ELISA showed a significant (p < 0.05) increase after kisspeptin‐10 administration in all groups, whereas plasma testosterone concentration was significantly elevated (p < 0.05) after kisspeptin‐10 injection only in the adult men group. Present results suggest that in men, central hypothalamic–pituitary axis remains active and shows responsiveness to kisspeptin stimulation across life. However, Leydig cell responsiveness to kisspeptin‐induced LH decreases with age in men. [ABSTRACT FROM AUTHOR]