The pubertal transition to adulthood involves both gonadal and behavioral maturation. A developmental clock, along with permissive signals that provide information on somatic growth, energy balance and season, time the awakening of gonadotropin releasing hormone (GnRH) neurons at the onset of puberty. High-frequency GnRH release results from disinhibition and activation of GnRH neurons at puberty onset, leading to gametogenesis and an increase in gonadal steroid hormone secretion. Steroid hormones, in turn, both remodel and activate neural circuits during adolescent brain development, leading to the development of sexual salience of sensory stimuli, sexual motivation, and expression of copulatory behaviors in specific social contexts. These influences of hormones on reproductive behavior depend in part on changes in the adolescent brain that occur independently of gonadal maturation. Reproductive maturity is therefore the product of developmentally timed, brain-driven and recurrent interactions between steroid hormones and the adolescent nervous system.

The neural basis of puberty and adolescence

An increase in pulsatile release of LHRH is essential for the onset of puberty. However, the mechanism controlling the pubertal increase in LHRH release is still unclear. In primates the LHRH neurosecretory system is already active during the neonatal period but subsequently enters a dormant state in the juvenile/prepubertal period. Neither gonadal steroid hormones nor the absence of facilitatory neuronal inputs to LHRH neurons is responsible for the low levels of LHRH release before the onset of puberty in primates. Recent studies suggest that during the prepubertal period an inhibitory neuronal system suppresses LHRH release and that during the subsequent maturation of the hypothalamus this prepubertal inhibition is removed, allowing the adult pattern of pulsatile LHRH release. In fact, y-aminobutyric acid (GABA) appears to be an inhibitory neurotransmitter responsible for restricting LHRH release before the onset of puberty in female rhesus monkeys. In addition, it appears that the reduction in tonic GABA inhibition allows an increase in the release of glutamate as well as other neurotransmitters, which contributes to the increase in pubertal LHRH release. In this review, developmental changes in several neurotransmitter systems controlling pulsatile LHRH release are extensively reviewed.

Neurobiological mechanisms of the onset of puberty in primates.

This chapter reviews the properties and functioning of the gonadotropin-releasing hormone (GnRH) neuronal network in the adult mammal. The initial focus is upon the GnRH neuron itself where the neuroanatomical and morphological features of these neurons are considered alongside their electrophysiological properties and their biosynthesis of the GnRH decapeptide. Next, the neuronal and glial cell components of the “GnRH neuronal network” are reviewed with a particular focus upon the roles of GABA, glutamate, GnRH, kisspeptin, neurokinin B, neuropeptide Y, norepinephrine, and RFaminde-related peptides. The substantial heterogeneity displayed by GnRH neurons and mechanisms of pulse and surge generation are considered before examining how the various components of the network function to drive estrous cycles in rodents. Here the feedback actions of estradiol and progesterone are reviewed alongside circadian influences, and an integrated model of GnRH neuron network function is presented.

Physiology of the Adult Gonadotropin-Releasing Hormone Neuronal Network

Our understanding of kisspeptin and its actions depends, in part, on a detailed knowledge of the neuroanatomy of the kisspeptin signaling system in the brain. In this chapter, we will review our current knowledge of the distribution of kisspeptin cells, fibers, and receptors in the mammalian brain, including the development, phenotype, and projections of different kisspeptin subpopulations. A fairly consistent picture emerges from this analysis. There are two major groups of kisspeptin cell bodies: a large number in the arcuate nucleus (ARC) and a smaller collection in the rostral periventricular area of the third ventricle (RP3V) of rodents and preoptic area (POA) of non-rodents. Both sets of neurons project to GnRH cell bodies, which contain Kiss1r, and the ARC kisspeptin population also projects to GnRH axons in the median eminence. ARC kisspeptin neurons contain neurokinin B and dynorphin, while a variable percentage of those cells in the RP3V of rodents contain galanin and/or dopamine. Neurokinin B and dynorphin have been postulated to contribute to the control of GnRH pulses and sex steroid negative feedback, while the role of galanin and dopamine in rostral kisspeptin neurons is not entirely clear. Kisspeptin neurons, fibers, and Kiss1r are found in other areas, including widespread areas outside the hypothalamus, but their physiological role(s) in these regions remains to be determined.

/pdf/neuroanatomy-of-the-kisspeptin-signaling-system-in-mammals-1oawuks5o7.pdf

Neuroanatomy of the Kisspeptin Signaling System in Mammals: Comparative and Developmental Aspects

Puberty is a developmental phase during which profound hormonal, physical, behavioral, and psychological changes occur. The individual becomes capable of reproduction, that is, viable gametes are produced and transferred through a mature reproductive system.

Neuroendocrine Regulation of Puberty

During the period of development, prior to full sexual maturity, gonadotropin hormone-releasing hormone (GnRH) neurons are fully capable of synthesizing and processing the GnRH decapeptide. Nonetheless, the secretion of the hormone is not adequate to stimulate adult patterns of gonadotropin release. The present study was undertaken to examine ultrastructural characteristics of the GnRH neuron and its relationship to its environment in early- midpubertal female rhesus monkey. These neurons bore all the ultrastructural immunocytochemical characteristics of those in mature animals, but quantitative morphometrics revealed that they were extensively apposed by glial processes. Such ensheathment was described earlier in ovariectomized adult animals and was found to be reversible by administration of gonadal steroids. The density of synaptic input to GnRH neurons in the pubertal animals did not differ significantly from that of adult intact or ovariectomized animals from a previous study. Chemical identification will be required to determine whether there are age or hormonal differences in the innervation of these neurons.



These results provide anatomical evidence in support of indications from other studies that the ovarian steroidal milieu affects GnRH-glial relationships. Further testing will be required to determine whether the attainment of sexual maturity in the female rhesus macaque is dependent upon a reduction in glial ensheathment of GnRH neurons.

Glial ensheathment of GnRH neurons in pubertal female rhesus macaques.

A previous study in our laboratory revealed that the cell bodies of gonadotropin releasing hormone (GnRH) neurons in the preoptic area (POA) of early to midpubertal female rhesus monkeys were extensively invested with thick glial processes. Because the medial basal hypothalamus (MBH) plays a critical role in the control of pulsatile and cyclic gonadotropin release in the primate, we have now focused on the ultrastructural milieu of GnRH neurons of this region in the same sample of monkeys. The ensheathment of the perikarya of GnRH neurons in the MBH with such glial processes was more pronounced than in the POA. Whereas the mean proportion of the cell membrane covered by these glia was 57% in the POA, it was 72% in the MBH. In addition, the cell bodies of GnRH neurons in the MBH of the pubertal monkey (unlike those in the POA) were less well innervated than were those in the adult cycling monkey, further highlighting differences between these brain regions. Differences in the anatomical milieu of the MBH between immature monkeys, in which GnRH release is still relatively quiescent, and adult cycling monkeys are consistent with the hypothesis that GnRH neurons within the MBH are under particular constraint in the immature animals. The functional significance of these observations must, however, await further studies.

Honor O’Sullivan

Papers

Glial ensheathment of GnRH neurons in pubertal female rhesus macaques.

GnRH Perikarya in Medial Basal Hypothalamus of Pubertal Female Rhesus Macaque are Ensheathed With Glia