Gonadotropin-releasing Hormone Neuronal Activity Research Articles

The Role of the Brain in the Pathogenesis and Physiology of Polycystic Ovary Syndrome (PCOS).

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder, affecting at least 10% of women of reproductive age. PCOS is typically characterized by the presence of at least two of the three cardinal features of hyperandrogenemia (high circulating androgen levels), oligo- or anovulation, and cystic ovaries. Hyperandrogenemia increases the severity of the condition and is driven by increased luteinizing hormone (LH) pulse secretion from the pituitary. Indeed, PCOS women display both elevated mean LH levels, as well as an elevated frequency of LH pulsatile secretion. The abnormally high LH pulse frequency, reflective of a hyperactive gonadotropin-releasing hormone (GnRH) neural circuit, suggests a neuroendocrine basis to either the etiology or phenotype of PCOS. Several studies in preclinical animal models of PCOS have demonstrated alterations in GnRH neurons and their upstream afferent neuronal circuits. Some rodent PCOS models have demonstrated an increase in GnRH neuron activity that correlates with an increase in stimulatory GABAergic innervation and postsynaptic currents onto GnRH neurons. Additional studies have identified robust increases in hypothalamic levels of kisspeptin, another potent stimulator of GnRH neurons. This review outlines the different brain and neuroendocrine changes in the reproductive axis observed in PCOS animal models, discusses how they might contribute to either the etiology or adult phenotype of PCOS, and considers parallel findings in PCOS women.

Modulation of Gonadotropin-Releasing Hormone Neuron Activity and Secretion in Mice by Non-peptide Neurotransmitters, Gasotransmitters, and Gliotransmitters

Gonadotropin-releasing hormone (GnRH) neuron activity and GnRH secretion are essential for fertility in mammals. Here, I review findings from mouse studies on the direct modulation of GnRH neuron activity and GnRH secretion by non-peptide neurotransmitters (GABA, glutamate, dopamine, serotonin, norepinephrine, epinephrine, histamine, ATP, adenosine, and acetylcholine), gasotransmitters (nitric oxide and carbon monoxide), and gliotransmitters (prostaglandin E2 and possibly GABA, glutamate, and ATP). These neurotransmitters, gasotransmitters, and gliotransmitters have been shown to directly modulate activity and/or GnRH secretion in GnRH neurons in vivo or ex vivo (brain slices), from postnatal through adult mice, or in embryonic or immortalized mouse GnRH neurons. However, except for GABA, nitric oxide, and prostaglandin E2, which appear to be essential for normal GnRH neuron activity, GnRH secretion, and fertility in males and/or females, the biological significance of their direct modulation of GnRH neuron activity and/or GnRH secretion in the central regulation of reproduction remains largely unknown and requires further exploration.

SUN-LB083 Functional Role of Arcuate Nucleus NPY/AgRP Neurons in the GnRH Circuit Regulating LH Secretion

Homeostatic processes like metabolism and reproduction are tightly regulated by neural circuits, and any disruption of these neural circuits causes energy imbalance and infertility, respectively. Furthermore, in conditions of energy imbalance, such as anorexia or obesity, there is also reproductive dysfunction. This causal relationship between metabolism and reproduction, strongly suggests an interdependence of these neuronal networks. In order to better understand the mechanisms underlying infertility caused by metabolic imbalance, it is important to identify the specific circuitry governing the coordination of energy balance and reproductive function. Neuropeptide Y (NPY) / Agouti related peptide (AgRP) expressing neurons in the arcuate nucleus (ARN) are likely to play an important role as they are crucial in regulating food intake and also affect gonadotropin-releasing hormone (GnRH) neuronal activity and luteinizing hormone (LH) secretion. However, the precise impact of the ARN NPY/AgRP circuit on GnRH neuron activity and fertility remains unclear. To assess this, we used the stimulatory DREADD in AgRP-Cre mice to specifically activate ARN NPY/AgRP neurons and measured pulsatile LH secretion, as a readout of GnRH neuronal activity, in conscious male and female mice. We found that activation of NPY/AgRP neurons by injection of the DREADD ligand, clozapine-N-oxide (CNO), decreased post-castration LH pulse secretion in both sexes, suggesting a slowing of GnRH pulse generation. To map the specific circuit associated with slowing of LH secretion following ARN NPY/AgRP neuron activation, region specific activation of NPY/AgRP fibres was achieved with optogenetics. Selective optogenetic stimulation of NPY/AgRP terminals surrounding GnRH neuron cell bodies in the rostral preoptic area (rPOA) was capable of decreasing GnRH neuron activity in ex vivo slices and significantly decreased LH pulsatility in conscious animals, indicating a functional ARN NPY/AgRP to GnRH neuron circuit capable of slowing pulse generation. Chemogenetic and optogenetic activation of ARN NPY/AgRP neurons was also able to significantly reduce LH pulse frequency in a prenatally androgenised (PNA) model of polycystic ovary syndrome that exhibits high LH pulse frequency, thereby demonstrating therapeutic potential. However, chronic activation of ARN NPY/AgRP neurons with CNO delivery in drinking water over 2 weeks did not ameliorate the PCOS-like reproductive pathology in PNA mice. Together, these data show that activation of ARN NPY/AgRP neurons can slow GnRH/LH pulse generation, potentially through a direct circuit to GnRH neurons in the rPOA. These findings identify a specific mechanism by which ARN NPY/AgRP neurons mediate nutritional infertility and highlight the therapeutic potential of modulating ARN NPY/AgRP activity in infertile conditions associated with high GnRH/ LH pulsatility. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Functional Implications of RFRP-3 in the Central Control of Daily and Seasonal Rhythms in Reproduction.

Adaptation of reproductive activity to environmental changes is essential for breeding success and offspring survival. In mammals, the reproductive system displays regular cycles of activation and inactivation which are synchronized with seasonal and/or daily rhythms in environmental factors, notably light intensity and duration. Thus, most species adapt their breeding activity along the year to ensure that birth and weaning of the offspring occur at a time when resources are optimal. Additionally, female reproductive activity is highest at the beginning of the active phase during the period of full oocyte maturation, in order to improve breeding success. In reproductive physiology, it is therefore fundamental to delineate how geophysical signals are integrated in the hypothalamo-pituitary-gonadal axis, notably by the neurons expressing gonadotropin releasing hormone (GnRH). Several neurochemicals have been reported to regulate GnRH neuronal activity, but recently two hypothalamic neuropeptides belonging to the superfamily of (Arg)(Phe)-amide peptides, RFRP-3 and kisspeptin, have emerged as critical for the integration of environmental cues within the reproductive axis. The goal of this review is to survey the current understanding of the role played by RFRP-3 in the temporal regulation of reproduction, and consider how its effect might combine with that of kisspeptin to improve the synchronization of reproduction to environmental challenges.

GnRH Neurons Provide Direct Input to Hypothalamic Tyrosine Hydroxylase Immunoreactive Neurons Which Is Maintained During Lactation.

Gonadotropin releasing hormone (GnRH) neurons provide neuronal input to the preoptic area (POA) and the arcuate nucleus (Arc), two regions involved critically in the regulation of neuroendocrine functions and associated behaviors. These areas contain tyrosine hydroxylase immunoreactive (TH-IR) neurons, which play location-specific roles in the neuroendocrine control of both the luteinizing hormone and prolactin secretion, as well as, sexually motivated behaviors. Concerning changes in the activity of GnRH neurons and the secretion pattern of GnRH seen under the influence of rising serum estrogen levels and during lactation, we tested the hypothesis that the functional state of GnRH neurons is mediated via direct synaptic connections to TH-IR neurons in the POA and Arc. In addition, we examined putative changes of these inputs in lactating mice and in mothers separated from their pups. Confocal microscopic and pre-embedding immunohistochemical studies on ovariectomized mice treated with 17β-estradiol (OVX+E2) provided evidence for direct appositions and asymmetric synapses between GnRH-IR fiber varicosities and TH-IR neurons in the POA and the Arc. As TH co-localizes with kisspeptin (KP) in the POA, confocal microscopic analysis was continued on sections additionally labeled for KP. The TH-IR neurons showed a lower level of co-labeling for KP in lactating mice compared to OVX+E2 mice (16.1 ± 5% vs. 57.8 ± 4.3%). Removing the pups for 24 h did not alter significantly the KP production in TH-IR neurons (17.3 ± 4.6%). The mean number of GnRH-IR varicosities on preoptic and arcuate TH cells did not differ in the three animal models investigated. This study shows evidence that GnRH neurons provide direct synaptic inputs to POA and Arc dopaminergic neurons. The scale of anatomical connectivity with these target cells was unaltered during lactation indicating a maintained GnRH input, inspite of the altered hormonal condition.

Nociceptin/Orphanin-FQ Inhibits Gonadotropin-Releasing Hormone Neurons via G-Protein-Gated Inwardly Rectifying Potassium Channels.

The pulsatile release of gonadotropin-releasing hormone (GnRH) is a key feature of the hypothalamic–pituitary–gonadal axis. Kisspeptin neurons in the arcuate nucleus (ARC) trigger GnRH neuronal activity, but how GnRH neurons return to baseline electrical activity is unknown. Nociceptin/orphanin-FQ (OFQ) is an inhibitory neuromodulator. ARC proopiomelanocortin (POMC) neurons, known to receive inputs from ARC kisspeptin neurons, contact GnRH neurons and coexpress OFQ in the rat. In the present study, the effect of OFQ(1-13) on GnRH neurons was determined in the mouse. We identified transcripts for the OFQ receptor [opioid receptor like 1 (ORL1)] in GnRH neurons, and, using two-model systems (explants and slices), we found that OFQ exerted a potent inhibition on GnRH neurons, with or without excitatory inputs. We confirmed that the inhibition was mediated by ORL1 via Gi/o-protein coupling. The inhibition, occurring independently of levels of intracellular cyclic adenosine monophosphate, was sensitive to inwardly rectifying potassium channels. The only specific blocker of Gi/o-protein-coupled inwardly rectifying potassium (GIRK) channels, tertiapin-Q (TPNQ), was ineffective in the inhibition of OFQ. Two GIRK activators, one sharing the binding site of TPNQ and one active only on GIRK1-containing GIRK channels, failed to trigger an inhibition. In contrast, protein kinase C phosphorylation activation, known to inhibit GIRK2-mediated currents, prevented the OFQ inhibition. These results indicate a specific combination of GIRK subunits, GIRK2/3 in GnRH neurons. In vivo, double-labeled OFQ/POMC fibers were found in the vicinity of GnRH neurons, and OFQ fibers apposed GnRH neurons. Together, this study brings to light a potent neuromodulator of GnRH neurons.

Dynamic and Sex-Specific Changes in Gonadotropin-Releasing Hormone Neuron Activity and Excitability in a Mouse Model of Temporal Lobe Epilepsy

Reproductive endocrine disorders are prominent comorbidities of temporal lobe epilepsy (TLE) in both men and women. The neural mechanisms underlying these comorbidities remain unclear, but hypothalamic gonadotropin-releasing hormone (GnRH) neurons may be involved. Here, we report the first direct demonstrations of aberrant GnRH neuron function in an animal model of epilepsy. Recordings of GnRH neuron firing and excitability were made in acute mouse brain slices prepared two months after intrahippocampal injection of kainate (KA) or control saline, a well-established TLE model in which most females develop comorbid estrous cycle disruption. GnRH neurons from control females showed elevated firing and excitability on estrus compared with diestrus. By contrast, cells from KA-injected females that developed prolonged, disrupted estrous cycles (KA-long) showed the reverse pattern. Firing rates of cells from KA-injected females that maintained regular cycles (KA-regular) were not different from controls on diestrus, but were reduced on estrus. In KA-injected males, only GnRH neurons in the medial septum displayed elevated firing. In contrast to the diestrus versus estrus and sex-specific changes in firing, GnRH neuron intrinsic excitability was elevated in all KA-injected groups, indicating a role for afferent synaptic and neuromodulatory inputs in shaping overall changes in firing activity. Furthermore, KA-injected females showed cycle-stage-specific changes in circulating sex steroids on diestrus and estrus that also differed between KA-long and KA-regular groups. Together, these findings reveal that the effects of epilepsy on the neural control of reproduction are dynamic across the estrous cycle, distinct in association with comorbid estrous cycle disruption severity, and sex-specific.

Neuropeptidergic modulation of GnRH neuronal activity and GnRH secretion controlling reproduction: insights from recent mouse studies

Gonadotropin-releasing hormone (GnRH) secretion from GnRH neurons and its modulation by neuropeptides are essential for mammalian reproduction. Here, I review the neuropeptides that have been shown to act directly and that may also act indirectly, on GnRH neurons, the reproduction-related processes with which the neuropeptides may be associated or the physiological information they may convey, as well as their cognate receptors, signaling pathways and roles in the modulation of GnRH neuronal firing, [Ca2+]i, GnRH secretion and reproduction. The review focuses on recent research in mice, which offer the most tractable experimental system for studying mammalian GnRH neurons.

Perinatal BPA exposure and reproductive axis function in CD-1 mice

Perinatal Bisphenol-A (BPA) exposure reduces fertility and fecundity in mice. This study examined effects of early BPA exposure on activation of gonadotropin releasing hormone (GnRH) neurons in conjunction with a steroid-induced luteinizing hormone (LH) surge, characterized patterns of estrous cyclicity and fertility over time, and assessed the ovarian follicular reserve to further explore factors responsible for the reduced fertility we previously described in this model. The percent activated GnRH neurons was reduced in BPA-exposed females at 3–6 months, and periods of persistent proestrus were increased. These data suggest that perinatal exposure to BPA reduces GnRH neuronal activation required for the generation of the LH surge and estrous cyclicity. Assessments of anti-Müllerian hormone (AMH) levels failed to suggest a decline in the follicular reserve at the BPA exposure levels examined.

Stress CRasHes into fertility command center

Corticotropin-releasing hormone alters activity of gonadotropin-releasing hormone neurons in an estradiol-dependent manner.

Estradiol-Dependent Stimulation and Suppression of Gonadotropin-Releasing Hormone Neuron Firing Activity by Corticotropin-Releasing Hormone in Female Mice

Gonadotropin-releasing hormone (GnRH) neurons are the final central regulators of reproduction, integrating various inputs that modulate fertility. Stress typically inhibits reproduction but can be stimulatory; stress effects can also be modulated by steroid milieu. Corticotropin-releasing hormone (CRH) released during the stress response may suppress reproduction independent of downstream glucocorticoids. We hypothesized CRH suppresses fertility by decreasing GnRH neuron firing activity. To test this, mice were ovariectomized (OVX) and either implanted with an estradiol capsule (OVX+E) or not treated further to examine the influence of estradiol on GnRH neuron response to CRH. Targeted extracellular recordings were used to record firing activity from green fluorescent protein-identified GnRH neurons in brain slices before and during CRH treatment; recordings were done in the afternoon when estradiol has a positive feedback effect to increase GnRH neuron firing. In OVX mice, CRH did not affect the firing rate of GnRH neurons. In contrast, CRH exhibited dose-dependent stimulatory (30 nM) or inhibitory (100 nM) effects on GnRH neuron firing activity in OVX+E mice; both effects were reversible. The dose-dependent effects of CRH appear to result from activation of different receptor populations; a CRH receptor type-1 agonist increased firing activity in GnRH neurons, whereas a CRH receptor type-2 agonist decreased firing activity. CRH and specific agonists also differentially regulated short-term burst frequency and burst properties, including burst duration, spikes/burst, and/or intraburst interval. These results indicate that CRH alters GnRH neuron activity and that estradiol is required for CRH to exert both stimulatory and inhibitory effects on GnRH neurons.

Prepubertal Development of Gonadotropin-Releasing Hormone Neuron Activity Is Altered by Sex, Age, and Prenatal Androgen Exposure.

Gonadotropin-releasing hormone (GnRH) neurons regulate reproduction though pulsatile hormone release. Disruption of GnRH release as measured via luteinizing hormone (LH) pulses occurs in polycystic ovary syndrome (PCOS), and in young hyperandrogenemic girls. In adult prenatally androgenized (PNA) mice, which exhibit many aspects of PCOS, increased LH is associated with increased GnRH neuron action potential firing. How GnRH neuron activity develops over the prepubertal period and whether this is altered by sex or prenatal androgen treatment are unknown. We hypothesized GnRH neurons are active before puberty and that this activity is sexually differentiated and altered by PNA. Dams were injected with dihydrotestosterone (DHT) on days 16 to 18 post copulation to generate PNA mice. Action potential firing of GFP-identified GnRH neurons in brain slices from 1-, 2-, 3-, and 4-week-old and adult mice was monitored. GnRH neurons were active at all ages tested. In control females, activity increased with age through 3 weeks, then decreased to adult levels. In contrast, activity did not change in PNA females and was reduced at 3 weeks. Activity was higher in control females than males from 2 to 3 weeks. PNA did not affect GnRH neuron firing rate in males at any age. Short-term action potential patterns were also affected by age and PNA treatment. GnRH neurons are thus typically more active during the prepubertal period than adulthood, and PNA reduces prepubertal activity in females. Prepubertal activity may play a role in establishing sexually differentiated neuronal networks upstream of GnRH neurons; androgen-induced changes during this time may contribute to the adult PNA, and possibly PCOS, phenotype.

Dynamics of GnRH Neuron Ionotropic GABA and Glutamate Synaptic Receptors Are Unchanged during Estrogen Positive and Negative Feedback in Female Mice.

Inputs from GABAergic and glutamatergic neurons are suspected to play an important role in regulating the activity of the gonadotropin-releasing hormone (GnRH) neurons. The GnRH neurons exhibit marked plasticity to control the ovarian cycle with circulating estradiol concentrations having profound “feedback” effects on their activity. This includes “negative feedback” responsible for suppressing GnRH neuron activity and “positive feedback” that occurs at mid-cycle to activate the GnRH neurons to generate the preovulatory luteinizing hormone surge. In the present study, we employed brain slice electrophysiology to question whether synaptic ionotropic GABA and glutamate receptor signaling at the GnRH neuron changed at times of negative and positive feedback. We used a well characterized estradiol (E)–treated ovariectomized (OVX) mouse model to replicate negative and positive feedback. Miniature and spontaneous postsynaptic currents (mPSCs and sPSCs) attributable to GABAA and glutamatergic receptor signaling were recorded from GnRH neurons obtained from intact diestrous, OVX, OVX + E (negative feedback), and OVX + E+E (positive feedback) female mice. Approximately 90% of GnRH neurons exhibited spontaneous GABAA-mPSCs in all groups but no significant differences in the frequency or kinetics of mPSCs were found at the times of negative or positive feedback. Approximately 50% of GnRH neurons exhibited spontaneous glutamate mPSCs but again no differences were detected. The same was true for spontaneous PSCs in all cases. These observations indicate that the kinetics of ionotropic GABA and glutamate receptor synaptic transmission to GnRH neurons remain stable across the different estrogen feedback states.

Sex Differences in Steroid Receptor Coexpression and Circadian-Timed Activation of Kisspeptin and RFRP-3 Neurons May Contribute to the Sexually Dimorphic Basis of the LH Surge.

In rodents, the ovulation-inducing luteinizing hormone (LH) surge is sexually dimorphic, occurring only in females, but the reasons for this sex difference are unclear. Two neuropeptides, kisspeptin and RFamide-related peptide 3 (RFRP-3), are hypothesized to regulate the gonadotropin-releasing hormone (GnRH)/LH surge. In females, both of these systems show circadian changes coincident with the LH surge, but whether males show similar temporal changes under comparable hormonal conditions is unknown. Here, we evaluated circadian time (CT)-dependent changes in gene expression and neuronal activation of Kiss1 and Rfrp neurons of female and male mice given identical LH surge-inducing estrogen regimens. As expected, females, but not males, displayed a late afternoon LH surge and GnRH neuronal activation. Kiss1 expression in the anteroventral periventricular nucleus (AVPV) was temporally increased in females in the late afternoon, whereas males demonstrated no temporal changes in AVPV Kiss1 expression. Likewise, neuronal activation of AVPV Kiss1 neurons was dramatically elevated in the late afternoon in females but was low at all circadian times in males. Estrogen receptor α levels in AVPV Kiss1 neurons were sexually dimorphic, being higher in females than males. AVPV progesterone receptor levels were also higher in females than males. Hypothalamic Rfrp messenger RNA levels showed no CT-dependent changes in either sex. However, Rfrp neuronal activation was temporally diminished in the afternoon/evening in females but not males. Collectively, the identified sex differences in absolute and CT-dependent AVPV Kiss1 levels, AVPV sex steroid receptor levels, and circadian-timed changes in neuronal activation of both Kiss1 and Rfrp neurons suggest that multiple sexually dimorphic processes in the brain may underlie proper LH surge generation.

Progress and Challenges in the Search for the Mechanisms of Pulsatile Gonadotropin-Releasing Hormone Secretion.

Fertility relies on the proper functioning of the hypothalamic–pituitary–gonadal axis. The hormonal cascade begins with hypothalamic neurons secreting gonadotropin-releasing hormone (GnRH) into the hypophyseal portal system. In turn, the GnRH-activated gonadotrophs in the anterior pituitary release gonadotropins, which then act on the gonads to regulate gametogenesis and sex steroidogenesis. Finally, sex steroids close this axis by feeding back to the hypothalamus. Despite this seeming straightforwardness, the axis is orchestrated by a complex neuronal network in the central nervous system. For reproductive success, GnRH neurons, the final output of this network, must integrate and translate a wide range of cues, both environmental and physiological, to the gonadotrophs via pulsatile GnRH secretion. This secretory profile is critical for gonadotropic function, yet the mechanisms underlying these pulses remain unknown. Literature supports both intrinsically and extrinsically driven GnRH neuronal activity. However, the caveat of the techniques supporting either one of the two hypotheses is the gap between events recorded at a single-cell level and GnRH secretion measured at the population level. This review aims to compile data about GnRH neuronal activity focusing on the physiological output, GnRH secretion.

High-Frequency Firing Activity of GnRH1 Neurons in Female Medaka Induces the Release of GnRH1 Peptide From Their Nerve Terminals in the Pituitary.

Hypothalamic gonadotropin-releasing hormone (GnRH) neurons play an important role in promoting secretion of pituitary luteinizing hormone (LH) and ovulation by releasing GnRH peptide. The release of GnRH peptide is generally assumed to be mainly modulated according to the firing activity of GnRH neurons. However, the relationship between the firing activity and the release of GnRH peptide has been elusive. We analyzed the relationship using two lines of transgenic medaka (gnrh1:enhanced green fluorescent protein and lhb:inverse-pericam) for the combined electrophysiological and Ca2+ imaging analyses. We show that a high-frequency firing activity induced by an excitatory neurotransmitter, glutamate, strongly increases [Ca2+]i in the cell bodies of GnRH1 neurons, which should lead to stimulation of GnRH release. We examined whether this high-frequency firing actually leads to the release of endogenous GnRH1 peptide from the nerve terminals projecting to the pituitary LH cells using a whole brain-pituitary preparation of a fish generated by crossing the two types of transgenic fish. Ca2+ imaging analyses showed that local glutamate activation of GnRH1 cell bodies, but not their nerve terminals in the pituitary, induced a substantial Ca2+ response in LH cells that was abolished in the presence of a GnRH receptor antagonist, Analog M. These results suggest that such an evoked high-frequency firing activity of GnRH1 cell body stimulates the release of endogenous GnRH1 peptide from the axon terminals to the pituitary LH cells. Thus, the findings of the present study have clearly demonstrated the relationship between the firing activity of hypothalamic GnRH neurons and the release of GnRH peptide.

Rabconnectin-3\u03b1 is required for the morphological maturation of GnRH neurons and kisspeptin responsiveness

A few hundred hypothalamic neurons form a complex network that controls reproduction in mammals by secreting gonadotropin-releasing hormone (GnRH). Timely postnatal changes in GnRH secretion are essential for pubertal onset. During the juvenile period, GnRH neurons undergo morphological remodeling, concomitantly achieving an increased responsiveness to kisspeptin, the main secretagogue of GnRH. However, the link between GnRH neuron activity and their morphology remains unknown. Here, we show that brain expression levels of Dmxl2, which encodes the vesicular protein rabconnectin-3α, determine the capacity of GnRH neurons to be activated by kisspeptin and estradiol. We also demonstrate that Dmxl2 expression levels control the pruning of GnRH dendrites, highlighting an unexpected role for a vesicular protein in the maturation of GnRH neuronal network. This effect is mediated by rabconnectin-3α in neurons or glial cells afferent to GnRH neurons. The widespread expression of Dmxl2 in several brain areas raises the intriguing hypothesis that rabconnectin-3α could be involved in the maturation of other neuronal populations.

Editorial: Reproductive Neuroendocrinology and Social Behavior

Reproduction consists of various physiological events including fertilization, development of sexual characteristics, social behavior, maturation, and aging. Reproductive functions are ultimately regulated by the hypothalamus-pituitary-gonadal (HPG) axis. Gonadotropin-releasing hormone (GnRH) is a pivotal hypothalamic neuropeptide that regulates vertebrate reproduction (Schally et al., 1972). In tetrapods, GnRH neurons are located in the preoptic-hypothalamic region and project their fibers to the median eminence to regulate gonadotropin secretion from the anterior pituitary gland, which stimulates sex steroid secretion and gametogenesis in the gonads. It was also shown that central administration of GnRH can stimulate female sexual behavior in rats (Moss and McCann, 1973; Pfaff, 1973). GnRH release is regulated by other neuropeptides, neurotransmitters, and steroid hormones. Watanabe et al. summarize the role of gamma-amino butyric acid (GABA) in the regulation of GnRH neuronal activity and discuss functional consequences of GABAergic inputs to GnRH neurons in physiological aspects of reproduction. Recently, two neuropeptides containing the C-terminal Arg-Phe-NH2 (RFamide peptides), kisspeptin, and gonadotropin-inhibitory hormone (GnIH), emerged as critical accelerator, and suppressor, respectively, of vertebrate reproduction. Parhar et al. highlight classical and recent findings regarding the role of GnRH, kisspeptin, and GnIH in the regulation of social behaviors in fish, birds, and mammals, and discuss their importance in future biological and biomedical researches (Perspectives).

Hypothalamic control of the male neonatal testosterone surge.

Sex differences in brain neuroanatomy and neurophysiology underpin considerable physiological and behavioural differences between females and males. Sexual differentiation of the brain is regulated by testosterone secreted by the testes predominantly during embryogenesis in humans and the neonatal period in rodents. Despite huge advances in understanding how testosterone, and its metabolite oestradiol, sexually differentiate the brain, little is known about the mechanism that actually generates the male-specific neonatal testosterone surge. This review examines the evidence for the role of the hypothalamus, and particularly the gonadotropin-releasing hormone (GnRH) neurons, in generating the neonatal testosterone surge in rodents and primates. Kisspeptin-GPR54 signalling is well established as a potent and critical regulator of GnRH neuron activity during puberty and adulthood, and we argue here for an equally important role at birth in driving the male-specific neonatal testosterone surge in rodents. The presence of a male-specific population of preoptic area kisspeptin neurons that appear transiently in the perinatal period provide one possible source of kisspeptin drive to neonatal GnRH neurons in the mouse.

The increase in the number of spines on the gonadotropin-releasing hormone neuron across pubertal development in rats.

The onset of puberty is initiated by an increase in the release of the gonadotropin-releasing hormone (GnRH) from GnRH neurons in the hypothalamus. However, the precise mechanism that leads to the activation of GnRH neurons at puberty remains controversial. Spines are small protrusions on the surface of dendrites that normally receive excitatory inputs. In this study, we analyzed the number and morphology of spines on GnRH neurons to investigate changes in synaptic inputs across puberty in rats. For morphological estimation, we measured the diameter of the head (DH) of each spine and classified them into small-type (DH < 0.65μm), large-type (DH > 0.65μm) and giant-type (DH > 0.9μm). The greatest number of spines was observed at the proximal dendrite within 50μm of the soma. At the soma and proximal dendrite, the number of spines was greater in adults than in juveniles in both male and female individuals. Classification of spines revealed that the increase in spine number was due to increases in large- and giant-type spines. To furtherexplore the relationship between spines on GnRH neurons and pubertal development, we next analyzed adult rats neonatally exposed to estradiol benzoate, in which puberty onset and reproductive functionsare disrupted. We found a decrease in the number of all types of spines. These results suggest that GnRH neurons become to receive more and greater excitatory inputs on the soma and proximal dendrites as a result of the changes that occur at puberty and that alteration to spines plays a pivotal role in normal pubertal development.