Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.
ISSN: 0001-6322

hal-00875723
https://hal.archives-ouvertes.fr/hal-00875723
DOI : 10.1007/s00401-013-1084-y
PUBMED : 23400299

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The cyp19a1 gene that encodes aromatase, the only enzyme permitting conversion of C19 aromatizable androgens into estrogens, is present as a single copy in the genome of most vertebrate species, except in teleosts in which it has been duplicated. This study aimed at investigating the brain expression of a cyp19a1 gene expressed in both gonad and brain of Japanese eel, a basal teleost. By means of immunohistochemistry and in situ hybridization, we show that cyp19a1 is expressed only in radial glial cells of the brain and in pituitary cells. Treatments with salmon pituitary homogenates (female) or human chorionic gonadotrophin (male), known to turn on steroid production in immature eels, strongly stimulated cyp19a1 messenger and protein expression in radial glial cells and pituitary cells. Using double staining studies, we also showed that aromatase-expressing radial glial cells exhibit proliferative activity in both the brain and the pituitary. Altogether, these data indicate that brain and pituitary expression of Japanese eel cyp19a1 exhibits characteristics similar to those reported for the brain specific cyp19a1b gene in teleosts having duplicated cyp19a1 genes. This supports the hypothesis that, despite the fact that eels also underwent the teleost specific genome duplication, they have a single cyp19a1 expressed in both brain and gonad. Such data also suggest that the intriguing features of brain aromatase expression in teleost fishes were not gained after the whole genome duplication and may reflect properties of the cyp19a1 gene of ancestral Actinopterygians.
ISSN: 1932-6203

hal-00877375
https://hal.archives-ouvertes.fr/hal-00877375
https://hal.archives-ouvertes.fr/hal-00877375/document
https://hal.archives-ouvertes.fr/hal-00877375/file/Expressionsur Aromatase-accepted.pdf
DOI : 10.1371/journal.pone.0044750

Éditeur(s) : HAL CCSD
Résumé : International audience
OBJECTIVE: To analyze complications of endoscopic transsphenoidal surgery (ETS) for nonfunctioning pituitary macroadenomas (NFPAs).ăMETHODS: A retrospective study of 300 NFPAs was performed. Complications and factors that could influence these complications were analyzed.ăRESULTS: Visual and pituitary functions worsened in 2.4% and 13.7% of cases, respectively. Postoperative diabetes insipidus was permanent in 6.2% of cases. Postoperative meningitis occurred in 3.3% of patients. Meningitis was strongly associated with intraoperative cerebrospinal fluid (CSF) leaks (P = 0.01), postoperative CSF leaks (P = 0.0001), and operation times longer than 1 hour (P = 0.023). Detection of Staphylococcus aureus and preoperative treatment with mupirocin in the nostrils did not impact the occurrence of meningitis. Two patients with meningitis died (unique causes of death). Postoperative CSF leaks occurred in 2.7% of cases and were associated with intraoperative CSF leaks (P = 0.007) and permanent diabetes insipidus (P = 0.028). The rate of CSF leak decreased from 4% to 0.8% (P = 0.048) after we moved from a soft to hard reconstruction of the sella. The rate of postoperative epistaxis decreased from 6.7% to 1.25% after we stopped using monopolar coagulation (P = 0.013).ăCONCLUSIONS: ETS permits a wide view, allowing good conditions for a satisfactory resection in the majority of NFPAs. Some pitfalls of endoscopy can lead to complications that improve with modification of the operative technique (i.e., CSF leak and postoperative epistaxis). This study confirms an acceptable rate of complications associated with ETS.
World Neurosurgery

hal-01474296
https://hal.archives-ouvertes.fr/hal-01474296
DOI : 10.1016/j.wneu.2016.02.059
PUBMED : 26902781

Éditeur(s) : HAL CCSD Taylor & Francis
Résumé : International audience
The functional organization of the circadian system and the location of the main circadian oscillators vary through phylogeny. Present study investigates by in situ hybridization the anatomical location of the clock gene gPer1b in forebrain and midbrain, pituitary, and in two peripheral locations, the anterior intestine and liver, in a teleost fish, the goldfish (Carassius auratus). Moreover, the daily expression profiles of this gene were also studied by quantitative Real Time-PCR. Goldfish were maintained under a 12L–12D photoperiod and fed daily at 2 h after lights were switched on. A wide distribution of gPer1b mRNA in goldfish brain and pituitary was found in telencephalon, some hypothalamic nuclei (including the homologous to mammalian SCN), habenular nucleus, optic tectum, cerebellum and torus longitudinalis. Moreover, gPer1b expression was observed, for the first time in teleosts, in the pituitary, liver and anterior intestine. Day/night differences in gper1b mRNA abundance were found by in situ hybridization, with higher signal at nighttime that correlates with the results obtained by RT-PCR, where a rhythmic gPer1b expression was found in all tissues with acrophases at the end of the night. Amplitudes of gper1b rhythms vary among tissues, being higher in liver and intestine than in the brain, maybe because different cues entrain clocks in these locations. These results support the existence of functional clocks in many central and peripheral locations in goldfish coordinated, ticking at the same time
ISSN: 0742-0528

hal-01197353
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01197353
DOI : 10.3109/07420528.2015.1049615
PUBMED : 26171989

Éditeur(s) : HAL CCSD John Wiley & Sons
Résumé : International audience
Kisspeptins are now considered key players in the neuroendocrine control of puberty and reproduction, at least in mammals. Most teleosts have two kiss genes, kiss1 and kiss2, but their sites of expression are still poorly documented. As a first step in investigating the role of kisspeptins in the European sea bass, a perciform fish, we studied the distribution of kiss1 and kiss2-expressing cells in the brain of males and females undergoing their first sexual maturation. Animals were examined at early and late in the reproductive season. We also examined the putative expression of estrogen receptors in kiss-expressing cells and, finally, we investigated whether kisspeptins are expressed in the pituitary gland. We show that kiss1-expressing cells were consistently detected in the habenula and, in mature males and females, in the rostral mediobasal hypothalamus. In both sexes, kiss2-expressing cells were consistently detected at the level of the preoptic area, but the main kiss2 mRNA-positive population was observed in the dorsal hypothalamus, above and under the lateral recess. No obvious sexual differences in kiss1 and kiss2 mRNA expression were detected. Additional studies based on confocal imaging clearly showed that most kiss1 mRNA-containing cells of the mediobasal hypothalamus strongly express ERα and slightly express ERβ2. At the pituitary level, both sexes exhibited kiss1 mRNA expression in most FSHβ-positive cells and never in LHβ-positive cells.
ISSN: 0092-7317

hal-00877326
https://hal.archives-ouvertes.fr/hal-00877326
PUBMED : 22886357
DOI : 10.1002/cne.23211

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The hypothalamic-pituitary-adrenal (HPA) axis response to chronic stress is far from straight forward, particularly with regards to animal welfare. There are reports of no effect as well as both decreases and increases in cortisol after chronic stressors. Therefore, the first aim of the present study was to determine how measures of compromised welfare, such as chronic pain and haematological anomalies, related to cortisol levels in domestic horses (Equus caballus). Domestic horses are an informative model to investigate the impact of chronic stress (due to environment, pain, work, housing conditions…) on the HPA axis. The second aim was to determine whether levels of fecal cortisol metabolites (FCM) may be used as an indicator of welfare measures. The present study used fifty-nine horses (44 geldings and 15 mares), from three riding centres in Brittany, France. The primary findings show that horses whose welfare was clearly compromised (as indicated by an unusual ears backward position, presence of vertebral problems or haematological anomalies, e.g. anaemia) also had lower levels of both FCM and plasma cortisol. This work extends our previous findings showing that withdrawn postures, indicators of depressive-like behavior in horses, are associated with lower plasma cortisol levels. We also found that evening plasma cortisol levels positively correlated with FCM levels in horses. Future research aims to determine the extent to which factors of influence on welfare, such as living conditions (e.g. single stalls versus group housing in pasture or paddocks), early life factors, and human interaction, act as mediators of cortisol levels in horses.
ISSN: 1932-6203

hal-01588159
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01588159
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01588159/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01588159/file/Pawluski_et_al_-_PLOSONE-2017.pdf
DOI : 10.1371/journal.pone.0182257

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Maternal affective disorders are frequently treated with selective serotonin reuptake inhibitor medications (SSRIs); with up to 10% of women being prescribed these medications during pregnancy. Infant development depends on the early serotonergic environment, which is altered by perinatal SSRIs, raising concern about how these medications affect neural outcomes. While clinical and preclinical research suggests an impact of SSRIs on the developing brain, more research is needed to determine the effects on neuroplasticity, the serotonergic system, and the hypothalamic-pituitary-adrenal axis in neural regions mediating behavior. The current work investigated the effects of the SSRI, fluoxetine, on the serotonergic system in the prefrontal cortex (PFC) during pre-adolescence, and changes to synaptic markers and glucocorticoid receptor density in the cingulate cortex (medial PFC) of pre-adolescent and adult Sprague-Dawley male and female rats. To model aspects of Perinatal Depression and maternal anxiety, pre-gestational maternal stress was used resulting in male and female offspring from 4 groups: 1) control, 2) perinatal fluoxetine exposed, 3) pre-gestational maternal stress exposed, and 4) pre-gestational maternal stress + fluoxetine. Perinatal fluoxetine prevented the effects of maternal stress on 5-HT levels and 5-HT turnover ratio in the PFC of pre-adolescent offspring, particularly in females. However, pre-gestational stress reduced synaptophysin and PSD-95 densities in the cingulate cortex, effects that were more pronounced in males. Interestingly, perinatal fluoxetine exposure reduced GR density in adult males in this same brain area. Together, results show differential effects of perinatal SSRIs and pre-gestational maternal stress on neurodevelopment in the PFC of males and females.
ISSN: 0028-3908

hal-01647158
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01647158
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01647158/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01647158/file/Gemmel%20-%20Perinatal%20fluoxetine%20prevents%20the%20effect.pdf
DOI : 10.1016/j.neuropharm.2017.10.009

Éditeur(s) : HAL CCSD
Résumé : International audience
Kisspeptins are well known as mediators of the coordinated communication between the brain-pituitary axis and the gonads in many vertebrates. To test the hypothesis that gonadal steroids regulate kiss1 and kiss2 mRNA expression in European sea bass (a teleost fish), we examined the brains of gonad-intact (control) and castrated animals, as well as castrated males (GDX) and ovariectomized females (OVX) that received testosterone (T) and estradiol (E2) replacement, respectively, during recrudescence. In GDX males, low expression of kiss1 mRNA is observed by in situ hybridization in the caudal hypothalamus (CH) and the mediobasal hypothalamus (MBH), although hypothalamic changes in kiss1 mRNA levels were not statistically different among the groups, as revealed by real-Time PCR. However, T strongly decreased kiss2 expression levels in the hypothalamus, which was documented in the MBH and the nucleus of the lateral recess (NRLd) in GDX T-Treated sea bass males. Conversely, it appears that E2 evokes lowkiss1mRNAin the CH, while there were cells expressing kiss2 in the MBH and NRLd in these OVX females. These results demonstrate that kisspeptin neurons are presumably sensitive to the feedback actions of sex steroids in the sea bass, suggesting that the MBH represents a major site for sex steroid actions on kisspeptins in this species. Also, recent data provide evidence that both positive and negative actions occur in key factors involved in sea bass reproductive function, including changes in the expression of gnrh-1/gonadotropin, cyp19b, er and ar genes and sex steroid and gonadotropin plasma levels in this teleost fish. © 2016. Published by The Company of Biologists Ltd.
Journal of Experimental Biology

hal-01406072
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01406072
DOI : 10.1242/jeb.137364
PUBMED : 27591305

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
In this study, we report the cloning of three transcripts for leptin receptor in the European sea bass, a marine teleost of economic interest. The two shortest variants, generated by different splice sites, encode all functional extracellular and intracellular domains but missed the transmembrane domain. The resulting proteins are therefore potential soluble binding proteins for leptin. The longest transcript (3605 bp), termed sblepr, includes all the essential domains for binding and transduction of the signal. Thus, it is proposed as the ortholog for the human LEPR gene, the main responsible for leptin signalling. Phylogenetic analysis shows the sblepr clustered within the teleost leptin receptor group in 100% of the bootstrap replicates. The neuroanatomical localization of sblepr expressing cells has been assessed by in situ hybridization in brains of sea bass of both sexes during their first sexual maturation. At histological level, the distribution pattern of sblepr expressing cells in the brain shows no clear differences regarding sex or reproductive season. Transcripts of the sblepr have a widespread distribution throughout the forebrain and midbrain until the caudal portion of the hypothalamus. A high hybridization signal is detected in the telencephalon, preoptic area, medial basal and caudal hypothalamus and in the pituitary gland. In a more caudal region, sblepr expressing cells are identified in the longitudinal torus. The expression pattern observed for sblepr suggests that in sea bass, leptin is very likely to be involved in the control of food intake, energy reserves and reproduction
ISSN: 0016-6480

hal-01290500
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01290500
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01290500/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01290500/file/Leptin%20receptor%20gene%20in%20the%20European%20sea%20bass%20postprint.pdf
DOI : 10.1016/j.ygcen.2016.03.017

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Ghrelin is a gut-brain peptide hormone, which binds to the growth hormone secretagogue receptor (GHS-R) to regulate a wide variety of biological processes in fish. Despite these prominent physiological roles, no studies have reported the anatomical distribution of preproghrelin transcripts using in situ hybridization in a non-mammalian vertebrate, and its mapping within the different encephalic areas remains unknown. Similarly, no information is available on the possible 24-h variations in the expression of preproghrelin and its receptor in any vertebrate species. The first aim of this study was to investigate the anatomical distribution of ghrelin and GHS-R1a ghrelin receptor subtype in brain and gastrointestinal tract of goldfish (Carassius auratus) using immunohistochemistry and in situ hybridization. Our second aim was to characterize possible daily variations of preproghrelin and ghs-r1 mRNA expression in central and peripheral tissues using real-time reverse transcription-quantitative PCR. Results show ghrelin expression and immunoreactivity in the gastrointestinal tract, with the most abundant signal observed in the mucosal epithelium. These are in agreement with previous findings on mucosal cells as the primary synthesizing site of ghrelin in goldfish. Ghrelin receptor was observed mainly in the hypothalamus with low expression in telencephalon, pineal and cerebellum, and in the same gastrointestinal areas as ghrelin. Daily rhythms in mRNA expression were found for preproghrelin and ghs-r1 in hypothalamus and pituitary with the acrophase occurring at nighttime. Preproghrelin, but not ghs-r1a, displayed a similar daily expression rhythm in the gastrointestinal tract with an amplitude 3-fold higher than the rest of tissues. Together, these results described for the first time in fish the mapping of preproghrelin and ghrelin receptor ghs-r1a in brain and gastrointestinal tract of goldfish, and provide the first evidence for a daily regulation of both genes expression in such locations, suggesting a possible connection between the ghrelinergic and circadian systems in teleosts
ISSN: 1932-6203

hal-01225511
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01225511
DOI : 10.1371/journal.pone.0141043
PUBMED : 26506093

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
This study, conducted in the brain of a perciform fish, the European sea bass, aimed at raising antibodies against the precursor of the kisspeptins in order to map the kiss systems and to correlate the expression of kisspeptins, kiss1 and kiss2, with that of kisspeptin receptors (kiss-R1 and kiss-R2). Specific antibodies could be raised against the preprokiss2, but not the preoprokiss1. The data indicate that kiss2 neurons are mainly located in the hypothalamus and project widely to the subpallium and pallium, the preoptic region, the thalamus, the pretectal area, the optic tectum, the torus semicircularis, the mediobasal medial and caudal hypothalamus, and the neurohypophysis. These results were compared to the expression of kiss-R1 and kiss-R2 messengers, indicating a very good correlation between the wide distribution of Kiss2-positive fibers and that of kiss-R2 expressing cells. The expression of kiss-R1 messengers was more limited to the habenula, the ventral telencephalon and the proximal pars distalis of the pituitary. Attempts to characterize the phenotype of the numerous cells expressing kiss-R2 showed that neurons expressing tyrosine hydroxylase, neuropeptide Y and neuronal nitric oxide synthase are targets for kisspeptins, while GnRH1 neurons did not appear to express kiss-R1 or kiss-R2 messengers. In addition, a striking result was that all somatostatin-positive neurons expressed-kissR2. These data show that kisspeptins are likely to regulate a wide range of neuronal systems in the brain of teleosts.
ISSN: 1932-6203

hal-00877315
https://hal.archives-ouvertes.fr/hal-00877315
https://hal.archives-ouvertes.fr/hal-00877315/document
https://hal.archives-ouvertes.fr/hal-00877315/file/Expressionsur Kisspeptins-accepted.pdf
DOI : 10.1371/journal.pone.0070177

Éditeur(s) : HAL CCSD
Résumé : International audience
In two swordtail species of the genus Xiphophorus, the onset of puberty has been shown to be modulated at the P locus by sequence polymorphism and gene copy-number variation affecting the type 4 melanocortin hormone receptor Mc4r. The system works through the interaction of two allelic types, one encoding wild type and the other dominant-negative receptors. We have analyzed the structure and evolution of the P locus in the platyfish Xiphophorus maculatus, where as many as nine alleles of P determining the onset of sexual maturity in males and females, fecundity in females, and adult size in males are located on both the X and Y chromosomes in a region linked to the master sex-determining locus. In this species, mc4r has been amplified to up to 10 copies on both the X and Y chromosomes through recent large serial duplications. Subsequently, mc4r paralogues have diverged considerably into many different subtypes. Certain copies have acquired new untranslated regions through genomic rearrangements, and transposable element insertions and other mutations have accumulated in promoter regions, possibly explaining observed deviations from the classical mc4r transcriptional pattern. In the mc4r-coding sequence, in-frame insertions and deletions as well as nonsense and missense mutations have generated a high diversity of Mc4r-predicted proteins. Most of these variants are expressed in embryos, adults, and/or tumors. Functional receptor characterization demonstrated major divergence in pharmacological behavior for Mc4r receptors encoded by different copies of platyfish mc4r, with differences in constitutive activity as well as binding and stimulation by hormones. The high degree of allelic and copy-number variation observed between individuals can explain the high level of polymorphism for sexual maturation, fecundity, and body size in the platyfish: multiple combinations of Mc4r variants with different biochemical properties might interact to modulate the melanocortin signaling that regulates the hypothalamus-pituitary-gonadal axis.
GENETICS

hal-01544912
https://hal.archives-ouvertes.fr/hal-01544912
DOI : 10.1534/genetics.113.155952

Éditeur(s) : HAL CCSD
Résumé : International audience
Selective serotonin reuptake inhibitor medications (SSRIs) are the first lines of treatment for maternal affective disorders, and are prescribed to up to 10% of pregnant women. Concern has been raised about how perinatal exposure to these medications affect offspring neurobehavioral outcomes, particularly those related to social interactions, as recent research has reported conflicting results related to autism spectrum disorder (ASD) risk in children prenatally exposed to SSRIs. Therefore, the aim of this work was to investigate the effects of perinatal exposure to the SSRI fluoxetine on social play behaviors and the hypothalamic pituitary adrenal system, using a model of pre-gestational maternal stress. We also investigated synaptic proteins in the CA2, CA3, and dentate gyrus of the hippocampus, as well as number of immature neurons in the granule cell layer, as both measures of plasticity in the hippocampus have been linked to social behaviors. In pre-adolescent male and female Sprague-Dawley rat offspring, main findings show that perinatal fluoxetine prevents the negative effect of maternal stress on sibling play behavior. However, perinatal fluoxetine increased social aggressive play with a novel conspecific in both sexes and decreased time grooming a novel conspecific in males only. Perinatal fluoxetine also increased serum corticosteroid binding globulin levels, 5-HT levels in the hippocampus, and pre-synaptic density assessed via synaptophysin in the dentate gyrus. Social interaction was significantly correlated with changes in plasticity in the CA2 region of the hippocampus. Pre-gestational maternal stress exposure resulted in significantly decreased rates of hippocampal neurogenesis and synaptophysin density in the dentate gyrus of pre-adolescent males, but not females. Together, these results further characterize the role of perinatal SSRIs, maternal stress prior to conception, and sex/gender on developing social behaviors and related plasticity in the hippocampus of pre-adolescent offspring.
Psychoneuroendocrinology

hal-01579611
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01579611
DOI : 10.1016/j.psyneuen.2017.07.480
PUBMED : 28735226

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Anti-Müllerian hormone (AMH) plays crucial roles in sexual differentiation and gonadal functions. However, the possible extragonadal effects of AMH on the hypothalamic-pituitary-gonadal axis remain unexplored. Here we demonstrate that a significant subset of GnRH neurons both in mice and humans express the AMH receptor, and that AMH potently activates the GnRH neuron firing in mice. Combining in vivo and in vitro experiments, we show that AMH increases GnRH-dependent LH pulsatility and secretion, supporting a central action of AMH on GnRH neurons. Increased LH pulsatility is an important pathophysiological feature in many cases of polycystic ovary syndrome (PCOS), the most common cause of female infertility, in which circulating AMH levels are also often elevated. However, the origin of this dysregulation remains unknown. Our findings raise the intriguing hypothesis that AMH-dependent regulation of GnRH release could be involved in the pathophysiology of fertility and could hold therapeutic potential for treating PCOS
ISSN: 2041-1723

hal-01259206
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01259206
DOI : 10.1038/ncomms10055
PUBMED : 26753790