Η συμμετοχή της γενετικής, έναντι της περιβαλλοντικής επίδρασης στη συμπεριφορά αποτελεί θεμελιώδες ερώτημα για τις νευροεπιστήμες και αποτελεί πεδίο έντονου ερευνητικού ενδιαφέροντος. Η σεξουαλικότητα είναι μια σύνθετη αλληλεπίδραση πολλαπλών παραγόντων, συμπεριλαμβανομένων ανατομικών, φυσιολογικών, ψυχολογικών, αναπτυξιακών, πολιτιστικών και σχεσιακών παραγόντων. Παρά την υψηλή συχνότητα εμφάνισης της γυναικείας σεξουαλικής δυσλειτουργίας, λιγότερη έμφαση έχει δοθεί στη μελέτη της από την επιστημονική κοινότητα. Το βιολογικό και ψυχολογικό υπόβαθρό της παραμένει ένα υποσχόμενο πεδίο έρευνας καθώς οι διαθέσιμες θεραπείες είναι πολύ λιγότερες συγκριτικά με την ανδρική σεξουαλική δυσλειτουργία. Η σεξουαλική λειτουργία των γυναικών έχει μελετηθεί κατά καιρούς στο σύνδρομο των πολυκυστικών ωοθηκών, λαμβάνοντας υπόψη ερωτηματολόγια σεξουαλικής δραστηριότητας και επίπεδα φυλετικών ορμονών αλλά όχι τους γενετικούς πολυμορφισμούς που μπορεί να εμπλέκονται και να δημιουργούν συγκεκριμένο βιολογικό υπόβαθρο. Η αλληλεπίδραση ορμονών, νευροδιαβιβαστών και περιβαλλοντικών παραγόντων είναι ευρέως αποδεκτή στη διαμόρφωση του υποστρώματος της γυναικείας σεξουαλικότητας αλλά οι τρόποι παραμένουν ακόμα ασαφείς. Για το λόγο αυτό, ο σκοπός της παρούσας μελέτης ήταν η συσχέτιση των πολυμορφισμών του ανδρογονικού υποδοχέα και του υποδοχέα της βαζοπρεσίνης με τη γυναικεία σεξουαλικότητα στις γυναίκες με σύνδρομο πολυκυστικών ωοθηκών. Η επίδραση των ανδρογόνων στη γυναικεία σεξουαλικότητα αποτελεί πεδίο έντονου ερευνητικού ενδιαφέροντος καθώς οι μηχανισμοί αλληλεπίδρασης είναι ιδιαίτερα πολύπλοκοι. Τα ανδρογόνα ασκούν τη δράση τους μέσω πρόσδεσης και ενεργοποίησης των ανδρογονικών υποδοχέων. Το γονίδιο του υποδοχέα των ανδρογόνων αποτελείται από δύο μοτίβα πολυμορφικών επαναλήψεων CAG & GGN που κωδικοποιούν ποικίλου μήκους πολυγλουταμινικών και πολυγλυκινικών περιοχών αντίστοιχα. Έχει επίσης φανεί ότι το αυξημένο μήκος της CAG επαναληπτικής αλληλουχίας πιθανόν να σχετίζεται με μειωμένη δραστικότητα του AR και ως εκ τούτου και με διαταραχές που σχετίζονται με μειωμένη δράση ανδρογόνων Διάφορα νευροπεπτίδια όπως η βαζοπρεσίνη, η αδενοκορτικοτροπίνη, η ωκυτοκίνη κ.α. επιδρούν στην ενήλικο σεξουαλική συμπεριφορά διαφόρων οργανισμών. Η βαζοπρεσίνη και ο υποδοχέας της αποτέλεσαν αντικείμενο μελέτης για την ερμηνεία της ανθρώπινης κοινωνικής και σεξουαλικής συμπεριφοράς. Οι πολυμορφισμοι του AVPR έχουν επίσης σχετιστεί με αλτρουισμό, με μονογαμία και ανάπτυξη σχέσεων δεσμού, γνώση μουσικής και χορού που αντανακλούν αρχέγονες κοινωνικές αλληλεπιδράσεις όπως ιεροτελεστικές κινήσεις και επικοινωνία μέσω ήχων. Το γονίδιο του υποδοχέα της βαζοπρεσίνης διαθέτει τέσσερα μικροδορυφορικά μοτίβα. Ακολουθώντας τις μελέτες στον αρουραίο του αγρού (vole), η προσοχή έχει κυρίως επικεντρωθεί στις μικροδορυφoρικές επαναλήψεις στην περιοχή του υποκινητή. Πρόκειται για τις RS1 {(GATA)14} και RS3 {(CT)4-TT-(CT)8-(GT)24}, που είναι εξαιρετικά πολυμορφικές. Σκοπός της παρούσας εργασίας είναι η διερεύνηση της συσχέτισης της πολυμορφικής CAG περιοχής του ανδρογονικού υποδοχέα και του RS1 πολυμορφισμού του υποδοχέα της βαζοπρεσίνης με την γυναικεία σεξουαλική συμπεριφορά στο σύνδρομο των πολυκυστικών ωοθηκών. Για το λόγο αυτό η παρούσα μελέτη συμπεριέλαβε 40 γυναίκες με σύνδρομο πολυκυστικών ωοθηκών και 94 υγιείς γυναίκες, στις οποίες διενεργήθηκαν ορμονικοί προσδιορισμοί, ψυχομετρικά τεστ για αξιολόγηση της σεξουαλικής λειτουργίας τους και διερεύνηση της συσχέτισης με τα γονοτυπικά τους χαρακτηριστικά (αριθμός επαναλήψεων των πολυμορφικών μοτίβων στα αλληλόμορφά τους). Τα αποτελέσματα της παρούσας εργασίας έδειξαν ότι στην κατηγορία των γυναικών με PCOS η ενεργότητα του υποδοχέα συσχετίστηκε με μειωμένα επίπεδα oιστρογόνων και με αυξημένη ικανοποίηση, γεγονός που υποδηλώνει ότι σε καθεστώς περίσσειας ανδρογονικού ερεθίσματος η γυναικεία σεξουαλικότητα επάγεται. Επίσης στην ίδια ομάδα γυναικών φάνηκε συσχέτιση μεταξύ των υψηλών επιπέδων FSH και των υψηλών αριθμών επαναλήψεων του RS1 πολυμορφισμού, υποδεικνύοντας έναν κεντρικό ρόλο του AVPR στη ρύθμιση της ωοθυλακιορρηξίας των γυναικών με σύνδρομο πολυκυστικών ωοθηκών. / The contribution of genetic versus environmental influence in behavioral analysis is a fundamental question for neuroscience and it is also an area of strong research interest, Sexuality is distinguished by a complex interaction between anatomic, physiologic, psychological, developmental, relational and cultural factors. Despite the high frequency of sexuality disorders in women, scientists have not placed emphasis on this. The biological and psychological background of women’s sexuality disorder still remains a promising field of research, since the available therapies are fewer than those that are used in male sexual dysfunction. Female sexuality has been studied frequently in women with PCOS and has been based on questionnaires of female’s sexual functionality and serum levels of sex steroid hormones. These studies didn’t take account of the genetic polymorphisms which can be involved in a specific biological background. The interaction of hormones, neurotransmitters and environmental factors is widely accepted in the composition of female’s sexual function but the ways that this interaction happens are still unclear. Thus, the aim of our study was to consider the possible association between the genetic polymorphism of androgen receptor gene and vasopressin receptor gene and female sexuality in women with PCOS. The influence of androgens in female sexuality is a field of intense interest in the scientific community, but the ways this interaction occurs are very complicated. Androgens bind and activate androgen receptors.The androgen receptor gene consists of eight exons and encodes a protein with 919 amino acid residues. Exon 1 of the gene consists of two polymorphic repeat (CAG and GGN) motifs, encoding variable lengths of polyglutamine and polyglycine stretches, respectively. Also, it has been proposed that that the increased length of the CAG repeat should associate with decreased AR activity and hence the disorders related to the reduced androgen actions. Many neuropeptides such as vasopressin, oxytocin, adrenocorticotropic hormone (ACTH) etc, affect sexual behavior in many species. Vasopressin and it’s receptor has been well studied in order to interpret human social and sexual behavior. The genetic polymorphisms of the vasopressin receptor gene has been also associated with altruism, monogamy, pair bonding, musical and dancing ability. The latter reflects primitive social interactions such as ritual movements and vocalization. Vasopressin receptor gene is distinguished by three microsatellites in the 5’ flanking region and a fourth in the single intron. Following the vole studies, attention has been primarily focused on two microsatellites in the promoter region, RS1 {{GATA)14} and RS3 {(CT)4-TT-(CT)8-(GT)24}, which are highly polymorphic. The aim of our study is to investigate the association between the polymorphic CAG region of androgen receptor gene and RS1 polymorphism of vasopressin receptor gene with sexual behavior in women with PCOS. Thus, our study included 40 women with PCOS and 94 healthy women. We performed hormonal analysis, psychometric tests to evaluate their sexual functionality and looked into the association with their genetic characteristics (the number of repeats of polymorphic motifs in their alleles). Our results showed that androgen receptor’s activity is associated with low estrogen levels and high sexual satisfaction in women with PCOS. This indicates that in a state of androgen excess, female sexuality is induced. In the same group of women, we noted an association between high levels of FSH and a high number of repeats of RS1 polymorphism. This suggests a central role of vasopressin receptor in the regulation of ovulation in women with PCOS.

This thesis aims to study the effects of endogenous and exogenous hormones and mammographic breast density (BD) on cellular markers in non-cancerous female breast tissue. Women on the waiting list for breast reduction plastic surgery were recruited (n = 79), and randomized to 2 months of hormone therapy or no therapy before surgery. The women had a mammogram and a needle biopsy 2 months before surgery and tissue samples were obtained at the operation. In premenopausal women, estrogen receptor (ER)α levels were associated with age (p = 0.0002), were similar in the follicular and luteal phases of the menstrual cycle and were higher in parous than in nulliparous women (p = 0.009). Current smokers had lower PR levels than non-smokers (p = 0.019). Women on oral contraception had lower ERα (p = 0.048) and PR (p = 0.007) levels than women in the follicular phase. The ERα levels did not differ significantly between postmenopausal estrogen and estrogen-progestogen users, but PR levels were lower among estrogen-progestogen users (p = 0.03). We found lower expression of the genes for decorin and syndecans 1 and 4 in the luteal phase than in the follicular phase, among parous women. Protein levels of the androgen receptor, syndecan-4 and decorin was lower in premenopausal women who were using oral contraceptives (OC) than in those in the follicular phase (p = 0.002 - 0.02), whereas no significant differences between OC use and the luteal phase were found. In premenopausal women, BD was negatively associated with age and body mass index but was similar for the menstrual phases. Breast density was associated with genetic expression of the androgen receptor and remained significant after adjustment for age (rs = 0.56; p = 0.04). After adjustement for age, breast density was also marginally associated with expression of the caspase 3 gene (0.55; 0.053). However, protein levels of caspase 3 was negatively associated (-0.61; 0.03).

We investigated the gestational expression of androgen receptor (AR) and defined its regulation and that of its co-repressors, PSF and p54nrb, by steroid hormones and myometrial stretch in vivo in pregnant and non-pregnant rats. Our data demonstrate that, 1) myometrial AR expression decreases prior to term; 2) AR expression is up-regulated by MPA treatment and down-regulated by mechanical stretch; (3) myometrial PSF protein expression is down-regulated by estrogen signaling and by mechanical stretch, and up-regulated by androgen signaling; (4) while myometrial PSF mRNA expression is also down-regulated by stretch, the regulation by estrogen and P4 on PSF mRNA appear to be opposite to the effects on PSF protein. We conclude that the decreased androgen signaling in late pregnancy (as a result of decreased AR and PSF expression mediated by hormonal and mechanical signals) may contribute to the mechanisms leading to labor initiation.

We investigated the gestational expression of androgen receptor (AR) and defined its regulation and that of its co-repressors, PSF and p54nrb, by steroid hormones and myometrial stretch in vivo in pregnant and non-pregnant rats. Our data demonstrate that, 1) myometrial AR expression decreases prior to term; 2) AR expression is up-regulated by MPA treatment and down-regulated by mechanical stretch; (3) myometrial PSF protein expression is down-regulated by estrogen signaling and by mechanical stretch, and up-regulated by androgen signaling; (4) while myometrial PSF mRNA expression is also down-regulated by stretch, the regulation by estrogen and P4 on PSF mRNA appear to be opposite to the effects on PSF protein. We conclude that the decreased androgen signaling in late pregnancy (as a result of decreased AR and PSF expression mediated by hormonal and mechanical signals) may contribute to the mechanisms leading to labor initiation.

Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro / O objetivo deste estudo foi avaliar o efeito da administração de leptina no lobo ventral da próstata de ratos adultos. Vinte ratos Wistar machos e adultos foram divididos em 2 grupos: L - animais foram injetados com 50 μL diária de leptina (8 μg / 100 g PC, subcutânea) durante quatro dias e C - animais receberam o mesmo volume de solução salina. Perfil lipídico e níveis séricos de testosterona foram avaliados. O lobo ventral da próstata foi processado para análise histomorfométrica. Expressão dos genes da aromatase, receptor de andrógeno, receptores de estrógeno (α e β) e as isoformas dos receptores de leptina longa (Ob-Rb) e curta (Ob-Ra) foram avaliados por PCR em tempo real. Proliferação celular foi avaliada por imuno-histoquímica com PCNA. Os dados foram expressos como média  erro padrão e analisados pelo teste t de Student. Níveis séricos de colesterol aumentaram (C = 39,7 4,2; L = 55,2 4,2, mg / dL, P ≤ 0,02) e de testosterona (C = 1,6 0,43; L = 0,6 0,15, ng / dL, P ≤ 0,03) diminuíram no grupo L. A análise histomorfométrica mostrou uma redução na densidade de células (C = 8868 242; L = 8.211 210, mm2; P ≤ 0,04), na área total (C = 0,24 0,026; L = 0,10 0,009, mm2; P ≤ 0,001) e na área interna dos ácinos (C = 0,16 0,009; L = 0,08 0,006, mm2; P ≤ 0,0002). Por outro lado, houve um aumento na altura do epitélio (C = 17,3 0,3; L = 22,8 0,2 m, P ≤ 0,0001) e no número de ácinos (C = 7,0 0,2; L = 8,7 0,1, mm2; P ≤ 0,0002). As análises histomorfométrica juntamente com os resultados imuno-histoquímicos para PCNA sugerem que a leptina aumenta a proliferação celular. Em relação à expressão gênica, o tratamento de leptina aumentou a expressão de todos os genes, mas ER-α, em mais de 200 vezes em comparação com a expressão no grupo C. Em conclusão, neste trabalho mostramos que a leptina tem um efeito direto sobre a próstata de ratos adultos levando a um aumento na proliferação celular e na expressão gênica da aromatase, receptor de androgênio, nas isoformas dos receptores de leptina e receptores de estrogênios alfa e beta que são importantes para a fisiologia normal do tecido prostático / The aim of this study was to evaluate the effect of leptin administration on the ventral prostate lobe of adult rat. Twenty adult male rats were divided into 2 groups: L - animals were daily injected with 50 μL of leptin (8 g / 100 g BW, subcutaneous) for four days and C -animals received the same volume of saline solution. Lipid profile and testosterone serum levels were evaluated. The prostate ventral lobe was processed for histomorphometric analysis. Gene expression of aromatase, androgen receptor, leptin and estrogen receptors isoforms was evaluated by real-time PCR. Cell proliferation was evaluated by PCNA immunohistochemistry. Data were expressed as mean  standard error and analyzed by students t-test. Serum levels of cholesterol (C = 39.7 4.2; L = 55.2 4.2, mg / dL; P ≤ 0.02) increased and testosterone (C = 1.6 0.43; L = 0.6 0.15, ng / dL; P ≤ 0.03) decreased in L group. The histomorphometric analysis showed a reduction in cell density (C = 8868 242; L = 8211 210, mm2; P ≤ 0.04), in total (C = 0.24 0.026; L = 0.10 0.009, mm2; P ≤ 0.001) and in the internal acini areas (C = 0.16 0.009; L = 0.08 0.006, mm2; P ≤ 0.0002). On the other hand, there was an increase in the epithelial height (C = 17.3 0.3; L = 22.8 0.2, m; P ≤ 0.0001) and in the number of acini (C = 7.0 0.2; L = 8.7 0.1, mm2; P ≤ 0.0002). The histomorphometric analyses together with PCNA immunohistochemistry results suggest that leptin increases cell proliferation. In relation to the gene expression, leptin treatment increased the expression of all genes, but ER-α, in more than 200 times compared to the expression in C group. In conclusion, in this paper we showed that leptin has a direct effect on the prostate gland of adult rats leading to an increase in proliferation and in the gene expression of aromatase, androgen, leptin and estrogen receptors isoforms that are important for the physiology of the prostate gland.

Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro / O objetivo deste estudo foi avaliar o efeito da administração de leptina no lobo ventral da próstata de ratos adultos. Vinte ratos Wistar machos e adultos foram divididos em 2 grupos: L - animais foram injetados com 50 μL diária de leptina (8 μg / 100 g PC, subcutânea) durante quatro dias e C - animais receberam o mesmo volume de solução salina. Perfil lipídico e níveis séricos de testosterona foram avaliados. O lobo ventral da próstata foi processado para análise histomorfométrica. Expressão dos genes da aromatase, receptor de andrógeno, receptores de estrógeno (α e β) e as isoformas dos receptores de leptina longa (Ob-Rb) e curta (Ob-Ra) foram avaliados por PCR em tempo real. Proliferação celular foi avaliada por imuno-histoquímica com PCNA. Os dados foram expressos como média  erro padrão e analisados pelo teste t de Student. Níveis séricos de colesterol aumentaram (C = 39,7 4,2; L = 55,2 4,2, mg / dL, P ≤ 0,02) e de testosterona (C = 1,6 0,43; L = 0,6 0,15, ng / dL, P ≤ 0,03) diminuíram no grupo L. A análise histomorfométrica mostrou uma redução na densidade de células (C = 8868 242; L = 8.211 210, mm2; P ≤ 0,04), na área total (C = 0,24 0,026; L = 0,10 0,009, mm2; P ≤ 0,001) e na área interna dos ácinos (C = 0,16 0,009; L = 0,08 0,006, mm2; P ≤ 0,0002). Por outro lado, houve um aumento na altura do epitélio (C = 17,3 0,3; L = 22,8 0,2 m, P ≤ 0,0001) e no número de ácinos (C = 7,0 0,2; L = 8,7 0,1, mm2; P ≤ 0,0002). As análises histomorfométrica juntamente com os resultados imuno-histoquímicos para PCNA sugerem que a leptina aumenta a proliferação celular. Em relação à expressão gênica, o tratamento de leptina aumentou a expressão de todos os genes, mas ER-α, em mais de 200 vezes em comparação com a expressão no grupo C. Em conclusão, neste trabalho mostramos que a leptina tem um efeito direto sobre a próstata de ratos adultos levando a um aumento na proliferação celular e na expressão gênica da aromatase, receptor de androgênio, nas isoformas dos receptores de leptina e receptores de estrogênios alfa e beta que são importantes para a fisiologia normal do tecido prostático / The aim of this study was to evaluate the effect of leptin administration on the ventral prostate lobe of adult rat. Twenty adult male rats were divided into 2 groups: L - animals were daily injected with 50 μL of leptin (8 g / 100 g BW, subcutaneous) for four days and C -animals received the same volume of saline solution. Lipid profile and testosterone serum levels were evaluated. The prostate ventral lobe was processed for histomorphometric analysis. Gene expression of aromatase, androgen receptor, leptin and estrogen receptors isoforms was evaluated by real-time PCR. Cell proliferation was evaluated by PCNA immunohistochemistry. Data were expressed as mean  standard error and analyzed by students t-test. Serum levels of cholesterol (C = 39.7 4.2; L = 55.2 4.2, mg / dL; P ≤ 0.02) increased and testosterone (C = 1.6 0.43; L = 0.6 0.15, ng / dL; P ≤ 0.03) decreased in L group. The histomorphometric analysis showed a reduction in cell density (C = 8868 242; L = 8211 210, mm2; P ≤ 0.04), in total (C = 0.24 0.026; L = 0.10 0.009, mm2; P ≤ 0.001) and in the internal acini areas (C = 0.16 0.009; L = 0.08 0.006, mm2; P ≤ 0.0002). On the other hand, there was an increase in the epithelial height (C = 17.3 0.3; L = 22.8 0.2, m; P ≤ 0.0001) and in the number of acini (C = 7.0 0.2; L = 8.7 0.1, mm2; P ≤ 0.0002). The histomorphometric analyses together with PCNA immunohistochemistry results suggest that leptin increases cell proliferation. In relation to the gene expression, leptin treatment increased the expression of all genes, but ER-α, in more than 200 times compared to the expression in C group. In conclusion, in this paper we showed that leptin has a direct effect on the prostate gland of adult rats leading to an increase in proliferation and in the gene expression of aromatase, androgen, leptin and estrogen receptors isoforms that are important for the physiology of the prostate gland.

Abstract Human prostatic acid phosphatase (hPAP) was the first laboratory parameter used for prostate cancer diagnosis, whereas the mechanisms behind the androgen regulation and tissue-specific expression of this prostate epithelium-specific differentiation antigen are not yet clear. In this study, a transient transfection model and transgenic animal model have been set up for functional analysis of the promoter and first intron region of the hPAP gene. The promoter constructs covering the region-734/+467 of the gene were functional in both prostatic and nonprostatic cells. Although hPAP constructs included two putative AREs with in vitro AR-binding ability at -178 and +336, androgen treatment had little effect on the promoter activity of the gene in transiently transfected cells. The hPAP fragment -734/+467 could trigger the expression of the CAT reporter gene and restrict the expression mainly in the prostates of transgenic mice. The DNA-binding site with the sequence GAAAATATGATA of a regulatory protein involved in prostate-specific and androgen receptor-dependent gene expression was identified from rPB promoter. The exact same 12 bp sequence was found in the first intron +1144/+1155 of the hPAP gene. Five homologous sequence, A, B, C, D and E, were located in the -734/+467 region of the hPAP gene, where site C and E could bind the regulatory protein in EMSA. Deletion of site C decreased the transcriptional activities significantly compared to those of corresponding wild-type constructs in LNCaP cells when androgens were present. Deletion of site E or both sites D and E increased the promoter activity in LNCaP when androgens were absent. In conclusion, androgens could not directly regulate hPAP expression via receptor-binding to the AREs in LNCaP cells. The promoter and first intron fragment -734/+467 of the hPAP gene could direct and restrict the gene expression mainly in prostate epithelium. A prostatic regulatory protein binds to multiple sites with the GAAAATATGATA or homologous sequences along the regulatory areas of the hPAP gene with different affinities, modulating the prostate-specific expression of the gene in a bidirectional manner, depending on the hormone status.

No description available.

Hormis leur implication dans les fonctions de reproduction, de développement et du maintien des caractères mâles, les androgènes (principalement la testostérone et la dihydrotestostérone, DHT) sont des hormones stéroïdiennes capables d’influencer plusieurs structures et fonctions du système nerveux. En effet, durant le développement, les androgènes ont un effet masculinisant sur le système nerveux central (SNC) le rendant sexuellement dimorphique. Chez les rongeurs mâles adultes, la substance blanche est plus volumineuse et les oligodendrocytes, cellules myélinisantes du SNC, sont plus nombreux. Cette différence est abolie après castration des mâles ; ce qui suggère l'implication de la testostérone dans le dimorphisme des oligodendrocytes et de la myéline.D’une part, mon travail de thèse visait à démontrer l’implication des androgènes et de leur récepteur (AR) dans l’établissement de ce dimorphisme. Nos résultats confirment l'implication de la testostérone et démontrent que son effet est médié par AR. En effet les corps calleux (CC) des souris mâles adultes ayant un AR non fonctionnel dans l'ensemble de l'organisme (souris Tfm) ou invalidé spécifiquement dans les cellules neurales (souris ARNesCre), présentent 20 à 30% moins d'oligodendrocytes et de surfaces myélinisées que ceux des contrôles. En outre, nos résultats montrent que ce dimorphisme apparait dès le dixième jour postnatal. De manière intéressante, le traitement pharmacologique des souriceaux mâles par un antagoniste du AR (flutamide) et des souriceaux femelles par l’agoniste d'AR (la DHT), pendant les dix premiers jours après la naissance inverse respectivement leurs profils oligodendrocytaires, suggérant un rôle organisationnel d'AR dans la substance blanche.D’autre part, mon sujet consistait à montrer l'importance de la testostérone et du AR dans la réparation de la myéline dans un modèle de démyélinisation de la moelle épinière des souris par injection stéréotaxique de lysolécithine. Nos résultats montrent que le traitement pendant 4 semaines des animaux par la testostérone permet le recrutement des oligodendrocytes et la réparation de la myéline dans les zones lésées. Il est à noter (1) qu’en absence de la testostérone ou d'AR, la réparation de la myéline est inefficace et se fait par des composants de la myéline périphérique et (2)que la présence des astrocytes semble nécessaire pour l’effet remyélinisant de la testostérone. Afin de mieux comprendre le ou les mécanisme(s) d'action(s) de la testostérone et du AR dans les processus de myélinisation et de remyélinisation, nous avons réalisé une étude transcriptomique comparative entre les animaux lésés et traités ou non avec la testostérone pour déterminer les gènes cibles et les voies de signalisations impliquées dans ces processus. Les résultats permettront probablement de définir une nouvelle cible thérapeutique pour les maladies démyélinisantes telle que la sclérose en plaques. / Androgens (mainly testosterone and dihydrotestosterone, DHT) are steroid hormones that are involved in reproduction functions, development and maintenance of male characteristics. They can also influence several structures and functions of the nervous system. Indeed, during development, androgens have a masculinizing effect on the central nervous system (CNS) making it sexually dimorphic. In addition, in adult male rodents,the white matter is larger and presents more oligodendrocytes, myelinating cells of the CNS. This difference is abolished after castration of males ; witch suggests the involvement of testosterone in the dimorphism of oligodendrocytes and myelin.One aim of my thesis was to study the involvement of androgens and their receptor (AR) in the establishment of this dimorphism. Our results confirm that testosterone is involved and demonstrate that its effect is mediated by AR. Indeed, the corpus callosum (CC) of adult male mice having a non-functional AR in the entire body (Tfm mice) or invalidated specifically in neural cells, (ARNesCre mice) have 20 to 30% fewer oligodendrocytes and myelinated area than those of controls. Moreover, our results show that this dimorphism appears early during postnatal life. Interestingly, pharmacological treatment of male pups with an AR antagonist (flutamide) and female ones with an AR agonist (DHT) during the first ten days after the birth reverses their oligodendrocytic profiles. These results suggest an organizational role of the AR in the white matter development.The aim of the second part of my study was to investigate the importance of testosterone and the AR in myelin repair in a rodent model of spinal cord demyelinationby stereotactic injection of lysolecithin. Our results show that a 4 weeks testosterone treatment allows the recruitment of oligodendrocyte and myelin repair. Interestingly, in the absence of testosterone or the AR, myelin repair was ineffeciant and was done by components of peripheral myelin. Moreover, the presence of astrocytes seems necessary for the remyelinating effect of testosterone since myelin repair was confined to astrocyte populated area.An important goal of my work is to better understand the mechanism of action of testosterone and the AR in the process of myelin formation and repair. For this, we performed a comparative transcriptomic study between animals injected or not with LPC than treated or not with testosterone to determine new target genes and signaling pathways involved in these processes. The results will probably define a new therapeutic target for demyelinating diseases such as multiple sclerosis.

No description available.