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1.
Neurosci Lett ; : 135852, 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33785380

RESUMO

Testosterone (T) exerts anxiolytic effects through functional androgen receptors (ARs) in rodents. T treatment of castrated mice reduces anxiety-like behavior in wild-type (WT) males, but not males with a spontaneous mutation that renders AR dysfunctional (testicular feminization mutation, Tfm). Using Cre-LoxP technology we created males carrying induced dysfunctional AR allele (induced TFM; iTfm) to determine the brain regions responsible for T-induced anxiolysis. Adult WT and iTfm mice were castrated and T treated. Castrated WTs given a blank capsule (WT + B) served as additional controls. Mice were later exposed to the anxiogenic light/dark box, sacrificed and their brains processed for immediate early gene cFos immunoreactivity. Analyses revealed that T treatment increased cFos-expressing neurons in the basolateral amygdala (blAMY) of WT males, but not in iTfm males, which did not differ from WT + B mice. In contrast, WT + T males displayed fewer cFos + cells than iTfm + T or WT + B groups in the suprachiasmatic nucleus of the hypothalamus (SCN). No effects of genotype or hormone were seen in cFos expression in the hippocampus, medial prefrontal cortex, paraventricular nucleus of the hypothalamus, oval and anterodorsal bed nucleus of the stria terminalis, or dorsal periaqueductal grey. AR immunohistochemistry indicated that ∼65% of cells in the blAMY and SCN were AR + in WT males, so AR could act directly within neurons in these regions to modulate the animals' response to anxiogenic stimuli. Because absence of a functional AR did not affect cFos response to mild stress in the other brain regions, they are unlikely to mediate androgen's anxiolytic effects.

2.
Horm Behav ; 127: 104886, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33202246

RESUMO

Circulating gonadal hormones have been linked to variation in the structure and function of the adult human brain, raising the question of how cognition is affected by sex hormones in adulthood. The impacts of progestogens and estrogens are of special interest due to the widespread use of hormone supplementation. Multiple studies have analyzed relationships between ovarian hormones and mental rotation performance, one of the largest known cognitive sex differences; however, results are conflicting. These discrepancies are likely due in part to modest sample sizes and reliance on self-report measures to assess menstrual cycle phase. The present study aimed to clarify the impact of progestogens and estrogens on visuospatial cognition by relating mental rotation task performance to salivary hormone concentrations. Across two studies totaling 528 naturally-cycling premenopausal women, an internal meta-analysis suggested a small, positive effect of within-subjects changes in progesterone on MRT performance (estimate = 0.44, p = 0.014), though this result should be interpreted with caution given multiple statistical analyses. Between-subjects differences and within-subject changes in estradiol did not significantly predict MRT. These results shed light on the potential cognitive effects of endogenous and exogenous hormone action, and the proximate mechanisms modulating spatial cognition.

3.
Psychoneuroendocrinology ; 119: 104733, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32563936

RESUMO

Evidence suggests that psychosexuality in humans is modulated by both organizational effects of prenatal and peripubertal sex steroid hormones, and by activational effects of circulating hormones in adulthood. Experimental work in male rodents indicates that sensitivity to androgen-driven organization of sexual motivation decreases across the pubertal window, such that earlier puberty leads to greater sex-typicality. We test this hypothesis in typically developing men (n = 231) and women (n = 648), and in men (n = 72) and women (n = 32) with isolated GnRH deficiency (IGD), in whom the precise timing of peripubertal hormone exposure can be ascertained via the age at which hormone replacement therapy (HRT) was initiated. Psychosexuality was measured with the Sexual Desire Inventory-2 (SDI-2) and Sociosexual Orientation Inventory-Revised (SOI-R). In both sexes, earlier recalled absolute pubertal timing predicted higher psychosexuality in adulthood, although the magnitude of these associations varied with psychosexuality type and group (i.e., typically developing and IGD). Results were robust when controlling for circulating steroid hormones in typically developing participants. Age of initiation of HRT in men with IGD negatively predicted SOI-R. We discuss the clinical implications of our findings for conditions in which pubertal timing is medically altered.

4.
J Physiol ; 598(13): 2719-2739, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32306402

RESUMO

KEY POINTS: Muscle-derived neurotrophic factors may offer therapeutic promise for treating neuromuscular diseases. We report that a muscle-derived neurotrophic factor, BDNF, rescues synaptic and muscle function in a muscle-type specific manner in mice modelling Kennedy's disease (KD). We also find that BDNF rescues select molecular mechanisms in slow and fast muscle that may underlie the improved cellular function. We also report for the first time that expression of BDNF, but not other members of the neurotrophin family, is perturbed in muscle from patients with KD. Given that muscle BDNF had divergent therapeutic effects that depended on muscle type, a combination of neurotrophic factors may optimally rescue neuromuscular function via effects on both pre- and postsynaptic function, in the face of disease. ABSTRACT: Deficits in muscle brain-derived neurotrophic factor (BDNF) correlate with neuromuscular deficits in mouse models of Kennedy's disease (KD), suggesting that restoring muscle BDNF might restore function. To test this possibility, transgenic mice expressing human BDNF in skeletal muscle were crossed with '97Q' KD mice. We found that muscle BDNF slowed disease, doubling the time between symptom onset and endstage. BDNF also improved expression of genes in muscle known to play key roles in neuromuscular function, including counteracting the expression of neonatal isoforms induced by disease. Intriguingly, BDNF's ameliorative effects differed between muscle types: synaptic strength was rescued only in slow-twitch muscle, while contractile strength was improved only in fast-twitch muscle. In sum, muscle BDNF slows disease progression, rescuing select cellular and molecular mechanisms that depend on fibre type. Muscle BDNF expression was also affected in KD patients, reinforcing its translational and therapeutic potential for treating this disorder.

5.
Horm Behav ; 121: 104712, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32059854

RESUMO

Experiments in male rodents demonstrate that sensitivity to the organizational effects of steroid hormones decreases across the pubertal window, with earlier androgen exposure leading to greater masculinization of the brain and behavior. Similarly, some research suggests the timing of peripubertal exposure to sex steroids influences aspects of human psychology, including visuospatial cognition. However, prior studies have been limited by small samples and/or imprecise measures of pubertal timing. We conducted 4 studies to clarify whether the timing of peripubertal hormone exposure predicts performance on male-typed tests of spatial cognition in adulthood. In Studies 1 (n = 1095) and 2 (n = 173), we investigated associations between recalled pubertal age and spatial cognition in typically developing men, controlling for current testosterone levels in Study 2. In Study 3 (n = 51), we examined the relationship between spatial performance and the age at which peripubertal hormone replacement therapy was initiated in a sample of men with Isolated GnRH Deficiency. Across Studies 1-3, effect size estimates for the relationship between spatial performance and pubertal timing ranged from. -0.04 and -0.27, and spatial performance was unrelated to salivary testosterone in Study 2. In Study 4, we conducted two meta-analyses of Studies 1-3 and four previously published studies. The first meta-analysis was conducted on correlations between spatial performance and measures of the absolute age of pubertal timing, and the second replaced those correlations with correlations between spatial performance and measures of relative pubertal timing where available. Point estimates for correlations between pubertal timing and spatial cognition were -0.15 and -0.12 (both p < 0.001) in the first and second meta-analyses, respectively. These associations were robust to the exclusion of any individual study. Our results suggest that, for some aspects of neural development, sensitivity to gonadal hormones declines across puberty, with earlier pubertal hormone exposure predicting greater sex-typicality in psychological phenotypes in adulthood. These results shed light on the processes of behavioral and brain organization and have implications for the treatment of IGD and other conditions wherein pubertal timing is pharmacologically manipulated.

6.
Horm Behav ; 120: 104686, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32014464

RESUMO

On average, the length of the index finger (digit 2) divided by the length of the ring finger (digit 4) on the right hand, is greater in women than in men. Converging evidence makes it clear that prenatal androgens affect the development of digit ratios in humans and so are likely responsible for this sex difference. Thus, differences in 2D:4D between groups within a sex may be due to average differences between those groups in prenatal androgen exposure. There have been many reports that lesbians, on average, have a smaller (more masculine) digit ratio than straight women, which has been confirmed by metaanalysis. These findings indicate that lesbians were, on average, exposed to greater prenatal androgen than straight women, which further indicates that greater levels of prenatal androgen predispose humans to be attracted to women in adulthood. Nevertheless, these results only apply to group differences between straight women and lesbians; digit ratios cannot be used to classify individual women as gay or straight.

7.
Horm Behav ; 119: 104647, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31778719

RESUMO

Relatively little is known about the effects of endogenous and exogenous steroid hormones on ecologically relevant behavioral and cognitive phenotypes in women, such as emotion recognition, despite the widespread use of steroid hormone-altering hormonal contraceptives (HCs). Though some previous studies have examined the effect of HC use, estradiol, progesterone, and testosterone on emotion recognition in women, they have been limited by cross-sectional designs, small sample sizes (total n < 100), and compromised statistical power to detect significant effects. Using data from two test sessions in a large sample of naturally cycling women (NC; n = 192) and women on HCs (n = 203), we found no group differences in emotion recognition; further, the lack of group differences in emotion recognition was not modulated by item difficulty or emotional valence. Among NC women who provided saliva samples across two sessions that were assayed for estradiol and progesterone concentrations, we found no compelling evidence across models that between-subject differences and within-subject fluctuations in these ovarian hormones predicted emotion recognition accuracy, with the exception that between-subjects estradiol negatively predicted emotion recognition for emotions of neutral valence (p = .042). Among HC women who provided saliva samples across two sessions that were assayed for testosterone, we found no compelling evidence that between-subjects differences and within-subject fluctuations in testosterone predicted emotion recognition accuracy. Overall, our analyses provide little support for the idea that circulating endogenous or exogenous ovarian hormones influence emotion recognition in women.


Assuntos
Anticoncepcionais Orais Hormonais/farmacologia , Inteligência Emocional/efeitos dos fármacos , Hormônios Esteroides Gonadais/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Adulto , Estudos Transversais , Inteligência Emocional/fisiologia , Emoções , Estradiol/análise , Estradiol/metabolismo , Feminino , Hormônios Esteroides Gonadais/análise , Humanos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Progesterona/análise , Progesterona/metabolismo , Reconhecimento Psicológico/fisiologia , Saliva/química , Saliva/metabolismo , Testosterona/análise , Testosterona/metabolismo , Adulto Jovem
8.
Science ; 365(6450): 230, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31320528

Assuntos
Dedos , Mãos
9.
J Neuroendocrinol ; 31(8): e12760, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31233647

RESUMO

Oxytocin (OT) often regulates social behaviours in sex-specific ways, and this may be a result of sex differences in the brain OT system. Adult male rats show higher OT receptor (OTR) binding in the posterior bed nucleus of the stria terminalis (pBNST) than adult female rats. In the present study, we investigated the mechanisms that lead to this sex difference. First, we found that male rats have higher OTR mRNA expression in the pBNST than females at postnatal day (P) 35 and P60, which demonstrates the presence of the sex difference in OTR binding density at message level. Second, the sex difference in OTR binding density in the pBNST was absent at P0 and P3, but was present by P5. Third, systemic administration of the oestrogen receptor (ER) antagonist fulvestrant at P0 and P1 dose-dependently reduced OTR binding density in the pBNST of 5-week-old male rats, but did not eliminate the sex difference in OTR binding density. Fourth, pBNST-OTR binding density was lower in androgen receptor (AR) deficient genetic male rats compared to wild-type males, but higher compared to wild-type females. Finally, systemic administration of the histone deacetylase inhibitor valproic acid at P0 and P1 did not alter pBNST-OTR binding density in 5-week-old male and female rats. Interestingly, neonatal ER antagonism, AR deficiency, and neonatal valproic acid treatment each eliminated the sex difference in pBNST size. Overall, we demonstrate a role for neonatal ER and AR activation in setting up the sex difference in OTR binding density in the pBNST, which may underlie sexual differentiation of the pBNST and social behaviour.


Assuntos
Androgênios/farmacologia , Estrogênios/farmacologia , Receptores de Ocitocina/genética , Núcleos Septais/efeitos dos fármacos , Núcleos Septais/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Ocitocina/farmacologia , Ratos , Ratos Long-Evans , Ratos Wistar , Receptores Androgênicos/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Ocitocina/metabolismo , Caracteres Sexuais , Comportamento Social
10.
Arch Sex Behav ; 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31016493

RESUMO

Primate same-sex sexual behavior (SSSB) is rarely observed in strepsirrhine species, and only somewhat more common in platyrrhines, but is observed in nearly all catarrhine species, including humans, suggesting the common catarrhine ancestor as the origin of routine SSSB. In mice, disruption of the transient receptor potential cation channel 2 (TRPC2) gene, which is crucial for transducing chemosensory signals from pheromones in the vomeronasal organ, greatly increased the likelihood of SSSB. We note that catarrhine primates share a common deleterious mutation in this gene, indicating that the protein was dysfunctional in the common catarrhine ancestral primate approximately 25 mya (million years ago). We hypothesize that the loss of this protein for processing pheromonal signals in males and females made SSSB more likely in a primate ancestral species by effectively lifting a pheromonally mediated barrier to SSSB and that this was an important precursor to the evolution of such behavior in humans. Additional comparisons between SSSB and the functional status of the TRPC2 gene or related proteins across primate species could lend support to or falsify this hypothesis. Our current research indicates that loss of TRPC2 function in developing mice leads to the loss or attenuation of sexually dimorphisms in the adult brain, which may help us to understand the biological underpinnings of SSSB. Our hypothesis offers an ultimate evolutionary explanation for SSSB in humans.

11.
Int J Mol Sci ; 20(6)2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875922

RESUMO

Spinal bulbar muscular atrophy (SBMA) is a slowly progressive, androgen-dependent neuromuscular disease in men that is characterized by both muscle and synaptic dysfunction. Because gene expression in muscle is heterogeneous, with synaptic myonuclei expressing genes that regulate synaptic function and extrasynaptic myonuclei expressing genes to regulate contractile function, we used quantitative PCR to compare gene expression in these two domains of muscle from three different mouse models of SBMA: the "97Q" model that ubiquitously expresses mutant human androgen receptor (AR), the 113Q knock-in (KI) model that expresses humanized mouse AR with an expanded glutamine tract, and the "myogenic" model that overexpresses wild-type rat AR only in skeletal muscle. We were particularly interested in neurotrophic factors because of their role in maintaining neuromuscular function via effects on both muscle and synaptic function, and their implicated role in SBMA. We confirmed previous reports of the enriched expression of select genes (e.g., the acetylcholine receptor) in the synaptic region of muscle, and are the first to report the synaptic enrichment of others (e.g., glial cell line-derived neurotrophic factor). Interestingly, all three models displayed comparably dysregulated expression of most genes examined in both the synaptic and extrasynaptic domains of muscle, with only modest differences between regions and models. These findings of comprehensive gene dysregulation in muscle support the emerging view that skeletal muscle may be a prime therapeutic target for restoring function of both muscles and motoneurons in SBMA.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular Espinal/genética , Receptores Androgênicos/genética , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Atrofia Muscular Espinal/metabolismo , Ratos , Receptores Androgênicos/metabolismo
13.
Biol Sex Differ ; 9(1): 32, 2018 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-30001741

RESUMO

BACKGROUND: Our previous study revealed that adult female rats respond differently to trauma than adult males, recapitulating sex differences in symptoms of post-traumatic stress disorder (PTSD) exhibited by women and men. Here, we asked two questions: does the female phenotype depend on (1) social housing condition and/or (2) circulating gonadal hormones? METHODS: For the first study, the effects of single prolonged stress (SPS) were compared for females singly or pair-housed. For the second study, adult male and female rats were gonadectomized or sham-gonadectomized 2 weeks prior to exposure to SPS, with half the gonadectomized rats given testosterone. In addition to the typical measures of the trauma response in rats, acoustic startle response (ASR), and the dexamethasone suppression test (DST), we also used two other measures typically used to assess depressive-like responses, social interaction and sucrose preference. Glucocorticoid receptor (GR) expression in the hypothalamus was also examined. RESULTS: We now report that the distinct trauma response of female rats is not influenced by social housing condition. Moreover, sex differences in the response to SPS based on ASR and DST, replicated in the current study, are independent of adult gonadal hormones. Regardless of hormonal status, traumatized males show a hyper-responsive phenotype whereas traumatized females do not. Moreover, testosterone treatment in adulthood did not masculinize the response to trauma in females. Notably, both sucrose preference and social interaction tests revealed an effect of trauma in females but not in males, with the effects of SPS on sucrose preference dependent on ovarian hormones. Effects of SPS on GR expression in the hypothalamus also depended on gonadal hormones in females. CONCLUSIONS: We propose that the trauma response for female rats is depressive in nature, recapitulating the female bias in PTSD for internalizing symptoms and major depression in contrast to the externalizing symptoms of males. Presumed core markers of PTSD (enhanced ASR and negative feedback control of corticosterone) are apparently relevant only to males and are independent of adult gonadal hormones. Such sex differences in trauma responding are likely determined earlier in life. We conclude that males and females show fundamentally different responses to trauma that do not simply reflect differences in resilience.


Assuntos
Hormônios Gonadais/fisiologia , Caracteres Sexuais , Estresse Psicológico , Anedonia , Animais , Encéfalo/metabolismo , Dexametasona/administração & dosagem , Éter/administração & dosagem , Feminino , Relações Interpessoais , Masculino , Ratos Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Reflexo de Sobressalto , Restrição Física , Estresse Fisiológico , Natação
14.
Biol Sex Differ ; 9(1): 31, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29976248

RESUMO

BACKGROUND: Post-traumatic stress disorder (PTSD) affects men and women differently. Not only are women twice as likely as men to develop PTSD, they experience different symptoms and comorbidities associated with PTSD. Yet the dearth of preclinical research on females leaves a notable gap in understanding the underlying neuropathology of this sex difference. METHODS: Using two standard measures of PTSD-like responses in rats, the acoustic startle response (ASR) and dexamethasone suppression test (DST), we tested the effects of traumatic stress in adult male and female rats using two rodent models of PTSD, single prolonged stress and predator exposure. We then examined the neural correlates underlying these responses with cFos and glucocorticoid receptor immunohistochemistry in brain regions implicated in the traumatic stress response. RESULTS: We now report that adult male and female rats across two models of PTSD show consistent sex-specific responses that recapitulate fundamental differences of PTSD in men and women. Trauma-exposed males showed the well-established hyper-responsive phenotype of enhanced ASR and exaggerated negative feedback control of the hypothalamic-pituitary-adrenal axis, while the same traumatic event had little effect on these same measures in females. Dramatic sex differences in how trauma affected cFos and glucocorticoid receptor expression in the brain lend further support to the idea that the trauma response of male and female rats is fundamentally different. CONCLUSIONS: Two standard measures, ASR and DST, might suggest that females are resilient to the effects of traumatic stress, but other measures make it clear that females are not resilient, but simply respond differently to trauma. The next important question to answer is why. We conclude that males and females show fundamentally different responses to trauma that do not simply reflect differences in resilience. The divergent effects of trauma in the brains of males and females begin to shed light on the neurobiological underpinnings of these sex differences, paving the way for improved diagnostics and therapeutics that effectively treat both men and women.


Assuntos
Caracteres Sexuais , Estresse Psicológico , Animais , Encéfalo/metabolismo , Dexametasona/administração & dosagem , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Reflexo de Sobressalto , Transtornos de Estresse Pós-Traumáticos , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia
15.
Hum Mol Genet ; 27(14): 2425-2442, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29897452

RESUMO

A distinguishing aspect of spinal and bulbar muscular atrophy (SBMA) is its androgen-dependence, possibly explaining why only males are clinically affected. This disease, which impairs neuromuscular function, is linked to a polyglutamine expansion mutation in the androgen receptor (AR). In mouse models of SBMA, motor dysfunction is associated with pronounced defects in neuromuscular transmission, including defects in evoked transmitter release (quantal content, QC) and fiber membrane excitability (based on the resting membrane potential, RMP). However, whether such defects are androgen-dependent is unknown. Thus, we recorded synaptic potentials intracellularly from adult muscle fibers of transgenic (Tg) AR97Q male mice castrated pre-symptomatically. Although castration largely protects both QC and the RMP of fibers, correlating with the protective effect of castration on motor function, significant deficits in QC and RMP remained. Surprisingly, comparable defects in QC and RMP were also observed in pre-symptomatic AR97Q males, indicating that such defects emerge early and are pre-clinical. Exposing asymptomatic Tg females to androgens also induces both motor dysfunction and comparable defects in QC and RMP. Notably, asymptomatic Tg females also showed significant deficits in QC and RMP, albeit less severe, supporting their pre-clinical nature, but also raising questions about the androgen-dependence of pre-clinical symptoms. In summary, current evidence indicates that disease progression depends on androgens, but early pathogenic events may be triggered by the mutant AR allele independent of androgens. Such early, androgen-independent disease mechanisms may also be relevant to females carrying the SBMA allele.


Assuntos
Androgênios/genética , Atrofia Bulboespinal Ligada ao X/fisiopatologia , Neurônios Motores/patologia , Receptores Androgênicos/genética , Androgênios/metabolismo , Animais , Atrofia Bulboespinal Ligada ao X/genética , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia
17.
Arch Sex Behav ; 46(6): 1625-1629, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28741047
18.
Arch Sex Behav ; 46(6): 1583-1592, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28176027

RESUMO

In non-human vertebrate species, sexual differentiation of the brain is primarily driven by androgens such as testosterone organizing the brains of males in a masculine fashion early in life, while the lower levels of androgen in developing females organize their brains in a feminine fashion. These principles may be relevant to the development of sexual orientation in humans, because retrospective markers of prenatal androgen exposure, namely digit ratios and otoacoustic emissions, indicate that lesbians, on average, were exposed to greater prenatal androgen than were straight women. Thus, the even greater levels of prenatal androgen exposure experienced by fetal males may explain why the vast majority of them grow up to be attracted to women. However, the same markers indicate no significant differences between gay and straight men in terms of average prenatal androgen exposure, so the variance in orientation in men cannot be accounted for by variance in prenatal androgen exposure, but may be due to variance in response to prenatal androgens. These data contradict several popular notions about human sexual orientation. Sexual orientation in women is said to be fluid, sometimes implying that only social influences in adulthood are at work, yet the data indicate prenatal influences matter as well. Gay men are widely perceived as under-masculinized, yet the data indicate they are exposed to as much prenatal androgen as straight men. There is growing sentiment to reject "binary" conceptions of human sexual orientations, to emphasize instead a spectrum of orientations. Yet the data indicate that human sexual orientation is sufficiently polarized that groups of lesbians, on average, show evidence of greater prenatal androgen exposure than groups of straight women, while groups of gay men have, on average, a greater proportion of brothers among their older siblings than do straight men.


Assuntos
Efeitos Tardios da Exposição Pré-Natal , Caracteres Sexuais , Diferenciação Sexual/fisiologia , Comportamento Sexual/fisiologia , Androgênios/fisiologia , Ordem de Nascimento , Feminino , Dedos/anatomia & histologia , Humanos , Masculino , Emissões Otoacústicas Espontâneas , Gravidez , Estudos Retrospectivos , Aprendizado Social , Testosterona/fisiologia
20.
Hum Mol Genet ; 25(17): 3768-3783, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27493028

RESUMO

Spinal bulbar muscular atrophy (SBMA) is a progressive, late onset neuromuscular disease causing motor dysfunction in men. While the morphology of the neuromuscular junction (NMJ) is typically affected by neuromuscular disease, whether NMJs in SBMA are similarly affected by disease is not known. Such information will shed light on whether defective NMJs might contribute to the loss of motor function and represent a potential therapeutic target for treating symptoms of SBMA. To address this gap in information, the morphology of NMJs was examined in two mouse models of SBMA, a myogenic model that overexpresses wildtype androgen receptor (AR) exclusively in muscle fibres and a knockin (KI) model expressing a humanized mutant AR gene. The tripartite motor synapse consisting of motor nerve terminal, terminal Schwann cells (tSCs) and postsynaptic specialization were visualized and analysed using confocal microscopy. Counter to expectation, we found no evidence of denervation in either model, but junctions in both models show pathological fragmentation and an abnormal synaptophysin distribution consistent with functionally weak synapses. Neurofilament accumulations were observed only in the myogenic model, even though axonal transport dysfunction is characteristic of both models. The ultrastructure of NMJs revealed additional pathology, including deficits in docked vesicles presynaptically, wider synaptic clefts, and simpler secondary folds postsynaptically. The observed pathology of NMJs in diseased SBMA mice is likely the morphological correlates of defects in synaptic function which may underlie motor impairments associated with SBMA.


Assuntos
Neurônios Motores/patologia , Atrofia Muscular Espinal/patologia , Junção Neuromuscular/patologia , Receptores Androgênicos/genética , Animais , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Atrofia Muscular Espinal/genética , Células de Schwann/patologia , Transmissão Sináptica
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