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The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), which is crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. Whole-exome sequencing was performed on a cohort of 341 probands with congenital hypogonadotropic hypogonadism to identify ultrarare variants in NOS1 . The activity of the identified NOS1 mutant proteins was assessed by their ability to promote nitrite and cGMP production in vitro. In addition, physiological and pharmacological characterization was carried out in a Nos1 -deficient mouse model. We identified five heterozygous NOS1 loss-of-function mutations in six probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss, and intellectual disability. NOS1 was found to be transiently expressed by GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects in sexual maturation as well as in olfaction, hearing, and cognition. The pharmacological inhibition of NO production in postnatal mice revealed a critical time window during which Nos1 activity shaped minipuberty and sexual maturation. Inhaled NO treatment at minipuberty rescued both reproductive and behavioral phenotypes in Nos1 -deficient mice. In summary, lack of NOS1 activity led to GnRH deficiency associated with sensory and intellectual comorbidities in humans and mice. NO treatment during minipuberty reversed deficits in sexual maturation, olfaction, and cognition in Nos1 mutant mice, suggesting a potential therapy for humans with NO deficiency.

International audience; At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction—gonadotropin-releasing hormone (GnRH)—and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.

In adult mammals, neural stem cells emerge in three neurogenic regions, the subventricular zone of the lateral ventricle (SVZ), the subgranular zone of the dentate gyrus of the hippocampus (SGZ) and the hypothalamus. In the SVZ and the SGZ, neural stem/progenitor cells (NSPCs) express the glial fibrillary acidic protein (GFAP) and selective ablation of these NSPCs drastically decreases cell proliferation in vitro and in vivo. In the hypothalamus, GFAP is expressed by α-tanycytes, which are specialized radial glia-like cells in the wall of the third ventricle. To explore the role of these hypothalamic GFAP-positive tanycytes, we used transgenic mice expressing herpes simplex virus thymidine kinase (HSV-Tk) under the control of the mouse Gfap promoter and 4-week intracerebroventricular infusion of the antiviral agent ganciclovir (GCV) that kills dividing cells expressing Tk. While GCV drastically reduced the number and growth of hypothalamus-derived neurospheres from adult transgenic mice in vitro, it caused hypogonadism in vivo. The selective death of dividing tanycytes expressing GFAP indeed caused a marked decrease in testosterone levels and testicular weight, as well as vacuolization of the seminiferous tubules and loss of spermatogenesis. In addition, GCV-treated GFAP-Tk mice showed impaired sexual behavior, but no alteration in food intake or body weight. Our results also show that the selective ablation of GFAP-expressing tanycytes leads to a sharp decrease in the number of gonadotropin-releasing hormone (GnRH)-immunoreactive neurons and blunted LH secretion. Altogether, our data show that GFAP-expressing tanycytes play a central role in the regulation of male reproductive function.Main pointsKilling adult hypothalamic GFAP-expressing cells blunts neurosphere formation in vitro and leads to GnRH deficiency and hypogonadism in vivo. This work pinpoints an unreported role of dividing GFAP-expressing tanycytes in reproductive function.

A large proportion of the population suffers from endocrine disruption, e.g., menopausal women, which might result in accelerated aging and a higher risk for developing cognitive disorders. Therefore, it is crucial to fully understand the impact of such disruptions on the brain to identify potential therapeutic strategies. Here, we show using resting-state functional magnetic resonance imaging that ovariectomy and consequent hypothalamus-pituitary-gonadal disruption result in the selective dysconnectivity of 2 discrete brain regions in mice. This effect coincided with cognitive deficits and an underlying pathological molecular phenotype involving an imbalance of neurodevelopmental/neurodegenerative signaling. Furthermore, this quantitative mass spectrometry proteomics-based analysis of molecular signaling patterns further identified a strong involvement of altered dopaminergic functionality (e.g., DAT and predicted upstream regulators DRD3, NR4A2), reproductive signaling (e.g., Srd5a2), rotatin expression (rttn), cellular aging (e.g., Rxfp3, Git2), myelination, and axogenesis (e.g., Nefl, Mag). With this, we have provided an improved understanding of the impact of hypothalamus-pituitary-gonadal dysfunction and highlighted the potential of using a highly translational magnetic resonance imaging technique for monitoring these effects on the brain.

Premenopausal bilateral ovariectomy is considered to be one of the risk factors of Alzheimer's disease (AD). However, the underlying mechanisms remain unclear. Here, we aimed to investigate long-term neurological consequences of ovariectomy in a rodent AD model, TG2576 (TG), and wild-type mice (WT) that underwent an ovariectomy or sham-operation, using in vivo MRI biomarkers. An increase in osmoregulation and energy metabolism biomarkers in the hypothalamus, a decrease in white matter integrity, and a decrease in the resting-state functional connectivity was observed in ovariectomized TG mice compared to sham-operated TG mice. In addition, we observed an increase in functional connectivity in ovariectomized WT mice compared to sham-operated WT mice. Furthermore, genotype (TG vs. WT) effects on imaging markers and GFAP immunoreactivity levels were observed, but there was no effect of interaction (Genotype xSurgery) on amyloid-beta-and GFAP immunoreactivity levels. Taken together, our results indicated that both genotype and ovariectomy alters imaging biomarkers associated with AD. (C) 2021 Elsevier Inc. All rights reserved.

In female mammals, cycles in reproductive function depend both on the biological clock synchronized to the light/dark cycle and on a balance between the negative and positive feedbacks of estradiol, whose concentration varies during oocyte maturation. In women, studies report that chronodisruptive environments such as shiftwork may impair fertility and gestational success. The objective of this study was to explore the effects of shifted light/dark cycles on both the robustness of the estrous cycles and the timing of the preovulatory luteinizing hormone (LH) surge in female mice. When mice were exposed to a single 10-hour phase advance or 10-hour phase delay, the occurrence and timing of the LH surge and estrous cyclicity were recovered at the third estrous cycle. By contrast, when mice were exposed to chronic shifts (successive rotations of 10-hoursour phase advances for 3 days followed by 10-hour phase delays for 4 days), they exhibited a severely impaired reproductive activity. Most mice had no preovulatory LH surge at the beginning of the chronic shifts. Furthermore, the gestational success of mice exposed to chronic shifts was reduced, because the number of pups was 2 times lower in shifted than in control mice. In conclusion, this study reports that exposure of female mice to a single phase shift has minor reproductive effects, whereas exposure to chronically disrupted light/dark cycles markedly impairs the occurrence of the preovulatory LH surge, leading to reduced fertility.