Publications by authors named "Paolo Giacobini"

Article Synopsis
  • GnRH neurons in the brains of adult male mice help them recognize females and are important for reproduction.
  • These neurons can detect smells from females, like their urine, and send signals that trigger mating behaviors.
  • If these GnRH neurons don’t work properly, male mice struggle to identify female scents and may have trouble mating.
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Background: Estrogen secretion by the ovaries regulates the hypothalamic-pituitary-gonadal axis during the reproductive cycle, influencing gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion, and also plays a role in regulating metabolism. Here, we establish that hypothalamic tanycytes-specialized glia lining the floor and walls of the third ventricle-integrate estrogenic feedback signals from the gonads and couple reproduction with metabolism by relaying this information to orexigenic neuropeptide Y (NPY) neurons.

Methods: Using mouse models, including mice floxed for Esr1 (encoding estrogen receptor alpha, ERα) and those with Cre-dependent expression of designer receptors exclusively activated by designer drugs (DREADDs), along with viral-mediated, pharmacological and indirect calorimetric approaches, we evaluated the role of tanycytes and tanycytic estrogen signaling in pulsatile LH secretion, cFos expression in NPY neurons, estrous cyclicity, body-weight changes and metabolic parameters in adult females.

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Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the opposite pathway. In mice, the WNT/β-catenin pathway promotes ovarian development and the importance of actively inhibiting this pathway to ensure normal testis development has been recognised. However, the implications of alterations in the tightly regulated WNT/β-catenin signalling during human fetal gonad development has not yet been examined in detail.

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Aging is the main risk factor of cognitive neurodegenerative diseases such as Alzheimer's disease, with epigenome alterations as a contributing factor. Here, we compared transcriptomic/epigenomic changes in the hippocampus, modified by aging and by tauopathy, an AD-related feature. We show that the cholesterol biosynthesis pathway is severely impaired in hippocampal neurons of tauopathic but not of aged mice pointing to vulnerability of these neurons in the disease.

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Introduction: In humans, prenatal androgen excess can lead to a broad spectrum of pathologies in adulthood, including polycystic ovary syndrome (PCOS). Women with PCOS present a variety of reproductive and metabolic disturbances and they also face increased risk to develop neuropsychiatric disorders such as depression and anxiety. Despite the high prevalence, the cause of depressive and anxiety symptoms is not fully elucidated.

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Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age. It has a strong hereditary component estimated at 60 to 70% in daughters. It has been suggested that environmental factors during the fetal period may be involved in the development of the syndrome in adulthood.

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In recent years, the expanding roles of anti-Müllerian hormone (AMH) in various aspects of reproductive health have attracted significant attention. Initially recognized for its classical role in male sexual differentiation, AMH is produced postnatally by the Sertoli cells in the male testes and by the granulosa cells in the female ovaries. Traditionally, it was believed to primarily influence gonadal development and function.

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Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large heterogeneity of cellular distribution and transcriptomic states, their functions remain poorly characterized. Here, we uncovered a role for MG in the maintenance of structural integrity at two fetal cortical boundaries.

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Background: Triple-Negative Breast Cancer is particularly aggressive, and its metastasis to the brain has a significant psychological impact on patients' quality of life, in addition to reducing survival. The development of brain metastases is particularly harmful in triple-negative breast cancer (TNBC). To date, the mechanisms that induce brain metastasis in TNBC are poorly understood.

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The evolution and development of the head have long captivated researchers due to the crucial role of the head as the gateway for sensory stimuli and the intricate structural complexity of the head. Although significant progress has been made in understanding head development in various vertebrate species, our knowledge of early human head ontogeny remains limited. Here, we used advanced whole-mount immunostaining and 3D imaging techniques to generate a comprehensive 3D cellular atlas of human head embryogenesis.

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Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder leading to anovulatory infertility. Abnormalities in the central neuroendocrine system governed by gonadotropin-releasing hormone (GnRH) neurons might be related to ovarian dysfunction in PCOS, although the link in this disordered brain-to-ovary communication remains unclear. Here, we manipulated GnRH neurons using chemogenetics in adult female mice to unveil whether chronic overaction of these neurons would trigger PCOS-like hormonal and reproductive impairments.

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Article Synopsis
  • Recent research links loss of gonadotropin-releasing hormone (GnRH) to cognitive decline, suggesting a similar mechanism may underlie neurological symptoms in post-COVID patients.
  • Investigations revealed persistent low testosterone levels in some men post-COVID could indicate hypothalamic impact, connecting hormonal changes to cognitive issues.
  • Dysfunction of GnRH neurons and certain brain cells due to SARS-CoV-2 could lead to reproductive, metabolic, and mental health problems, potentially increasing risks for neurological disorders across all ages.
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Background: Polycystic ovary syndrome (PCOS) is the most common reproductive-endocrine disorder affecting between 5 and 18% of women worldwide. An elevated frequency of pulsatile luteinizing hormone (LH) secretion and higher serum levels of anti-Müllerian hormone (AMH) are frequently observed in women with PCOS. The origin of these abnormalities is, however, not well understood.

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Article Synopsis
  • The median eminence (ME) is a part of the brain that helps keep our body's balance in check.
  • Special cells called tanycytes in the ME play a role in how our body reacts to different signals, like hormones.
  • A specific group of these tanycytes help with taste and can affect how our body uses food and responds to fasting.
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Article Synopsis
  • Fertility in vertebrates is regulated by gonadotropin-releasing hormone (GnRH) neurons that migrate from the olfactory pit to the forebrain during embryonic development.
  • Disorders like congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome are linked to issues with GnRH neuron migration and signaling.
  • Research shows that the jagged-1/Notch signaling pathway is crucial for GnRH neuron development, with mutations in the JAG1 gene associated with CHH, impacting protein levels and localization.
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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 .

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Hypothalamic gonadotropin-releasing hormone (GnRH) neurons lay the foundation for human development and reproduction; however, the critical cell populations and the entangled mechanisms underlying the development of human GnRH neurons remain poorly understood. Here, by using our established human pluripotent stem cell-derived GnRH neuron model, we decoded the cellular heterogeneity and differentiation trajectories at the single-cell level. We found that a glutamatergic neuron population, which generated together with GnRH neurons, showed similar transcriptomic properties with olfactory sensory neuron and provided the migratory path for GnRH neurons.

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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.

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Women with polycystic ovary syndrome (PCOS) frequently experience decreased sexual arousal, desire, and sexual satisfaction. While the hypothalamus is known to regulate sexual behavior, the specific neuronal pathways affected in patients with PCOS are not known. To dissect the underlying neural circuitry, we capitalized on a robust preclinical animal model that reliably recapitulates all cardinal PCOS features.

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Article Synopsis
  • * Results showed a median serum AMH of 43.5 pmol/L and identified significant correlations between AMH levels, sperm concentration, and various reproductive hormones, indicating AMH's role in male fertility.
  • * The research also discovered the expression of AMH type II receptors in sperm and pituitary cells, suggesting new potential roles for AMH in influencing sperm motility and hormone secretion in men.
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p140Cap, encoded by the gene (, is an adaptor/scaffold protein highly expressed in the mouse brain, participating in several pre- and post-synaptic mechanisms. knock-out (KO) female mice show severe hypofertility, delayed puberty onset, altered estrus cycle, reduced ovulation, and defective production of luteinizing hormone and estradiol during proestrus. We investigated the role of p140Cap in the development and maturation of the hypothalamic gonadotropic system.

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This review summarizes the current understanding of the development of the neuroendocrine gonadotropin-releasing hormone (GnRH) system, including discussion on open questions regarding (1) transcriptional regulation of the Gnrh1 gene; (2) prenatal development of the GnRH1 system in rodents and humans; and (3) paracrine and synaptic communication during migration of the GnRH cells.

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