NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice

Science Translational Medicine, Год журнала: 2022, Номер 14(665)

Опубликована: Окт. 5, 2022

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

Язык: Английский

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A critical update on the l eptin‐melanocortin system

Journal of Neurochemistry, Год журнала: 2023, Номер 165(4), С. 467 - 486

Опубликована: Янв. 17, 2023

Abstract The discovery of leptin in 1994 was an “eureka moment” the field neurometabolism that provided new opportunities to better understand central control energy balance and glucose metabolism. Rapidly, a prevalent model emerged pro‐opiomelanocortin (POMC) neurons were key promoting leptin's anorexigenic effects arcuate nucleus hypothalamus (ARC) region for regulation homeostasis. While this inspired many important discoveries, growing body literature indicates is now outdated. In review, we re‐evaluate hypothalamic leptin–melanocortin light recent advances directly tackle previous assumptions, with particular focus on ARC. We discuss how segregated heterogeneous these are, examine development modern approaches allowing spatiotemporal, intersectional, chemogenetic manipulations melanocortin has allowed definition complexity system. review importance regulating homeostasis, but not food intake, through direct actions ARC POMC neurons. further highlight non‐POMC, GABAergic mediate influence image

Язык: Английский

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Metabolic control of puberty: 60 years in the footsteps of Kennedy and Mitra’s seminal work

Nature Reviews Endocrinology, Год журнала: 2023, Номер 20(2), С. 111 - 123

Опубликована: Дек. 4, 2023

Язык: Английский

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Distinct Neuronal Projections From the Hypothalamic Ventromedial Nucleus Mediate Glycemic and Behavioral Effects

Diabetes, Год журнала: 2018, Номер 67(12), С. 2518 - 2529

Опубликована: Сен. 26, 2018

The hypothalamic ventromedial nucleus (VMN) is implicated both in autonomic control of blood glucose and behaviors including fear aggression, but whether these divergent effects involve the same or distinct neuronal subsets their projections unknown. To address this question, we used an optogenetic approach to selectively activate subset VMN neurons that express nitric oxide synthase 1 (VMNNOS1 neurons) counterregulation. We found photoactivation elicits 1) robust hyperglycemia achieved by activation counterregulatory responses usually reserved for physiological response hypoglycemia 2) defensive immobility behavior. Moreover, show glucagon, not corticosterone, insulin-induced blunted photoinhibition neurons. investigate neurocircuitry which VMNNOS1 mediate effects, determine diverse are dissociable from one another, activated downstream either anterior bed stria terminalis (aBNST) periaqueductal gray (PAG). Whereas glycemic fully recapitulated aBNST, freezing occurred only upon terminals PAG. These findings support previous evidence a VMN→aBNST neurocircuit involved counterregulation demonstrate supplying PAG robustly behaviors.

Язык: Английский

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Ventromedial hypothalamus glucose‐inhibited neurones: A role in glucose and energy homeostasis?

Journal of Neuroendocrinology, Год журнала: 2019, Номер 32(1)

Опубликована: Июль 22, 2019

Abstract The ventromedial hypothalamus ( VMH ) plays a complex role in glucose and energy homeostasis. is necessary for the counter‐regulatory response to hypoglycaemia CRR that increases hepatic gluconeogenesis restore euglycaemia. On other hand, also restrains production during euglycaemia stimulates peripheral uptake. important ability of oestrogen increase expenditure. This latter function mediated by modulation lateral/perifornical hypothalamic area orexin neurones. Activation AMP ‐activated protein kinase AMPK . By contrast, inhibition favours decreased basal levels required Specialised glucose‐sensing neurones confer sense respond changes blood levels. Glucose‐excited GE glucose‐inhibited GI decrease their activity as rise. neurones, particular, appear be , although cannot discounted. mediates sensing suggesting that, activation these it silence them lower enable In support this, we found reduces low inhibiting this review, present evidence underlying We then discuss mediating effects, with strong emphasis on oestrogenic regulation how may affect

Язык: Английский

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Modulation of Gonadotropin-Releasing Hormone Neuron Activity and Secretion in Mice by Non-peptide Neurotransmitters, Gasotransmitters, and Gliotransmitters

Frontiers in Endocrinology, Год журнала: 2019, Номер 10

Опубликована: Май 22, 2019

Gonadotropin-releasing hormone (GnRH) neuron activity and GnRH secretion are essential for fertility in mammals. Here, I review findings from mouse studies on the direct modulation of by non-peptide neurotransmitters (GABA, glutamate, dopamine, serotonin, norepinephrine, epinephrine, histamine, ATP, adenosine, acetylcholine), gasotransmitters (nitric oxide carbon monoxide), gliotransmitters (prostaglandin E2 possibly GABA, ATP). These neurotransmitters, gasotransmitters, have been shown to directly modulate and/or neurons vivo or ex (brain slices), postnatal through adult mice, embryonic immortalized neurons. However, except nitric oxide, prostaglandin E2, which appear be normal activity, secretion, males females, biological significance their central regulation reproduction remains largely unknown requires further exploration.

Язык: Английский

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GnRH neurons recruit astrocytes in infancy to facilitate network integration and sexual maturation

Nature Neuroscience, Год журнала: 2021, Номер 24(12), С. 1660 - 1672

Опубликована: Ноя. 18, 2021

Язык: Английский

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New Horizons: Gonadotropin-Releasing Hormone and Cognition

The Journal of Clinical Endocrinology & Metabolism, Год журнала: 2023, Номер 108(11), С. 2747 - 2758

Опубликована: Июнь 1, 2023

Abstract Pulsatile secretion of gonadotropin-releasing hormone (GnRH) is essential for activating and maintaining the function hypothalamic–pituitary–gonadal axis, which controls onset puberty fertility. Two recent studies suggest that, in addition to controlling reproduction, neurons brain that produce GnRH are also involved control postnatal maturation, odor discrimination, adult cognition. This review will summarize development establishment system, with particular attention importance its first activation, a phenomenon known as minipuberty, later reproductive nonreproductive functions. In addition, we discuss beneficial effects restoring physiological (ie, pulsatile) levels on olfactory cognitive alterations preclinical Down syndrome Alzheimer disease models, well potential risks associated long-term continuous nonphysiological) administration certain disorders. Finally, this addresses intriguing possibility pulsatile therapy may hold therapeutic management some neurodevelopmental disorders pathological aging elderly people.

Язык: Английский

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Estrogen receptor-α signaling in tanycytes lies at the crossroads of fertility and metabolism

Metabolism, Год журнала: 2024, Номер 158, С. 155976 - 155976

Опубликована: Июль 15, 2024

Язык: Английский

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Female sexual behavior is disrupted in a preclinical mouse model of PCOS via an attenuated hypothalamic nitric oxide pathway

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(30)

Опубликована: Июль 22, 2022

Women with polycystic ovary syndrome (PCOS) frequently experience decreased sexual arousal, desire, and satisfaction. While the hypothalamus is known to regulate behavior, specific neuronal pathways affected in patients PCOS are not known. To dissect underlying neural circuitry, we capitalized on a robust preclinical animal model that reliably recapitulates all cardinal features. We discovered female mice prenatally treated anti-Müllerian hormone (PAMH) display impaired behavior partner preference over reproductive age. Blunted was associated increased rejection independent of sex steroid status. Structurally, dysfunction substantial loss nitric oxide synthase (nNOS)-expressing neurons ventromedial nucleus (VMH) other areas hypothalamic nuclei involved social behaviors. Using vivo chemogenetic manipulation, show nNOS VMH required for normal pharmacological replenishment restores performance PAMH mice. Our data provide framework investigate facets neuron biology implications disturbances PCOS.

Язык: Английский

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