Journal of Neuroendocrinology最新文献

Neurotrophins (BDNF, NGF, NT3, and NT4/5) acting through different receptors are able to impact numerous functions, including cell fate and morphological plasticity, an asset for the maturation and differentiation of cells from neurogenic niches. They bind to the neurotrophin receptor p75 (p75), which could either heterodimerize with Trk receptors or act on its own to relay the varied physiological functions of neurotrophins. Published data suggest a preponderant role of p75 for NGF stimulation of GnRH neurons in vitro. We therefore focused on this receptor and its relationships with neuronal populations involved in the central control of reproduction. Here we investigated the distribution and phenotype of p75 cells in the hypothalamus of ovariectomized estrogen-replaced mice using several combinations of immunohistochemical labeling. We found that p75 is expressed mainly in neurons of the organum vasculosum of the lamina terminalis (OVLT)–medial septum continuum and in the arcuate nucleus (ARC). In this latter region, p75 was also seen in tanycytic cells lining the third ventricle. Co-distribution of p75 with TrkA was only seen in the OVLT, an area in which p75 is present in 16% of nitric oxide synthase-expressing neurons. In the ARC, 33% of p75 neurons were colocalized with tyrosine hydroxylase, an enzyme essential for catecholamine production. Anatomical distribution and co-expression with neurotransmitters involved in reproduction control, together with data suggesting that β-NGF induced ovulation in camelidae, prompted us to perform immunohistochemical double labeling against p75 and kisspeptin or GnRH, two neuropeptides essential for the central control of ovulation. However, no colocalization of p75 with kisspeptin or GnRH neurons was seen. These results suggest that neurotrophins, acting via the p75 receptor, do not directly modulate GnRH or Kp neurons. On the other hand, they may influence dopamine and nitric oxide production, and possibly induce remodeling of tanycytic endfeet, ultimately impacting indirectly the central regulation of reproduction in mice.

In female mammals, many aspects of the reproductive function require precise synchronization of neuroendocrine and behavioral events for optimal fertility. To this end, the circadian timing system entrained by light exposure, in addition to the cyclical variations of sex steroid hormones, sets the pace of the hypothalamic–pituitary–ovarian axis. This is best illustrated by the preovulatory LH surge triggered by a daily signal generated by the master circadian clock at the resting-active period transition combined with the positive feedback from estradiol produced by maturing ovarian follicles at the end of the follicular phase. This ensures that ovulation occurs when sexual arousal is maximal, optimizing the chances for reproductive success. Although increasing evidence reports the direct impact of circadian disruption on female reproductive function in animals and humans, the potential long-term consequences remain unknown. Using a light-based shift work model in which adult female mice experienced a 10-h phase advance and a 10-h phase delay each week for 4 weeks (rotating shift condition), we investigated the long-term effects of such circadian disruption by monitoring reproductive rhythms after light exposure was normalized. Our results report a significant alteration in the timing and amplitude of the LH surge on the day of proestrus for up to 3 weeks after pre-exposure to disrupted light–dark cycles, despite regular estrous cycles. This long-lasting dysregulation of LH secretion may be linked to a delayed resynchronization of the internal timing system after exposure to rotating shift condition since locomotor activity also takes approximately 2 weeks to recover a robust daily rhythm. Given the significance of temporal homeostasis to proper reproduction, these findings emphasize the importance of investigating the long-lasting negative impacts of shift work on women's reproductive health.

Median preoptic nucleus (MnPO) neurons projecting to the hypothalamic paraventricular nucleus (PVN) are linked to hypertension induced by chronic intermittent hypoxia (CIH), a model of obstructive sleep apnea. The modulation of MnPO-driven synaptic activity in PVN magnocellular neurons (MNCs) by CIH remains unexamined. We hypothesized that single and repetitive activation of MnPO–PVN projections causes differential synaptic plasticity in MnPO–PVN synapses with and without CIH exposure. Adult male rats were prepared using an intersectional viral approach to induce Cre-dependent channelrhodopsin expression in PVN-projecting MnPO neurons. Two weeks after stereotaxic surgery, some rats were exposed to 7 days of CIH. All rats were anesthetized and their brains were prepared for in vitro electrophysiological recording from PVN MNCs and optogenetic stimulation of the MnPO. We observed distinct EPSC and IPSC response patterns to the optogenetic stimulation of the MnPO. Low-frequency optogenetic stimulation (15 Hz) resulted in short-term potentiation manifested in increased poststimulatory spontaneous EPSC (sEPSC) frequency without altering amplitude while gradually increasing poststimulatory sIPSC frequency and amplitude, shifting some neurons to a more inhibitory state. CIH increased the amplitude of both sEPSCs and stimulation-evoked EPSCs while reducing their frequency. In contrast, CIH enhanced both the amplitude and frequency of sIPSCs and stimulation-evoked IPSC. Stimulation-evoked currents recorded during train protocols reflected a mixture of spontaneous and evoked events. Optogenetic stimulation increased the intrinsic excitability of MNCs in rats exposed to CIH. Activation of the MnPO–PVN pathway recruits both excitatory and inhibitory synaptic circuits converging onto PVN MNCs. CIH induces metaplasticity within this pathway, manifested as strengthened excitatory synaptic drive and heightened intrinsic excitability of PVN MNCs, which is counterbalanced by an adaptive increase in inhibitory tone. These parallel changes could explain why CIH is not associated with increased neurohypophysial hormone release.

The mouse brain is masculinized by postnatal testicular androgens, which are active after conversion to estrogens and modulate gene expression epigenetically, at least in part. The preoptic area contains a sexually dimorphic nucleus (SDN) comprising calbindin D-28K (Calb) neurons with a male-biased sex difference in cell number (Calb-SDN), although the mechanisms responsible for the sex difference are not fully understood. We have previously demonstrated that Calb neurons expressing the androgen receptor (AR) are a male-dominant cell group of the Calb-SDN in pubertal mice, while Calb neurons without AR exist in both sexes with equal cell numbers. In this study, we investigated the mechanisms by which more Calb/AR neurons emerge in the male Calb-SDN than in the female one. Immunohistochemistry for Calb and AR was performed using the brain sections from pubertal male mice subjected to sham surgery or neonatal orchidectomy, from pubertal female mice treated with vehicle, testosterone, or estradiol during the postnatal period, and from pubertal male mice whose brains were treated with trichostatin A, a histone deacetylase inhibitor, during the postnatal period. Immunostained brain sections were analyzed stereologically to determine the numbers of Calb-immunopositive and AR-immunopositive cells (Calb⁺/AR⁺ cells) and Calb-immunopositive and AR-immunonegative cells (Calb⁺/AR⁻ cells) in the Calb-SDN. The number of Calb⁺/AR⁺ cells in the Calb-SDN during the pubertal period was significantly decreased in neonatally orchidectomized males compared with sham males and increased in testosterone- or estradiol-treated females compared with vehicle-treated females; however, the number of Calb⁺/AR⁻ cells remained unchanged. Trichostatin A treatment significantly reduced the number of Calb⁺/AR⁺ cells, but not the number of Calb⁺/AR⁻ cells, in the Calb-SDN of males. These findings suggest that estrogens synthesized from postnatal testicular androgens act selectively on the AR-expressing subpopulation of Calb neurons, contributing to the sex difference in the number of Calb neurons in the mouse Calb-SDN. Epigenetic regulation of gene expression, possibly mediated by histone deacetylation, may be involved in the emergence of the AR-expressing subpopulation of Calb neurons.

The olfactory bulb (OB) is an emerging neuroendocrine centre regulating appetite, metabolism, and behaviours such as those linked to anxiety, motivation and spatial navigation. These processes are likely mediated by one or more of the many hormone receptors found in the OB. For instance, recent studies show that selective OB deletion of the receptor for ghrelin and LEAP2 (GHSR; growth hormone secretagogue receptor) increases anxiety-like behaviour and impacts peripheral glucose and energy homeostasis. As GHSR function has been linked to motivated behaviours and spatial navigation, we decided to investigate whether OB-selective GHSR (OB^GHSR) deletion affects motivation, using an operant progressive ratio schedule, and/or spatial navigation, using a Y maze and radial arm maze. In contrast to wild-type mice, our study shows that OB^GHSR deletion increased motivated sucrose seeking after a short fast, but not in ad libitum fed mice, and had a mild effect to delay extinction learning. In both Y-maze and radial arm maze studies for spatial navigation, OB^GHSR deletion reduced spatial exploration in terms of distance moved and arm entries. However, the proportion of correct and incorrect arm entries relative to the total number of entries was not affected in either the Y-maze or the radial arm maze, suggesting that spatial memory was not affected. Our study demonstrates that intact OB^GHSRs in male mice normally restrain motivated sucrose seeking in a metabolic state-dependent manner and optimise spatial navigation by increasing exploration, without affecting spatial memory.

Migraine is a complex neurovascular disorder characterized by activation and sensitization of the trigeminovascular system. Hyperprolactinemia is associated with headache, and improvement following prolactin-lowering therapy has been reported in observational studies. Preclinical evidence indicates that prolactin promotes neuronal excitability and sensitization within trigeminal pathways, particularly in females. Downregulation of the protective long prolactin receptor isoform further increases susceptibility to migraine-relevant triggers. Prolactin secretion is under tonic inhibition by dopamine, a key hypothalamic regulator that also modulates central pain pathways. The role of dopamine in migraine pathophysiology is complex. On one hand, prodromal symptoms such as nausea and yawning are considered dopamine-mediated. On the other hand, experimental studies show that dopamine directly inhibits nociceptive trigeminovascular activity in addition to lowering prolactin. Dopamine receptor agonists are established treatments for hyperprolactinemia and have demonstrated a positive effect on hyperprolactinemia-associated headache. A recent placebo-controlled randomized clinical trial suggests that dopamine agonist treatment can be used as a preventive migraine treatment. In conclusion, prolactin and dopamine may modulate migraine via distinct but converging neuroendocrine pathways, which could represent targets for migraine prevention.

The rapid increase in urbanization is drastically altering the habitat composition of the wild population. Urbanization is predominantly changing the landscape, composition of flora and fauna, availability of night light, and the rise in temperature. In the natural habitat, photoperiod and temperature are inseparable. In the present study, we examined the effect of mild temperature change from the thermoneutral zone of Syrian hamsters on reproduction-linked activities. To investigate the neuroendocrine mechanisms underlying heat stress effects on reproduction in hamsters, two experiments were performed on adult male animals. In experiment one, animals were divided into two groups (n = 5/group) and exposed to a long photoperiod (15L:9D) with either low (LT; 20 ± 2°C) or high temperature (HT; 32 ± 2°C). After 21 days, all animals were sampled. In experiment two, hamsters (n = 20) were divided equally into two groups and were exposed to the first short photoperiod of 8L:16D, but with low temperature (LT; 20 ± 2°C) or high temperature (HT; 32 ± 2°C). After 30 days, all animals were exposed to a long day (15L:9D), but animals from each temperature treatment were divided equally into two groups (n = 5/group). Half of the animals (n = 5) of low temperature remained in low temperature (LL group) while the remaining animals were moved to high temperature (LH group). Similarly, half of the animals (n = 5) of high temperature remained in high temperature (HH group), and the rest of the animals were moved to low temperature (HL group). Body mass and testicular volume were measured at different intervals. After 30 days of long-day treatment, the animals were sampled. Findings suggest that exposure to 3 weeks of high temperature attenuates testicular growth, coupled with low testosterone levels and downregulation of Kiss1, Eya3, Tshβ, GnRh, Tet1, Tet2, and Hat1, while upregulation of Dio3, GnIh, Dnmt1, Dnmt3A, Hdac1, and Hdac5 occurs in HT groups. Results from experiment two suggest that low temperature promotes, while high temperature attenuates reproduction and the linked phenomenon. Together, these findings suggest that high temperature modulates the reproductive responses of Syrian hamsters.

Small intestinal neuroendocrine tumours (SI-NETs) are associated with mesenteric fibrosis, which causes significant morbidity and mortality. Telotristat ethyl was developed to treat carcinoid syndrome in SI-NET patients. Recent studies indicated telotristat ethyl could have anti-tumour activity; however, the mechanism remains unclear. This study aimed to investigate the effects of telotristat ethyl on SI-NET–fibroblast crosstalk in tumour progression and mesenteric fibrosis. A co-culture paracrine model with GOT1 (tumour) cells and LX2 (stromal) cells was optimized. Cells were treated with conditioned medium with/without telotristat ethyl followed by RNA sequencing and Gene Set Enrichment Analysis. Quantitative RT-PCR, immunohistochemistry, and Western blot were performed on first and second tier targets in tissue from 34 SI-NET patients grouped into categories of mesenteric fibrosis severity. Telotristat ethyl significantly decreased proliferation and serotonin secretion in a dose-dependent manner in GOT1 cells. GSEA data indicated ECM-related reactomes were downregulated in GOT1 cells grown in conditioned medium of LX2 cells with telotristat ethyl. LAMA5, COL6A2, and COL12A1 expression was significantly increased in mild and severely fibrotic patients. Immunohistochemistry determined the localization of proteins such as COL4A2 in the stroma and ADAM12 in tumour cells. Protein analysis of second tier targets showed differences in expression, including β-catenin, which was significantly upregulated, and pAKT/AKT, which tended to increase in primary tumour compared to normal SI. Telotristat ethyl affects the expression of genes associated with the ECM and interferes with SI-NET–fibroblast crosstalk. Further analysis is required; however, this study represents an important step in understanding the mechanisms of telotristat ethyl when treating SI-NET patients.

Oxytocin (OXT), a neuropeptide hormone essential to a wide range of social functions, has drawn increasing attention as a crucial contributor to the neurobiology of autism spectrum disorder (ASD). Central OXT system disruptions have been reported in several genetic mouse models of ASD; however, a detailed and systematic characterization of these phenotypes, and cross-model identification of shared and distinct features, are presently lacking. We integrated whole-brain OXT immunolabeling, SHIELD tissue clearing, light-sheet microscopy, and three-dimensional (3D) machine learning-based cell detection to establish a high-throughput, intact-tissue pipeline and quantified OXT immunopositive (OXT+) neurons across subregions of the paraventricular nucleus of the hypothalamus (PVN) in two genetic mouse models of ASD: Cntnap2 and Fmr1 knockout (KO) mice. We validated this pipeline alongside conventional immunohistochemistry using tissue sections. We show subregion- and sex-specific differences in PVN OXT+ cell counts in the two KO models. Notably, whole-PVN analysis revealed additional subregion- and sex-specific differences that were not evident in section-based quantification. These results identify subregion- and sex-specific differences in PVN OXT+ neuronal distribution as a shared phenotype in two genetic mouse models of ASD. This work highlights the importance of region-specific, high-resolution 3D approaches in intact tissue for quantifying cell populations within anatomically complex brain regions.

Hormones within the hypothalamic–pituitary–thyroid (HPT) axis play a central role in acclimatization, dynamically responding to nutritional, thermal, and photoperiodic cues to coordinate metabolic, thermoregulatory, and reproductive functions. Abundant food elevates thyroid hormone (TH), driving energy storage and foraging behaviors, while scarcity reduces TH levels, inducing energy-saving states like hypometabolism or hibernation, in which TH-leptin crosstalk is important. Cold exposure upregulates TH to enhance mitochondrial thermogenesis, with TH acting as a pivotal mediator in the coordination between the hypothalamic thermoregulatory center and peripheral organs. The photoperiodic response converges evolutionarily on the TSH-DIO2-T3 axis, modulating seasonal GnRH release for seasonal reproductive activity. Humans display an annual rhythm of HPT-axis hormones, characterized by winter TSH elevation with TH variability, which affects thyroid dysfunction diagnosis and necessitates seasonally adjusted therapies. Extreme natural environmental stressors and modern environmental changes can profoundly disrupt this acclimatization to decompensate into a pathophysiological state. Meanwhile, thyroid diseases like hypo- and hyperthyroidism show seasonal patterns of disease onset and exacerbation, indicating that the environment impacts disease progression. Thus, cross-species analysis of seasonal dynamics of TH signaling can enhance our understanding of environmental impacts on thyroid function and inform therapeutic strategies aligned with endogenous annual rhythms to optimize the management of thyroid disorders.