Journal of Neuroendocrinology最新文献

There is a need for accurate and less invasive methods of hormonal measurements. Here, we longitudinally determined luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion measured in the tail-tip blood of male and female rats by ultrasensitive enzyme-linked immunosorbent assay (ELISA). In males, the ELISAs detected a significant increase in LH and FSH secretion after orchiectomy compared with the gonad-intact condition. The subsequent treatment with testosterone in the orchiectomized condition returned LH concentrations to the basal levels, whereas FSH secretion was partially restored to the gonad-intact levels. During the rat estrous cycle, LH and FSH secretion fluctuated around basal levels on diestrus, and the preovulatory surges of both hormones occurred on the late afternoon of proestrus. On estrus, LH secretion was continually low, while FSH concentrations progressively declined from elevated concentrations in the morning to lower levels in the afternoon. After ovariectomy, secretion of both LH and FSH rose above the basal levels of the estrous cycle. Estradiol treatment in the ovariectomized condition reduced LH and FSH secretion towards gonad-intact levels in the morning, with a greater effect on FSH. In the afternoon, estradiol treatment prompted a sharp proestrus-like surge of LH alongside a slower, gradual increase in FSH levels. In the present study, we characterize LH and FSH secretion in rats of both sexes under different hormonal conditions, using longitudinal hormonal measurement in the tail-tip blood by ultrasensitive ELISA. These findings provide novel methodological and conceptual information about gonadotropin secretion in rats relevant to the knowledge in reproductive endocrinology.

Typical carcinoids (TC) are neuroendocrine malignancies of the lung with low risk of recurrence and a favorable prognosis. It is unclear whether lymph node status and tumor size affect the recurrence risk. Following radical surgery, current guidelines recommend comprehensive follow-up including regular computed tomography (CT) imaging. We aimed to estimate the risk of recurrence in curatively treated patients with TC and to discuss the justification of the current comprehensive follow-up program. We identified all patients diagnosed with TC from 2009 to 2020 at Aarhus University Hospital, Denmark and Copenhagen University Hospital, Rigshospitalet, Denmark. Patients without distant metastases (M0) who underwent radical surgery (R0) were included in the analysis. The risk of recurrence was estimated using the Aalen-Johansen method treating death as a competing risk. Fine-Gray models were used to evaluate the effect of lymph node status and tumor size. Three-hundred and thirty patients were included in the analysis, of whom 40 had lymph node involvement and 290 did not. During a total follow-up time of 2806 years across all patients, with an individual median of 8.1 years (IQR: 5.9-11.2), 10 patients had recurrence: four in the node-negative group and six in the node-positive group. The 10-year cumulative risk of recurrence for all patients was 3.4% (95% confidence interval (CI): 1.7-6.0), for patients without lymph node involvement 1.6% (95% CI: 0.5-3.8), and for patients with lymph node involvement 15.6% (95% CI: 6.3-28.8). Of the four recurrences in the node-negative group, one led to re-resection with curative intent. Patients with TC without lymph node involvement have a very low risk of recurrence. Thus, we recommend tailoring the follow-up program based on lymph node status, with node-negative patients being excluded from regular follow-up programs.

Augmentor α (Fam150b)-induced activation of the ALK receptor (Alk) has gained significance as a hypothalamic signaling pathway with relevance to the control of food intake and energy homeostasis. In contrast, much less is known about the sensitivity of Fam150b-Alk expression and signaling upon noxious challenges. In this regard, acute stress is of particular interest because augmentor α, released from afferents of the food intake circuit of the arcuate nucleus within the paraventricular hypothalamus (PVN), could link stress-induced changes in food consumption. Nevertheless, conflicting data exist on whether Fam150b mRNA is expressed in the PVN. Here, we combined single-cell RNA-seq and multiplexed in situ hybridization to demonstrate that both Fam150b and Alk are expressed in the PVN of adult mice, including corticotropin-releasing hormone (CRH)-containing neurons. As such, a dichotomy of CRH neurons is present through their mutually exclusive expression of either Fam150b or Scgn (secretagogin). Fam150b and Alk were not co-expressed. When inducing inflammation-associated stress, Fam150b but not Alk mRNA expression increased in a mifepristone-sensitive manner, implying regulation by peripheral glucocorticoid feedback. We suggest that augmentor α-ALK signaling could underpin, at least partly, stress-induced changes in feeding and the control of body weight.

Neuroendocrine tumors (NETs) are rare tumors that may arise in the small intestine (siNET) or pancreas (pNET). The tumors have heterogeneous clinical characteristics, and diagnosis may be challenging. Current non-invasive biomarkers perform suboptimally, and novel biomarkers are highly needed. We aimed to investigate the use of RNA aptamer panels, selected by the APTASHAPE technology, in distinguishing healthy individuals from individuals with NET as well as discriminating siNET from pNET. Plasma samples from 68 individuals with NET and 24 healthy individuals were collected and randomly divided into a development set and a test set. A panel of aptamers recognizing disease-specific plasma proteins was selected in the development set, and the accuracy for disease prediction was evaluated in the test set. The aptamer panels demonstrated high discriminative power, accurately distinguishing between healthy individuals and NET patients with AUCs of 0.74 and 0.87 in the development set and test set, respectively. Furthermore, the aptamer panels were able to differentiate between siNET and pNET patients with AUCs of 0.72 in both the development set and the test set. In addition, mass spectrometry analysis identified ITIH2 and IGHG3 as potential novel biomarkers for the diagnosis of NET. The APTASHAPE platform is a capable tool for selecting protein biomarker-directed aptamer panels for the diagnosis of NET and discrimination between siNET and pNET. Furthermore, the identification of ITIH2 and IGHG3 highlights the potential of APTASHAPE to identify novel protein biomarkers in NET.

More women than men are diagnosed with Alzheimer's disease (AD). Sex hormones have been ascribed neuroprotective properties, and their decline, particularly the reduction of estrogen during menopause, has been implicated in AD risk. In this study, we examined how loss of circulating sex hormones affects cognitive performance and amyloid pathology in two mouse models of AD, the aggressive App^NL-G-F and the slower App^NL-F models of brain amyloidosis. Bilateral gonadectomy was induced in both male and female App^NL-G-F and App^NL-F mice. Pathology was assessed using cognitive tests and histological evaluations of amyloid depositions and neuroinflammation. Serum and brain estrogen and testosterone levels were measured by ELISA, and the expression of key estrogenic signaling genes was evaluated using qPCR. We report that female gonadectomy had little impact on behavior or pathology in the App^NL-G-F model, whereas male gonadectomy improved learning and reduced hippocampal amyloid depositions. In the App^NL-F model, gonadectomy worsened amyloid pathology in both sexes. Hormone analysis revealed that significant levels of estrogen in females, but not testosterone in males, remain partly preserved in the brain after gonadectomy, and that low testosterone levels associate with increased insulin-like growth factor 1 (IGF-1) expression which may play a compensatory role in maintaining estrogenic signaling. Our study provides new insights into how the loss of circulating sex hormones influences brain sex hormone levels and AD pathology and contributes to a better understanding of the sex differences observed in this disease.

Adolescence is a critical developmental period with heightened stress susceptibility. Traumatic experiences during this phase are highly predictive of future affective disorders, such as social anxiety disorder (SAD), which may manifest during early adolescence. Social avoidance, a major symptom of SAD, can be robustly generated in adult male and female mice using the social fear conditioning (SFC) paradigm. Using the SFC paradigm in adolescent mice, we analyze behavioral and neuroendocrine responses after adolescent social trauma. Here, we demonstrate that social fear elicited by SFC in early adolescent (EA) male mice (SFC⁺EA/29d) persists until adulthood (SFC⁺EA/57d). We further compared neuroendocrine responses to a heterotypic (elevated platform) or homotypic (exposure to a conspecific) stressor after SFC performed either in EA (SFC⁺EA/29d, SFC⁺EA/57d) or adulthood (SFC⁺AD). While in non-conditioned SFC^-EA/29d mice plasma corticosterone concentrations remained unchanged after social exposure in adolescence, SFC⁺EA/29d resulted in a hyper-response of the HPA axis to the social, but not heterotypic stressor, with a negative correlation of plasma corticosterone concentrations and social investigation times. This effect of SFC⁺EA/29d on plasma corticosterone response was absent in SFC⁺EA/57d and SFC⁺AD mice indicating a higher sensitivity to social trauma in EA. We further revealed a rise in plasma oxytocin (OXT) levels in adult SFC^- mice in response to the social challenge, whereas the OXT system of SFC^-EA/29d mice still seems to be unresponsive to the social stimulus. Importantly, after SFC⁺ either in EA or AD, the OXT response to social exposure found in SFC^-AD controls was completely abolished, whereas in SFC^-EA/57d mice OXT levels positively correlated with social investigation times, indicating social trauma-induced acute and long-lasting dysfunctions of the OXT system. In summary, we show that exposure to social trauma (SFC⁺) in early adolescence exerts both short-term as well as long-term effects on social behavior. We further reveal that SFC⁺EA/29d prevents the corticosterone hypo-response to social stimuli characteristic for early adolescence. Moreover, SFC⁺/AD and SFC⁺EA/57d impair the plasma OXT response to a social, but not heterotypic, stressor.

Oxytocin plays an emerging role in vascular regulation and neuroprotection, but its effect on brain endothelial cells and blood-brain barrier functionality is not fully defined. To assess oxytocin and vasopressin receptor expression in brain endothelial cells and to evaluate the impact of oxytocin on endothelial barrier integrity under physiological (normoxic) and low-oxygen (hypoxic) conditions we used bEnd.3 brain endothelial cells. Receptor expression was evaluated by real-time PCR and RNAscope. Oxytocin treatment was applied under normoxic and hypoxic conditions and Transendothelial Electrical Resistance and tight junction proteins expression (claudin-5, zonula occludens-1) were analyzed. Our results indicate that 1) bEnd.3 cells express oxytocin and V1a receptors. 2) Activation of the oxytocin receptor enhanced brain endothelial barrier integrity by increasing claudin-5 expression and its localization at the cell surface, without affecting zonula occludens-1.3) Under hypoxic conditions, oxytocin preserved Transendothelial Electrical Resistance and claudin-5 expression at the cell membrane, thereby preventing endothelial barrier impairment. Our findings demonstrate that oxytocin receptor signaling enhances and preserves brain endothelial barrier function, underscoring the relevance of oxytocin in neurovascular regulation and its therapeutic potential in blood-brain barrier dysfunction.

Sex differences in tobacco intake are closely associated with hormonal fluctuations during the menstrual cycle in women. Elevated estrogen levels have been associated with increased stress, which may lead to a higher likelihood of seeking psychoactive substances. Additionally, tobacco use has been associated with negative effects on reproductive health. Preclinical studies suggested that the estrous cycle significantly influences addictive behaviors, emphasizing the role of ovarian hormones. Furthermore, psychoactive substances entrain circadian rhythms, with animals showing increased locomotor activity 1-2 h before drug administration time, known as anticipatory activity, reflecting seeking behavior. This study aims to evaluate the impact of ovarian hormones on nicotine-anticipatory behavior. A circadian model of forced administration of nicotine via nebulization was implemented in intact and ovariectomized female mice, exposing them to nicotine at a fixed time (ZT4) for 20 min daily over 14 days. The effects of nicotine intake on ovarian follicle morphology and maturation were also assessed. Daily nicotine exposure successfully entrained a clear anticipatory behavior in intact mice. Notably, this anticipatory activity was completely abolished in ovariectomized females, indicating a critical dependence on ovarian factors. Furthermore, nicotine exposure disrupted the estrous cycle and induced significant ovarian follicular damage in intact females. Our findings suggest that the hormonal state is a primary modulator of nicotine-anticipatory behavior. Moreover, the observed nicotine-induced ovarian damage highlights a significant risk to female reproductive health, suggesting a bidirectional relationship between nicotine use and the hypothalamic-pituitary-gonadal axis.