Journal of Neuroendocrinology最新文献

Early life stress (ELS) is a major risk factor for later psychiatric and neurological disorders. Glucocorticoids (GCs), the hormonal end-products of the neuroendocrine stress response, are central mediators of this risk, influencing how the developing brain grows and adapts. Research has shown that GCs affect processes such as cell proliferation, neuronal survival, and maturation, but much less attention has been given to whether they also shape cell fate—the developmental choices that determine whether stem and progenitor cells give rise to neurons, astrocytes, oligodendrocytes, or other specialised lineages. In this perspective, I argue that cell fate provides a valuable new lens for understanding how stress becomes embedded in brain architecture. Because GCs act directly on neural stem and progenitor populations, it is plausible that their influence extends beyond the quantity of cells produced, to the identities that emerge. I outline an initial framework for interpreting potential effects of GCs on fate, review emerging evidence from different model systems, and consider mechanisms by which stress hormones could alter developmental trajectories. By focusing on fate, this article highlights a novel dimension of neuroendocrine influence on brain development, with implications for how early experiences confer vulnerability, or resilience, to later mental health outcomes.

Gamma-aminobutyric acid (GABA) is a primary inhibitory neurotransmitter involved in several physiological functions, including reproduction in vertebrates. However, its role in stress-induced reproductive modulation in viviparous teleosts remains unclear. This study examined the receptor-specific GABAergic mechanisms influencing gonadal activity in response to stress in the black molly Poecilia sphenops. Four experiments were conducted. In the first experiment, fish were subjected to chronic intermittent stress, whereas in the second experiment, the effect of gabazine (a GABA_A receptor antagonist) and CGP-35348 (a GABA_B receptor antagonist) was assessed in unstressed and stressed fish. In the third and fourth experiments, the effect of GABA_A or GABA_B antagonists and agonists in vitro was examined in testicular tissues and interrenal tissues, respectively. Exposure to stress significantly elevated brain GABA levels and enhanced GABA immunoreactivity in the preoptic-hypothalamic-pituitary regions concomitant with a substantial increase in the whole-body and head kidney cortisol levels, but suppressed testicular spermatogenesis and steroidogenesis. In the second experiment, blockade of GABA_A receptors using gabazine effectively ameliorated stress-induced reductions in the testicular-somatic index, germ cell populations, and testicular 11-ketotestosterone (11-KT) levels, whereas GABA_B receptor blockade via CGP-35348 failed to restore these parameters. In the third experiment, treatment of GABA_A and GABA_B antagonists in vitro significantly increased 11-KT secretion in testicular tissues. Furthermore, selective receptor activation with muscimol (a GABA_A receptor agonist) and baclofen (a GABA_B receptor agonist) significantly enhanced cortisol secretion from the head-kidney, while gabazine and CGP-35348 suppressed cortisol production, indicating direct peripheral GABAergic modulation. These findings demonstrate a dual role for GABA in stress regulation, involving central activation of the GABAergic neuronal system and peripheral stimulation of cortisol secretion. The study provides novel insights into the GABA-mediated suppression of testicular spermatogenesis and steroidogenesis under stress, particularly through GABA_A receptors, and suggests that pharmacological antagonism of GABA_A receptors may help mitigate stress-induced reproductive dysfunction in viviparous teleosts.

Neuroendocrine tumors (NETs) frequently present at a metastatic stage, particularly with liver metastases. Identifying the site of the primary tumor is critical for guiding therapy but often proves difficult. Small intestine NETs are especially distinct in their prognosis and treatment. To address this challenge, we developed a novel, machine learning-based tool to predict the site of origin—specifically small intestine or pancreas—using routine hematoxylin and eosin (H&E)-stained slides from hepatic metastases. To avoid mislabeling in the clinically relevant scenario of any possible tumor origin, the method applies a two-step approach with optional abstention for uncertain classifications or non-small intestine/non-pancreas cases. In a retrospective, clinically realistic cohort with unrestricted tumor origin, the model identified small intestine NETs with a sensitivity of 71.4% at 100% specificity and positive predictive value (PPV), and high negative predictive value. A relevant subset of pancreatic NETs can also be reliably detected (sensitivity 33.3%, specificity 94.1%, PPV 85.7%). Generalizability and robustness were rigorously validated on an external dataset using different scanners, institutions, and resection techniques. The tool is intended as an additional method where other diagnostic modalities remain inconclusive regarding the location of the primary tumor. To facilitate further research and clinical translation, all models and extracted features are publicly released.

Pregnancy represents a period of profound endocrine activity and neural reorganization. While recent evidence highlights pituitary volume as a biomarker of endocrine dynamics during pregnancy, its precise trajectory (timing and relative magnitude of effect) across human pregnancy remains undescribed. Three healthy women (59 total observations) underwent T1-weighted MRI before conception (5 baseline observations), during pregnancy (38 total observations, spanning gestational weeks 1–36), and up to 1 year postpartum (16 total observations). Anterior and posterior pituitary lobes were manually delineated at every visit. A longitudinal pipeline co-registered each scan to all other intra-subject scans, propagated their labels, and generated majority-vote ensembles for objective and regularized volume estimates. Person-centered z-scores were computed, and generalized additive mixed models (GAMMs) with random intercepts estimated nonlinear volume trajectories. The anterior lobe followed a nonlinear trajectory, with gestational age explaining 73% of adjusted variance in anterior-pituitary volume (edf = 7.59, F = 20.2, p_bonf < 10⁻¹⁰). Specifically, volume exhibited a modest first trimester decrease (local fit minima: −0.9 SD at 10.6 weeks), followed by a steep rise into the 3rd trimester (local fit maxima: +1.8 SD at 34.1 weeks, or ~ 17.5% increase from 1st trimester minima, by volume), before returning to baseline near 3 months postpartum. Sensitivity analyses restricted to linear regression during early (−5 to 12 weeks) and late (12 to 40 weeks) windows replicated the observed non-linear decreasing/increasing slopes (β_early = −0.09 SD/week, p_early = 0.036; β_late = 0.14 SD/week, p_late < 10⁻¹⁰). In contrast, no significant volumetric changes in the posterior lobe were detected across the observation period (p_non-linear = 0.79). In one of the first studies of its kind to leverage a dense sampling approach in multiple pregnant women, non-linear analyses revealed rapid, reversible anterior pituitary hypertrophy across human pregnancy consistent with lactotrope expansion and heightened endocrine load.

The incidence of pancreatic neuroendocrine neoplasms (NENs) is rising; whether this reflects a true increase in disease occurrence or improved detection remains uncertain. We conducted a retrospective, population-based study using data from the Surveillance, Epidemiology, and End Results (SEER) Program (1975–2021) to examine temporal trends in the incidence of pancreatic NENs and assess whether changes reflect improved detection versus a true increase. Incidence trends were stratified by demographic and socioeconomic proxies of healthcare access, including income, residential setting, and race as recorded in SEER at the county level. We identified 16,253 cases of pancreatic NENs (44.6% women; median age 62 years). Incidence increased 7.75-fold between 1975 and 2021, rising from 0.21 cases per 100,000 population in 1975 to 1.58 per 100,000 in 2021. Median tumour size at diagnosis decreased significantly, with an average annual reduction of 0.73 mm (R² = 0.765; p < 0.001). After adjustment, incidence increased more steeply among men, individuals aged 40–65 years and >65 years (vs. <40 years), those recorded as White (vs. Black and other races), individuals with higher income, and those residing in urban (vs. rural) counties. Incidence also rose more steeply for tumours located in the pancreatic tail, for grade 1 tumours (vs. grades 2 and 3), and for smaller tumours (vs. larger ones). The rising incidence of pancreatic NENs is probably explained by improved detection, particularly among populations with greater access to healthcare, rather than by a true increase in disease occurrence.

Vasopressin (VP) magnocellular neurosecretory neurons of the hypothalamic supraoptic nucleus (SON) are critical regulators of renal water retention and vascular tone. VP neurons undergo detrimental plastic changes in cardiovascular diseases such as heart failure (HF), resulting in hyperexcitability and thus altered fluid/electrolyte balance. A major intrinsic mechanism that regulates the firing activity of VP neurons is the slow afterhyperpolarization (sAHP), a phenomenon underlain by a calcium-dependent K⁺ current (I_sAHP). The sAHP is activated by Ca²⁺ and results in an efflux of K⁺ from the cell, hyperpolarizing it and throttling firing. Importantly, we previously reported that a blunted sAHP contributes to hyperexcitability of VP neurons in heart failure rats. While the features of the sAHP are well characterized, the identity of the channel underlying the I_sAHP remains unknown. Combining patch clamp electrophysiology, pharmacology and immunohistochemistry in Wistar rats, we investigated Intermediate conductance Ca²⁺-dependent K⁺ (IK) channels as a potential candidate responsible for carrying the I_sAHP. We generated and measured the I_sAHP in voltage clamp via 20 Hz trains of 20 square voltage pulses (from −50 to +10) once per minute. After 4 min of baseline recording, we bath applied TRAM-34 (1 μM), a specific IK channel blocker. Blocking IK with TRAM-34 failed to inhibit I_sAHP peak amplitude, amplitude at 1 s after stimulus end, or area. Post hoc immunohistochemistry was performed to identify the phenotype of the recorded cell. We observed no inhibitory effect of TRAM-34 on the I_sAHP in either VP or OT neurons. We also saw no inhibition of I_sAHP (voltage clamp) or sAHP (current clamp) in slices preincubated in TRAM-34 for at least 1 h prior to recording. Conversely, we found that TRAM-34 inhibited isolated whole cell K⁺ currents, supporting the presence of functional, TRAM-34-sensitive IK channels in SON neurons. Taken together, our results indicate that despite the expression of IK in SON neurons and astrocytes, we observed no evidence of a significant contribution to the sAHP in either OT or VP SON neurons. Future studies will be needed to determine other potential K⁺ channel candidates contributing to the sAHP in SON neurons.

Disrupted gonadotropin-releasing hormone (GnRH) secretion patterns can impair fertility as in polycystic ovary syndrome (PCOS).We used prenatally androgenized (PNA) female mice, which recapitulate neuroendocrine abnormalities observed in PCOS patients, to study how changes in GnRH neuron intrinsic properties during development (prepubertal 3-week-old versus adult females) and with PNA treatment shape their postsynaptic response to GABAergic input. The properties of isolated GABAergic postsynaptic currents in GnRH neurons were used to generate representative model conductances of 1, 2, 5, and 10 nS, with decay time constants representing prepubertal and adult mice (7 vs. 10 ms). These conductances were applied to GnRH neurons from each experimental group using dynamic clamp, and response was measured. Neither development nor PNA altered the response of GnRH neurons to small conductances (1 or 2 nS), and these conductances did not initiate action potentials. In response to the 5 nS conductance, dynamic-clamp-induced postsynaptic potentials were larger in 3-week-old controls versus 3-week-old PNA mice at the 7 ms decay time constant and larger than vehicle-treated (VEH) adults at the 10 ms decay time constant. In response to larger conductances, only seven of 78 GnRH neurons from adults generated action potentials, whereas 14 of 73 GnRH neurons from 3-week-old females did. Interestingly, an altered action potential waveform was observed only in 3-week-old PNA females. The changes in GnRH neuron intrinsic properties occurring with development and PNA treatment result in differential responses to the same physiologic GABA input and may contribute to the action potential firing changes previously reported in this model.

Arginine vasopressin (AVP) modulates stress responsivity and social-affective behaviors, but its role in mood and trauma-related disorders remains poorly defined due to challenges in peripheral measurement. This study used copeptin, a stable, reliable, and well-validated surrogate marker of AVP secretion, to assess vasopressinergic function in a transdiagnostic sample of individuals experiencing a major depressive episode (MDE) with and without post-traumatic stress disorder (PTSD), as well as healthy volunteers (HVs). Baseline levels of copeptin, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and urine cortisol were compared across groups and examined in relation to clinical symptoms and behavioral traits. Acute changes in copeptin and other hypothalamic–pituitary–adrenal axis markers following a single subanesthetic-dose ketamine infusion were also investigated in a subset of patients. Participants with MDE + PTSD exhibited significantly lower baseline copeptin levels and a blunted reduction in copeptin levels post-ketamine compared to MDE-only participants. Copeptin was unrelated to primary mood diagnosis and to symptom severity of depression, anxiety, post-traumatic stress, anhedonia, suicidal ideation, childhood trauma history, or behavioral traits other than aggression. Higher baseline copeptin levels were associated with verbal aggression, and PTSD comorbidity attenuated these associations. Collectively, these findings suggest a possible biological subtype of attenuated AVP secretion in the dual diagnostic subgroup of co-occurring MDE and PTSD that is independent of symptom burden. Plasma copeptin might therefore serve not only as a peripheral biomarker but also as a proxy for central neuromodulatory changes relevant to AVP-driven circuits in the study of neuropsychiatric disorders. Future studies integrating the temporal dynamics of copeptin with neuroimaging, genetic, and stress-challenge paradigms are needed to delineate the potential neural pathways through which AVP contributes to the pathophysiology and treatment responsiveness of mood and trauma-related disorders. Clinical Trial Registration: www.clinicaltrials.gov (NCT02543983).

Glucocorticoids are produced through activation of the hypothalamic–pituitary–adrenal (HPA) axis, initiated by the release of corticotropin-releasing factor (CRF) from the hypothalamus. CRF acts through two receptor subtypes, CRF1 and CRF2. However, the specific contributions of CRF₁ and CRF₂ receptors to age-related changes in brain glucocorticoid activity remain largely unexplored. In certain tissues, including the hippocampus, glucocorticoid signaling is further amplified by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates inactive glucocorticoid metabolites into their active form. Notably, prior research investigating the role of hippocampal 11β-HSD1 in aging has focused exclusively on male subjects. In this study, we used genetic mouse models lacking functional CRF₁ or CRF₂ receptors to investigate their respective roles in regulating hippocampal 11β-HSD1 activity and glucocorticoid levels across age and sex. Mice of both sexes at 6 and 18 months of age were analyzed. Hippocampal 11β-HSD1 activity was assessed by measuring the ratio of corticosterone to dehydrocorticosterone using mass spectrometry in tissue extracts from CRF₁ and CRF₂ wild-type (WT), heterozygous (HET), and knockout (KO) mice. Our results demonstrate that hippocampal 11β-HSD1 activity increases with age in female CRF₁ WT and HET mice but not in CRF₁ KO females. In contrast, aged males exhibit elevated 11β-HSD1 activity regardless of CRF₁ genotype. In CRF₁ males, the age-related increase in hippocampal 11β-HSD1 activity is associated with higher hippocampal corticosterone levels, whereas in CRF₁ females, it corresponds with a decrease in hippocampal dehydrocorticosterone. CRF₁ deficiency leads to reduced hippocampal levels of both corticosterone and dehydrocorticosterone in males and females at both ages. CRF₁ deficiency is also associated with decreased plasma corticosterone levels in both male and female mice. Male, but not female, CRF₂ mice show an age-dependent increase in hippocampal 11β-HSD1 activity, which is not altered by CRF₂ deficiency. Moreover, CRF₂ deficiency results in increased plasma corticosterone in female, but not in male, mice. Overall, our findings reveal that hippocampal 11β-HSD1 activity increases with age in both sexes. In females, this increase is dependent on the presence of functional CRF₁ receptors. In contrast, males exhibit age-related increases in 11β-HSD1 activity independent of CRF₁ function. These findings underscore the importance of considering sex as a biological variable when developing therapeutic strategies targeting 11β-HSD1 to mitigate age-related memory decline.