Lung neuroendocrine tumors (LNETs) are rare, with surgical resection as the mainstay of treatment, although the optimal extent remains uncertain. Herein, we present the first meta-analysis to assess the effect of resection extent (lobar vs. sub-lobar) on overall survival. We conducted a systematic review of the literature to identify studies comparing overall survival following lobectomy versus sub-lobar resection in LNETs. An inverse-variance meta-analysis was performed, and a Cox regression model was applied to reconstructed time-to-event data estimated from published Kaplan-Meier curves to generate pooled survival estimates. Six studies encompassing 3,700 patients (lobectomy, n = 2,409; sub-lobar resection, n = 1,291) were included in the final analysis. The pooled 5-year overall survival for the entire cohort was 78.8% (95% CI, 76.6-81.1). No statistically significant difference in overall survival was observed between lobectomy and sub-lobar resection (HR = 1.21; 95% CI, 0.80-1.83; I2 = 0%). Segmentectomy and lobectomy demonstrated comparable survival (p = 0.38), whereas wedge resection was associated with higher mortality (HR = 2.02; 95% CI, 1.64-2.49; I2 = 0%). Sampling of >10 lymph nodes was more frequent in lobectomy than sub-lobar resection (29.1% [95% CI, 0.8-95.3] vs 7.4% [95% CI, 0.01-98], respectively), likely contributing to the higher rate of nodal pathologic upstaging observed in the lobectomy group (6.2% [95% CI, 0.2-64.9] vs 2.2% [95% CI, 0-99]). In this first meta-analysis of surgical resection for LNETs, sub-lobar resection and lobectomy showed no clear difference in overall survival. Adequate lymph node assessment remains essential, irrespective of the surgical approach.

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.

Puberty is a critical developmental stage during which individuals acquire the capacity for sexual reproduction. This transition involves a series of complex biological events primarily orchestrated by the activation of the hypothalamo-pituitary-gonadal (HPG) axis. Central to this process are gonadotropin-releasing hormone (GnRH) neurons, which play a key role in regulating reproductive maturation and function throughout life. However, the precise mechanisms that trigger the pubertal increase in GnRH activity remain incompletely understood. Evidence from our laboratory indicates that a profound remodeling of the hypothalamus is crucial for sexual maturation. In this review, we discuss findings from our research utilizing a combination of RNA sequencing, conditional genetic manipulation with mouse models and viral vectors, and systems neuroscience approaches. Our results reveal that the pubertal transition involves changes in the chemical phenotype and site-specific innervation of key hypothalamic neurons. Among these neuronal populations, those expressing growth hormone-releasing hormone (GHRH), kisspeptin, or dopamine transporter (DAT) are the focus of this review. Building upon data from other laboratories, our findings offer new insights into the neural and molecular mechanisms by which the hypothalamus orchestrates sexual maturation.

Severe calorie restriction in mouse models has highlighted the crucial role of the ghrelin system in maintaining glycemia and promoting survival. We hypothesized that if ghrelin acts as a survival signal, enhancing the responsivity of the GH secretagogue receptor (GHSR) should favor GHSR protective responses. To test this, we used rats with genetically enhanced GHSR sensitivity (GhsrQ343X) and wild‐type littermate controls and examined their acute responses to pharmacological challenges. Consistent with our hypothesis, GhsrQ343X rats, despite normal glucose and insulin tolerance, exhibited a significant increase in blood glucose in response to GHSR agonism, accompanied by elevated counter‐regulatory hormones including corticosterone. Concurrently, these rats displayed a notable decrease in locomotor activity and delayed feeding response. Also, GHSR agonism partially altered the cocaine‐induced hyperlocomotion of GhsrQ343X rats while they showed unaltered locomotor sensitization to cocaine. At the cellular level, functional studies indicated that the GhsrQ343X mutation prolongs ghrelin‐induced GHSR‐G protein canonical signaling. Altogether, in a model of increased GHSR sensitivity, GHSR agonist stimulation was sufficient to promote a robust blood glucose increase, while the acute feeding response was delayed in a context of unexpected hypolocomotor response. This mechanism may have implications for severe states of undernutrition such as restrictive anorexia nervosa.

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.

Successful reproduction requires coordinated regulation of gonadal function and sexual behavior. Nonetheless, the mechanisms underlying this coordination in teleosts remain elusive. Here, we aimed to find out the possible involvement of ovulation in the control of female sexual behavior using medaka. We analyzed the sexual behavior of medaka with targeted knockouts of genes involved in ovulation. We also examined the actual timing of ovulation and sexual behavior. Furthermore, we investigated the possible contribution of a progesterone derivative through pharmacological treatment and analyzed the localization of the progesterone receptor in the brain using in situ hybridization. Genetically anovulatory female medaka did not show female receptivity, although they were normally courted by males. Consistently, intact females exhibited sexual behavior only after ovulation. Additionally, the administration of progesterone, which is released during ovulation, partially reinstated the sexual receptivity of anovulatory knockout females. Taken together with our result that progesterone receptor is expressed in brain regions that are considered strong candidates for regulation of sexual behavior, we propose that female sexual receptivity is facilitated in synchrony with the ovulatory cycle via progesterone receptor signaling in specific brain regions around the time of ovulation.

Early detection of metastases and timely surgical intervention play a crucial role in the management of neuroendocrine tumors. In large‐sized pheochromocytomas and sympathetic paragangliomas (PPGL), functional imaging with positron emission tomography (PET) is recommended, as it improves the detection of metastases, which may go undetected on conventional radiologic imaging. 11C‐hydroxyephedrine binds to the norepinephrine transporter receptor and is detected by PET/CT (HED‐PET/CT). It has previously demonstrated high accuracy in detecting primary and metastatic PPGL; however, its impact on preoperative staging is unclear. In this study, we retrospectively analyzed a selected cohort of 44 patients with large PPGL to evaluate whether HED‐PET/CT influences preoperative clinical decision‐making. All patients who underwent HED‐PET/CT at Uppsala University Hospital between 2004 and 2024 were screened for inclusion. In total, 44 patients with pheochromocytomas >5 cm and paragangliomas >4 cm were included. HED‐PET/CT results were compared with CT/MR findings, and a final consensus was reached on whether preoperative HED‐PET/CT would have altered clinical decision‐making. HED‐PET/CT identified previously undetected metastatic disease in three patients (6.8%), which had not been visualized on CT/MR. Additionally, two patients had discordant findings, where HED‐PET/CT revealed additional metastases. In one case, a liver metastasis was identified postoperatively with HED‐PET/CT, leading to a metastasectomy that could have potentially been avoided. These findings suggest that HED‐PET/CT is highly accurate in detecting metastases; however, its routine preoperative use may be limited and appears to provide significant clinical benefit only in selected patients.

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 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.