Breathing movements driven by the brainstem rhythmogenic neural networks rely on chemosensory inputs to produce a motor output that is homeostatically adjusted to the prevailing metabolic demand. The central CO2 chemoreflex is a critical component of respiratory neural circuitry, as defects in these sensors cause hypoventilation syndromes, which are typically difficult to manage pharmacologically. Progesterone has long been known to stimulate breathing in both sexes, and remarkably, a potent progestin drug, etonogestrel (ETO), has been shown to enhance CO2-chemosensitivity in animal models and in a subset of female patients affected by congenital central hypoventilation syndrome. Our recent work shows that systemic chronic ETO treatment recovered the CO2 chemoreflex in female rats in which <80% of neurons of the key CO2 chemosensory structure of the retrotrapezoid nucleus (RTN) were eliminated, whereas male rats with similar lesions and ETO serum levels did not show recovery of the CO2 chemoreflex. Interestingly, female respiratory recovery was associated with increased expression of the pH sensors Task2 and Gpr4 mRNA in the surviving RTN neurons, suggesting that progestin drugs may recover the CO2 chemoreflex responses in a sex-specific fashion.
The evolutionary origin(s) of neuropeptide signalling is still largely unknown. It has been hypothesised that signal transmission via neuropeptides played a crucial role in the regulation of nervous systems in the bilaterian ancestor. Identification, expression and functional analyses of neuropeptides and their receptors across different taxonomic groups are important for better understanding the origin(s) of bilaterian neuropeptide signalling. An example is flatworms belonging to the Platyhelminthes (spiralian protostomes) and Xenacoelomorpha (sister to all Bilateria or sister to Ambulacraria). Despite their simple morphology (i.e., a body plan lacking a coelom and circulatory system), they often possess brain-like central nervous systems and a number of bilaterian-conserved neuropeptides. This feature makes them useful models for analyses of neuropeptides and their links to nervous systems. Although previous studies have revealed orthologous relationships between vertebrate neuropeptides and those found in both marine Platyhelminthes and Xenacoelomorpha, our work suggests possible ancestral functions of vasopressin/oxytocin (VP/OT) peptides (platytocin) in these groups.
Emerging research suggests that pregnancy and motherhood are associated with neural adaptations that support caregiving. Maternal-fetal attachment (MFA), representing the emotional bond between a pregnant woman and their fetus, is thought to be an early precursor to maternal-infant bonding and sensitive caregiving, yet its neural underpinnings remain largely unexplored. Resting-state electroencephalogram (EEG) coherence is a well-established measure of regional cortical connectivity and has been implicated in cognitive, attentional, and emotional processes related to parenting and might be implicated in MFA. Thirty-five pregnant women in their third trimester (mean 36.8 gestational weeks) participated. Resting-state EEG was collected, and alpha band coherence was computed for intra-frontal, intra-parietal, and frontoparietal regions. MFA was assessed using the Prenatal Attachment Inventory-Revised (PAI-R). Increased left frontoparietal and intra-frontal alpha coherence was associated with higher scores on the anticipation and interaction subscales of the PAI-R. These associations remained after controlling for parity and gestational age. No significant associations were observed between alpha coherence and the differentiation PAI-R subscale. These findings suggest that individual differences in cortical connectivity are associated with MFA, particularly anticipatory and interactional aspects of psychological engagement with the fetus. Identifying neural correlates of MFA suggests that maternal attachment-related processes toward the fetus are reflected in brain connectivity during pregnancy and offers insight into the neurobiological basis of early bonding.
Polycystic ovary syndrome (PCOS) is a multifaceted, complex metabolic and endocrine disease where gut flora is considered an important factor in causing PCOS. This study aimed to identify a suitable PCOS model that contributes to gut microbial dysbiosis and metabolic and hormonal disturbances. Prepubertal SD rats were administered with normal control (NC), dihydrotestosterone (DHT), DHT with fructose (F), DHT+ high fat diet (HFD) for 91 days, dehydroepiandrosterone (DHEA), DHEA with fructose, DHEA with HFD for 30 days, sodium valproate (SV), sodium valproate with fructose, and sodium valproate with HFD for 21 days. The estrous cycles were assessed over this timeframe. At the end of the experiment, superoxide dismutase and uterine and ovarian morphology were evaluated, along with hormone levels, lipid profiles, and 16S rRNA genomic sequencing. All models exhibited PCOS characteristics, including hormonal imbalances, insulin resistance (p ≤ .001), multiple follicular cysts on ultrasonography, and histological alterations. Gut microbial dysbiosis was observed across all PCOS-induced groups; however, the DHT alone group showed more pronounced alterations in microbial composition than the other experimental groups. Specifically, the DHT alone group exhibited reduced abundance of Firmicutes and increased abundance of Proteobacteria. Among the evaluated models, the DHT-only model showed more pronounced metabolic, hormonal, reproductive, and gut microbial alterations and may serve as a suitable model for PCOS research.
Pregnancy is characterized by pronounced neuroplasticity and heightened risk for psychopathology. While previous research has primarily examined postpartum depression, less work has investigated changes in internalizing symptoms measured dimensionally across the peripartum period. Furthermore, limited research has identified functional changes in the prefrontal cortex (PFC) across pregnancy, a brain area implicated in psychopathology. Understanding the dynamic changes in internalizing symptoms and PFC neuroconnectivity throughout pregnancy and their interrelations is crucial for early identification of perinatal psychopathology. This pre-registered longitudinal study examined changes in and associations between internalizing symptoms and PFC functional connectivity throughout the first and third trimesters of pregnancy. Pregnant individuals recruited from a community sample of females engaged in prenatal care (N = 60, Mage = 32.31, SD = 5.34, 90% White, 91.7% non-Hispanic/Latine) completed structured clinical interviews assessing mood and anxiety symptoms and resting-state functional near-infrared spectroscopy measuring PFC connectivity during the first and third trimesters of pregnancy. From the first to third trimester, longitudinal results revealed a significant decrease in symptoms of distress and fear and significant increases in neuroconnectivity anchored in left medial frontal areas of the PFC. Cross-sectionally, higher first trimester fear was associated with lower within-region right medial PFC and higher within-region left medial PFC connectivity. Longitudinal decreases in distress from first to third trimester were associated with increased connectivity between left medial and right lateral PFC, alongside weakened connectivity between bilateral medial frontal regions. These findings demonstrate that internalizing symptoms relate to prefrontal connectivity from first to third trimester in a community sample of pregnant women. Examining internalizing symptoms dimensionally across pregnancy allows for characterization of the full range of symptoms that impact pregnant individuals. Future research should explore prevention and intervention implications of the relations between neural profiles and internalizing symptoms during pregnancy to improve long-term outcomes for the mother and child.
Oxytocin (Oxt) is a neuropeptide critical for higher brain functions, with its physiological functions dependent on the activity of Oxt-producing neurons in the paraventricular nucleus (PVN). However, the postnatal maturation process of these neurons remains poorly understood, particularly whether it involves a uniform trajectory or a dynamic functional reorganization. Here, we investigated the electrophysiological maturation of PVN Oxt neurons in rats using a multifaceted approach including electrophysiology, principal component analysis (PCA), and f-I curve fitting. Our analysis revealed a highly heterogeneous maturation timeline for individual electrophysiological parameters. While action potential amplitude and half-width matured relatively early, the resting membrane potential (RMP) and firing threshold showed a much more protracted maturation. To comprehensively capture this, we applied PCA and found that the first principal component (PC1) exhibited a striking inverted U-shaped pattern over time. This pattern suggests a dynamic transition through three distinct functional states: an initial immature state, an intermediate transitional state, and a later mature state. Furthermore, f-I curve fitting provided mechanistic insights, identifying a "high-gain" state around postnatal Day 7, characterized by high firing threshold (Ith) and gain (k). This period temporally overlaps with peak Oxt receptor expression, hinting at a critical window for experience-dependent circuit refinement. Our findings provide a new perspective on neuronal maturation as a complex process of dynamic functional reorganization. The identified "high-gain" state may represent a critical period for Oxt system development, offering a crucial foundation for understanding neurodevelopmental disorders and developing targeted early interventions.
Perimenopause is characterised by irregular reproductive cycles and hormonal fluctuations, notably decreased estradiol (E2), which are linked to increased susceptibility to panic disorder and neuroinflammation. We examined whether panic-related respiratory and behavioural responses to respiratory challenges vary across reproductive stages. Female rats with regular estrous cycles (RC), representing reproductive cyclicity, and rats in periestropause (PE), a stage similar to perimenopause, were exposed to normoxia, hypoxia, and hypercapnia. Ventilation (V̇E) and metabolism (V̇O2) were measured during diestrus in RC and PE rats. Additionally, to measure levels of neuroinflammation, microglial reactivity in the Locus coeruleus (LC) in response to hypoxia-induced panic-like attacks was assessed. Under normoxia, there were no differences in V̇E or V̇O2 between groups. Hypercapnia increased V̇E in both groups by elevating respiratory frequency (fR) and tidal volume (VT), without changing body temperature (Tb). Hypoxia also raised V̇E in both groups, primarily driven by increased fR, and hypoxia-induced hypothermia occurred in RC and PE females. Both hypercapnia and hypoxia elevated the V̇E/V̇O2 ratio. Exposure to 7% O2 heightened panic-like behaviours in PE rats. Hypoxia increased LC microglial number, density, and mean soma size, while decreasing arborization area. PE rats also showed a higher microglial morphological index and a shorter nearest neighbour distance (NND). Jump frequency and freezing duration positively correlated with the morphological index and negatively with arborization area. These findings suggest that respiratory regulation remains intact, but behavioural and neuroimmune responses are amplified during the transition to estropause, heightening vulnerability to panic and anxiety-related disorders in ageing females.
Neurosteroids and their role in the pathophysiology of perinatal depression have been in the focus of scientific investigation for several decades. Recently, two synthetic analogs of the neurosteroid allopregnanolone-brexanolone and zuranolone-received approval in the United States for the treatment of postpartum depression (PPD) exhibiting a rapid, long-lasting antidepressant effect through a novel mechanism of action. These developments mark a milestone in psychiatric research and advancement in available treatment options. In this review, we examine the role of neurosteroids in perinatal depression, with particular emphasis on their impact on network states and functional connectivity. We synthesize current clinical experience with brexanolone and zuranolone in the treatment of PPD, highlighting efficacy and practical considerations. Finally, we explore emerging precision medicine approaches that leverage the heterogeneity of clinical presentations and treatment responses in PPD to guide the development of targeted therapeutic strategies for this widely prevalent and debilitating condition.
Grief is an all-encompassing human experience that reverberates across mind, brain, and body. Historically, the scientific study of grief has been rooted primarily in psychological frameworks. Pioneering work has begun to elucidate how attachment loss is encoded not only psychologically but also biologically, and this may be particularly significant during the perinatal period.
Loss-of-function mutations in DLK1, encoding Delta Like Non-Canonical Notch Ligand 1, have been linked to central precocious puberty (CPP) and increased body fat in girls, suggesting a role in the connection between metabolism and reproduction. DLK1 is located in the imprinted region of human chromosome 14, and mice lacking Dlk1 exhibit growth retardation and metabolic changes, phenotypes that overlap with Temple syndrome, an imprinting disorder associated with precocious puberty. However, the mechanisms by which DLK1 influences pubertal timing remain unclear. We investigated pubertal timing in Dlk1 knockout (KO) mice with either global or selective central nervous system (CNS) deletion of Dlk1, compared with control mice. Puberty onset and body weight were assessed, along with potential mediators of pubertal timing, including leptin and kisspeptin. Dlk1KO females reached puberty at the same age as controls, despite lower body weight. Dlk1KO males had delayed preputial separation but, like females, reached puberty at significantly lower body weight. Serum leptin and hypothalamic Socs3 mRNA, a downstream leptin effector, were lower peri-pubertally in Dlk1KO females than in controls. Kiss1 mRNA levels in the mediobasal hypothalamus were significantly lower in Dlk1KO females at puberty onset. Selective Dlk1 deletion in neurons and glial cells did not affect pubertal timing. These findings suggest that peripheral sources of Dlk1 contribute to the metabolic and endocrine regulation of pubertal timing. The absence of Dlk1 appears to alter the metabolic milieu in which puberty occurs, allowing activation of the reproductive axis despite low body weight and reduced hypothalamic kisspeptin expression.
Primary amenorrhoea is defined as the absence of menarche by the expected age, with or without delayed pubertal development in adolescents. It may result from anatomical, genetic, endocrine, and functional causes. Among the latter, we propose the term primary functional hypothalamic amenorrhoea (P-FHA) to describe primary amenorrhoea characterised by hypothalamic-pituitary-ovarian axis suppression in the absence of organic disease. P-FHA is frequently associated with low energy availability (LEA), particularly in individuals with feeding and eating disorders (FEDs) or excessive exercise, often within the spectrum of Relative Energy Deficiency in Sport (REDs). Despite its clinical relevance, P-FHA remains under-recognised, with limited dedicated research. This review aims to synthesise clinical studies addressing P-FHA in the context of FEDs or excessive exercise. A systematic literature search was conducted using PubMed, Web of Science, and Scopus. Studies focusing on P-FHA and its association with FEDs, excessive exercise, and REDs were included. Case reports and aggregated studies combining P-FHA and S-FHA were excluded to ensure specificity. Twenty-four studies addressing patients with P-FHA were identified. Available evidence suggests that the reported frequency of functional hypothalamic causes of primary amenorrhoea may have increased over time, although estimates varied substantially across populations and study designs. In patients with FEDs, the prevalence of PA ranged from 2.4% to 14.8%, while athlete cohorts reported frequencies ranging from 7.3% to 53.8%. FEDs and excessive exercise, including REDs-related conditions, emerged as major clinical settings. Data specifically addressing hormonal profiles or body composition in this context remain limited. P-FHA may represent an early clinical manifestation of chronic LEA occurring during a critical developmental window. Early recognition and multidisciplinary management are essential to minimise potential consequences on growth, skeletal health, reproductive function, body composition, and psychological well-being. Further prospective studies are needed to better define its epidemiology, neuroendocrine mechanisms, and optimal management strategies.
Nucleoporins (NUPs) constitute the nuclear pore complex (NPC) and are essentially involved in nuclear transport, chromatin organization, and context-dependent gene regulation. However, the role of NUPs in neuroendocrine (tumor)biology and related diagnostic potential is poorly defined. In this study, we comparatively analyzed immunohistochemical expression patterns of NUP98 and NUP153 (sharing structural and functional similarities) across a large variety of human tissues and tumors (total N > 600), with a focus on neuroendocrine neoplasms (NENs (n = 361)). While both NUPs showed a nuclear rim accentuated staining pattern, NUP98 exhibited ubiquitous and NUP153 a striking cell- and tissue/tumor-type-dependent immunoreactivity. More specifically, NUP153 immunoreactivity was consistently detectable in neuroendocrine tissues (e.g., pancreatic islets) and retained in neuroendocrine tumors (NETs) of the pancreas, lung, appendix, and small intestine, but almost completely absent in neuroendocrine carcinomas (NECs) and non-neuroendocrine carcinomas. Loss of NUP153 staining correlated with poorer clinical outcomes in pancreatic NETs. Further analyses revealed that NUP153 messenger ribonucleic acid (mRNA) and total protein levels were not significantly different between NETs and non-neuroendocrine carcinomas, as evaluated by quantitative real-time polymerase chain reaction and targeted proteomics. Differential isoform usage was ruled out by polymerase chain reaction and sequencing as another possible explanation for the discriminative immunohistochemical findings. Finally, a high density of post-translational modifications (PTMs) within the antigen sequence could be discovered and indicated PTM-dependent detection as the likely cause of differential staining. Collectively, our findings suggest that NUP153 is a differentiation-dependent and PTM-sensitive immunohistochemical marker in NENs with diagnostic and prognostic potential. It also emphasizes the importance of orthogonal molecular analyses for correct interpretation of IHC stainings.
Metabolic syndrome and Alzheimer's disease (AD) are increasingly recognised as interconnected, sharing vascular, metabolic and inflammatory pathways that accelerate brain ageing and cognitive decline. This review critically examines the evidence that glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for diabetes and obesity, may influence AD related pathways or reduce AD risk in metabolically vulnerable populations. Metabolic syndrome and AD related cognitive impairment share biological mechanisms including vascular damage, insulin resistance and chronic inflammation, suggesting that therapies targeting metabolic dysfunction could influence neurological outcomes. GLP-1RAs are notable for combining systemic benefits, like weight loss, improved glycaemic control, and reduced cardiovascular risk, with possible but incompletely established central nervous system effects. Experimental studies suggest that some GLP-1RAs may reduce amyloid and tau pathology, support mitochondrial function, and limit neuroinflammation, although recent preclinical studies and limited brain penetrance argue against a direct neuroprotective effect. Observational data suggest lower dementia rates among users compared with other antidiabetic treatments. However, the recent EVOKE and EVOKE + trials showed that oral semaglutide did not slow clinical progression in early symptomatic AD, despite positive biomarker effects. This highlights the challenge of translating biological plausibility into meaningful clinical benefit and refocuses attention on disease stage, target population, and mechanism. Beyond summarising evidence, this review advocates a more cautious and mechanism specific framework: preserving cognitive health may require addressing systemic metabolic dysfunction rather than targeting the brain alone. GLP-1 RAs have failed to show an effect in symptomatic AD, but their effects on metabolism might still be beneficial at earlier stages, such as the preclinical phase of AD. Future studies should determine whether earlier intervention in metabolically enriched groups can alter AD related cognitive, vascular, and biomarker trajectories.
Rolf Christian Gaillard was a Swiss physician, scientist, and academic leader whose career contributed significantly to the development of modern European endocrinology and neuroendocrinology. Among his most remarkable qualities was an exceptional talent for organisation and institution-building. Together with his collaborators, Gaillard became internationally recognised for his work on regulation of the hypothalamic-pituitary-adrenal axis. His research demonstrated how immune mediators influence endocrine regulation during infection, inflammation, trauma, and chronic stress. His scientific interests extended beyond neuroendocrinology and included leptin physiology, obesity, appetite regulation, adrenal disorders, adult growth hormone deficiency, metabolic diseases, reproductive endocrinology, and neuroendocrine adaptation. A founding member of European Neuroendocrine Association (ENEA), he subsequently served as its Treasurer and then as its President and largely contributed the success of the ENEA Congresses and Workshops.
Pancreatic neuroendocrine tumors (PanNETs) are increasingly detected, and the optimal extent of resection remains uncertain because perioperative burden and oncologic assessment may differ by procedure. Enucleation (EN) and central pancreatectomy (CP) are often grouped together as parenchyma-sparing resections (PSRs) despite substantial differences in technical complexity, postoperative risk, and oncologic evaluation.We conducted a multicenter retrospective study of consecutive patients who underwent resection for pathologically confirmed PanNETs ≤20 mm. Procedures were categorized as EN, CP, pancreatoduodenectomy (PD), total pancreatectomy (TP), or distal pancreatectomy (DP). Primary outcomes were clinically relevant postoperative pancreatic fistula (CR-POPF) and major morbidity, defined as Clavien-Dindo grade ≥IIIa. A prespecified pairwise comparison focused on EN and CP, and pathologic assessment patterns were analyzed descriptively across procedures. Of 460 patients, 164 (35.7%) underwent EN, 40 (8.7%) CP, 84 (18.2%) PD/TP, and 172 (37.4%) DP. CR-POPF occurred in 115 patients (25.0%), major morbidity in 68 (14.8%), and 90-day mortality in 4 (0.9%). Among PSRs, CP had higher major morbidity than EN (25.0% vs 10.4%, p =.020), higher CR-POPF (50.0% vs. 24.4%, p =.003), and a longer median hospital stay (19.5 vs. 10.0 days, p <.001). Lymph node (LN) assessment was less frequent after EN than CP (40.4% vs. 87.5%, p <.001). Among assessed cases, LN metastases were identified in 44/320 patients (13.8%). EN and CP are not interchangeable as parenchyma-sparing options for small PanNETs. Among patients selected for resection, procedure selection should consider tumor location, function, technical feasibility, and oncologic requirements rather than size alone.
Acromegaly is a rare disease, due in most of the cases to a growth hormone (GH)-secreting pituitary adenoma (PA), namely neuroendocrine tumour (PitNET). The treatment of patients with acromegaly is multimodal and multi-step, including surgery, medical therapies, and radiotherapy. In the last 30 years, the therapeutic armamentarium for the treatment of acromegaly has progressively increased, and the therapeutic algorithm has been significantly modified through the identification of clinical, biochemical, and molecular biomarkers of treatment outcome. The personalization of acromegaly treatment has shifted the paradigm from a 'trial-and-error' to a 'target-to-treat' treatment approach to achieve early disease control and to reduce the risk of disease-related comorbidities that may lead to an increased mortality. Nevertheless, despite the numerous improvements in the treatment of patients with acromegaly, disease control is not achieved in all patients, according to the results of randomized clinical trials, interventional studies, and prospective and retrospective observational studies. In parallel, the normalization of GH and IGF-I levels may not be sufficient to control acromegaly related symptoms and prevent disease-related comorbidities. In this review, we will report on the most recent aims of treatment and cure in patients with acromegaly, on the efficacy and predictors of response to conventional treatments (such as first- and second-generation somatostatin receptor ligands and growth hormone receptor antagonist). A specific section will focus on the rarer aggressive disease pictures and on the treatment with systemic therapies (such as temozolomide and capecitabine) and on target therapies (such as neo-angiogenesis and immune checkpoint inhibitors).
The aim of this study was to investigate the effects of cannabidiol (CBD) on memory deficits induced by ovariectomy and to directly compare its effects with those of hormone therapy, in order to better understand potential shared mechanisms related to menopause-associated cognitive decline, with a particular focus on the endocannabinoid system. Three-month-old female Wistar rats were randomly assigned to four experimental groups: SHAM-Veh (Vehicle), OVX-Veh, OVX-E2 (estradiol), and OVX-CBD. Animals underwent either bilateral ovariectomy or sham surgery. Following a three-week recovery period, rats received daily subcutaneous injections of CBD (10 mg/kg), estradiol (10 μg/kg), or vehicle for 21 consecutive days. Behavioral assessments included object recognition and fear-motivated memory tests. Twenty-four hours after the final treatment, animals were euthanized for neurochemical and molecular analyses. Levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured using high-performance liquid chromatography. Gene expression of cannabinoid receptors CB1 and CB2, as well as enzymes involved in the synthesis and degradation of endocannabinoids (NAPE-PLD, DAGL-A, FAAH, and MGLL), was evaluated in the hippocampus by RT-qPCR. The results demonstrated that CBD treatment produced memory improvements in the object recognition task comparable to those observed with estradiol. Ovariectomy-induced impairments in fear-motivated memory were completely reversed by both CBD and estradiol treatments. Additionally, CBD reduced the expression of FAAH and MGLL, resulting in increased hippocampal levels of AEA and 2-AG, effects similar to those observed with hormone therapy. Estradiol also increased NAPE-PLD expression, contributing to elevated AEA levels. Overall, the findings suggest that CBD exerts a protective effect on memory comparable to standard estrogen therapy, supporting its therapeutic potential for menopause-related cognitive impairments.
