Neuroendocrine Function Research Articles

Cell scientist to watch – Bhavani Shankar Sahu

ABSTRACT Bhavani Shankar Sahu is an Associate Professor at the National Brain Research Centre (NBRC) in Manesar, India. He completed his PhD in cell biology and molecular genetics at the Indian Institute of Technology Madras, studying links between neuroendocrine function and metabolic disease. Inspired to better understand fundamental mechanisms of neuropeptide secretion, he then completed postdoctoral research in Prof. Margaret Robinson's lab at the University of Cambridge, UK and with Prof. Alessandro Bartolomucci at the University of Minnesota and University of California San Diego, USA. In 2019, he returned to India to start his own lab at the NBRC, where he and his team investigate the biology of exocytosis in neurons and neuroendocrine cells from the molecular to the physiological level. We spoke with Bhavani over Zoom about his career journey, mentorship philosophy and enthusiasm for science outreach.

Organization of enkephalinergic neuronal system in the central nervous system of the gecko Hemidactylus frenatus.

Enkephalins are endogenous opioid pentapeptides that play a role in neurotransmission and pain modulation in vertebrates. However, the distribution pattern of enkephalinergic neurons in the brains of reptiles has been understudied. This study reports the organization of the methionine-enkephalin (M-ENK) and leucine-enkephalin (L-ENK) neuronal systems in the central nervous system of the gecko Hemidactylus frenatus using an immunofluorescence labeling method. Although M-ENK and L-ENK-immunoreactive (ir) fibers extended throughout the pallial and subpallial subdivisions, including the olfactory bulbs, M-ENK and L-ENK-ir cells were found only in the dorsal septal nucleus. Enkephalinergic perikarya and fibers were highly concentrated in the periventricular and lateral preoptic areas, as well as in the anterior and lateral subdivisions of the hypothalamus, while enkephalinergic innervation was observed in the hypothalamic periventricular nucleus, infundibular recess nucleus and median eminence. The dense accumulation of enkephalinergic content was noticed in the pars distalis of the hypophysis. In the thalamus, the nucleus rotundus and the dorsolateral, medial, and medial posterior thalamic nuclei contained M-ENK and L-ENK-ir fibers, whereas clusters of M-ENK and L-ENK-ir neurons were observed in the pretectum, mesencephalon, and rhombencephalon. The enkephalinergic fibers were also seen in the area X around the central canal, as well as the dorsal and ventral horns. The widespread distribution of enkephalin-containing neurons within the central nervous system implies that enkephalins regulate a variety of functions in the gecko, including sensory, behavioral, hypophysiotropic, and neuroendocrine functions.

Research status and prospects of pituitary adenomas in conjunction with neurological and psychiatric disorders and the tumor microenvironment.

Patients with pituitary neuroendocrine tumors (PitNETs) often experience neuropsychiatric disorders due to factors such as hormonal imbalances, and inadequate management of medications, surgeries, and radiation therapies. Commonly observed disorders include depression, anxiety, and cognitive dysfunction, which significantly impact patients' quality of life and prognosis. PitNETs have a significant presence of immune cells within the tumor microenvironment (TME), predominantly macrophages and T lymphocytes. These immune cells secrete a variety of cytokines, growth factors, and chemokines, which regulate the biological behaviors of PitNETs, including tumor initiation, proliferation, migration, invasion, and angiogenesis. In addition, this review provides a pioneering summary of the close relationships between the aberrant secretion of proinflammatory cytokines within the TME of PitNETs and the occurrence of neuropsychiatric disorders, along with their potential underlying mechanisms. The cytokines produced as a result of TME dysregulation may affect various aspects of the central nervous system, including neurotransmitter metabolism, neuroendocrine function, and neurovascular plasticity, thereby leading to a higher susceptibility to neurobehavioral disorders in PitNET patients.

Coping and empowerment preventive intervention buffers early adolescent neuroendocrine-related risk for internalizing problems

There is an absence of mechanism-driven interventions equipped to reduce the large mental health disparities that exist for preadolescent youth living in poverty. Building a Strong Identity and Coping Skills (BaSICS) is a preventive intervention designed to target multiple aspects of poverty-related stress adaptation, including altered neuroendocrine function. The purpose of the current study was to examine whether pre-post shifts in preadolescent hypothalamic-pituitary-adrenal (HPA) activation could longitudinally predict internalizing outcomes and to determine whether BaSICS could buffer such HPA-related risk for psychopathology. Low-income youth (n = 112) ages 11–12 years were randomized to the 16-session intervention or assessment-only control (53% intervention; 54% female; 40% Hispanic, 63% Black, 20% White). Youth completed questionnaires and the Trier Social Stress Test, and provided cortisol via saliva at six timepoints during the 90-minute assessment. Adjusting for pre-intervention Cortisol Area Under the Curve–Ground (CAUCg) scores and internalizing problems, post-intervention CAUCg and intervention main and interactive effects were modeled as predictors of internalizing outcomes across post-intervention, 6-month, and 12-month follow-up assessments using multilevel regression methods. A significant post-intervention CAUCg by intervention interaction emerged (B=1.198, SE=0.433, p = .006). For control youth, baseline-adjusted decreases in cortisol output were associated with increases in internalizing problems that remained stably elevated across follow-up assessments. For BaSICS youth, however, internalizing problems decreased and remained stably low following program delivery, irrespective of post-intervention increases or decreases in cortisol output. Findings illustrate how BaSICS may buffer against HPA-related risk for internalizing psychopathology and provide support for interventions targeting biological mechanisms of risk for low-income preadolescents.

The 26RFa (QRFP)/GPR103 Neuropeptidergic System: A Key Regulator of Energy and Glucose Metabolism.

Obesity and type 2 diabetes are strongly associated pathologies, currently considered as a worldwide epidemic problem. Understanding the mechanisms that drive the development of these diseases would enable to develop new therapeutic strategies for their prevention and treatment. Particularly, the role of the brain in energy and glucose homeostasis has been studied for 2 decades. In specific, the hypothalamus contains well-identified neural networks that regulate appetite and potentially also glucose homeostasis. A new concept has thus emerged, suggesting that obesity and diabetes could be due to a dysfunction of the same, still poorly understood, neural networks. The neuropeptide 26RFa (also termed QRFP) belongs to the family of RFamide regulatory peptides and has been identified as the endogenous ligand of the human G protein-coupled receptor GPR103 (QRFPR). The primary structure of 26RFa is strongly conserved during vertebrate evolution, suggesting its crucial roles in the control of vital functions. Indeed, the 26RFa/GPR103 peptidergic system is reported to be involved in the control of various neuroendocrine functions, notably the control of energy metabolism in which it plays an important role, both centrally and peripherally, since 26RFa regulates feeding behavior, thermogenesis and lipogenesis. Moreover, 26RFa is reported to control glucose homeostasis both peripherally, where it acts as an incretin, and centrally, where the 26RFa/GPR103 system relays insulin signaling in the brain to control glucose metabolism. This review gives a comprehensive overview of the role of the 26RFa/GPR103 system as a key player in the control of energy and glucose metabolism. In a pathophysiological context, this neuropeptidergic system represents a prime therapeutic target whose mechanisms are highly relevant to decipher.

Multifaced roles of the long non-coding RNA DRAIC in cancer progression.

Long non-coding RNAs (lncRNA) are functional RNAs, with over 200 nucleotides in length and lacking protein-coding potential. Studies have indicated that lncRNAs are important gene regulators under physiological conditions. Aberrant lncRNA expression is associated with the initiation and progression of various diseases, including cancers. High-throughput transcriptome analyses have revealed thousands of lncRNAs as putative tumor suppressors or promoters in various cancers, but the detailed molecular mechanisms of each lncRNA remain unclear. Downregulated RNA In Cancer, inhibitor of cell invasion and migration (DRAIC) (also known as LOC145837 and RP11-279F6.1) is a lncRNA that inhibits or promotes cancer progression with several modes of action. DRAIC was originally identified as a tumor-suppressive lncRNA in prostate adenocarcinoma. Subsequent studies also revealed that it has an anti-tumor role in glioblastoma, triple-negative breast cancer, and stomach adenocarcinoma. However, DRAIC exhibits oncogenic functions in other malignancies, such as lung adenocarcinoma and esophageal carcinoma, indicating its highly context-dependent effects on cancer progression and clinical outcomes. DRAIC and its associated pathways regulate various biological processes, including proliferation, invasion, metastasis, autophagy, and neuroendocrine function. This review introduces the multifaceted roles of DRAIC, particularly in cancer progression, and discusses its biological significance and clinical implications.

Neuroendocrine functions of monoamines in invertebrates: Focus on bivalve molluscs

Monoamines (MA) such as serotonin, catecholamines (dopamine, norepinephrine, epinephrine), and trace amines (octopamine, tyramine), are neurotransmitters and neuroendocrine modulators in vertebrates, that contribute to adaptation to the environment. Although MA are conserved in evolution, information is still fragmentary in invertebrates, given the diversity of phyla and species. However, MA are crucial in homeostatic processes in these organisms, where the absence of canonical endocrine glands in many groups implies that the modulation of physiological functions is essentially neuroendocrine.In this review, we summarize available information on MA systems in invertebrates, with focus on bivalve molluscs, that are widespread in different aquatic environments, where they are subjected to a variety of environmental stimuli. Available data are reviewed on the presence of the different MA in bivalve tissues, their metabolism, target cells, signaling pathways, and the physiological functions modulated in larval and adult stages. Research gaps and perspectives are highlighted, in order to enrich the framework of knowledge on MA neuroendocrine functions, and on their role in adaptation to ongoing and future environmental changes.

Family risk, parental cortisol contagion, and parenting: A process-oriented approach to spillover.

This multi-method longitudinal study sought to investigate linkage in parental neuroendocrine functioning - indicated by cortisol - over two measurement occasions. In addition, we examined how parental cortisol linkage may operate as an intermediate factor in the cascade of contextual risks and parenting. Participants were 235 families with a young child (Mage = 33.56, 36.00 years for mothers and fathers respectively), who were followed for two annual measurement occasions. Parental cortisol linkage was measured around a laboratory conflict discussion task at both measurement occasions (i.e., pre-discussion, 20- and 40-minute post-discussion for each measurement occasion). Maternal and paternal parenting behavior was observed during a parent-child discipline discussion task. Findings indicated similar levels of cortisol linkage between parents over the two measurement occasions. Furthermore, cortisol linkage between parents operated as an intermediate factor between contextual risks and more compromised parenting behavior. That is, greater contextual risks, indicated by greater neighborhood risk and interparental conflict, were linked to greater cortisol linkage between parents over time, which was in turn linked to greater authoritarian parenting during parent-child interaction. Findings highlighted the importance of understanding physiological-linkage processes with respect to the impact of contextual risks on family functioning and may have crucial implications for clinical work.

Immunological Aspects of Depressive Disorder - The Review

Abstract Depression represents a mood disorder and is considered to be one of the most common mental disorders in general. World Health Organization estimates that depression will be the leading cause of disability-adjusted life years, until 2030. Depression is a complex heterogeneous disorder where immune system and its regulation play an important role. Innate and adaptive immunity mechanisms are included, along with processes of immune activation and suppression. The expression of humoral factors of innate immunity, especially pro-inflammatory cytokines, is increased, whereas the intensity of cellular immune mechanisms, primarily T cells and NK cells, are impaired. The influence of pro- inflammatory cytokines on depression is reflected in their effect on certain enzymes and ensuing reduction of neurotransmitters serotonin and dopamine. They also affect the neuroendocrine function in central nervous system, resulting in increase of cortisol levels and inactivation of glucocorticoid receptors in the periphery, which leads to neurodegeneration and decrease in neurotransmitter production. Certain cytokines affect neuroplasticity through the decreasing of concentration of neurotrophic brain factor and induction of brain cell apoptosis. The results are often contradictory talking about mechanisms of adaptive immunity. On one hand, an increased activity of Tlymphocytes is observed, while on the other, there are evidence of spontaneous apoptosis and impaired function of these cellsin depression. In addition, neuroprotective role of autoreactive and regulatory T cells in prevention of depression has also been demonstrated. The aim of this paper is to analyze the current knowledge on the role of immune mechanisms in the pathogenesis of depression.

Neuroendocrine effects of the duper mutation in Syrian hamsters: a role for Cryptochrome 1.

Molecular and physiological determinants of the timing of reproductive events, including the pre-ovulatory LH surge and seasonal fluctuations in fertility, are incompletely understood. We used the Cryptochrome 1-deficient duper mutant to examine the role of this core circadian clock gene in Syrian hamsters. We find that the phase of the LH surge and its stability upon shifts of the light: dark cycle are altered in duper mutants. The intensity of immunoreactive PER1 in GnRH cells of the preoptic area peaks earlier in the day in duper than wild type hamsters. We note that GnRH fibers coursing through the suprachiasmatic nucleus (SCN) contact vasopressin- and VIP-immunoreactive cells, suggesting a possible locus of circadian control of the LH surge. Unlike wild types, duper hamsters do not regress their gonads within 8weeks of constant darkness, despite evidence of melatonin secretion during the subjective night. In light of the finding that the duper allele is a stop codon in Cryptochrome 1, our results suggest important neuroendocrine functions of this core circadian clock gene.

A study of roflumilast treatment on functional and structural changes in hippocampus in depressed Adult male Wistar rats.

Depression is a common stress disability disorder that affects higher mental functions including emotion, cognition, and behavior. It may be mediated by inflammatory cytokines that interfere with neuroendocrine function, and synaptic plasticity. Therefore, reductions in inflammation might contribute to treatment response. The current study aims to evaluate the role of Protein Kinase (PKA)- cAMP response element-binding protein (CREB)- brain derived neurotropic factor (BDNF) signaling pathway in depression and the effects of roflumilast (PDE4 inhibitor) as potential antidepressant on the activity of the PKA-CREB-BDNF signaling pathway, histology, and pro-inflammatory cytokine production. Forty Adult male Wistar rats were divided into 4 groups: Control group, Positive Control group: similar to the controls but received Roflumilast (3 mg / kg / day) by oral gavage for the last 4 weeks of the experiment, Depressed group which were exposed to chronic stress for 6 weeks, and Roflumilast-treated group which were exposed to chronic stress for 6 weeks and treated by Roflumilast (3 mg / kg / day) by oral gavage for the last 4 weeks of the experiment. The depressed group showed significant increase in immobility time with significant decrease in swimming and struggling times, significant decrease in hippocampal PKA, CERB, BDNF, Dopamine, Cortisone, and Superoxide dismutase while hippocampal Phosphodiesterase-E4, Interleukin-6, and Malondialdhyde levels were significantly elevated. These findings were significantly reversed upon Roflumilast treatment. Therefore, it could be concluded that depression is a neurodegenerative inflammatory disease and oxidative stress plays a key role in depression. Roflumilast treatment attenuated the depression behavior in rats denoting its neuroprotective, and anti-inflammatory effects.

New developments in guidelines for brain death/death by neurological criteria.

The declaration of brain death (BD), or death by neurological criteria (DNC), is medically and legally accepted throughout much of the world. However, inconsistencies in national and international policies have prompted efforts to harmonize practice and central concepts, both between and within countries. The World Brain Death Project was published in 2020, followed by notable revisions to the Canadian and US guidelines in 2023. The mission of these initiatives was to ensure accurate and conservative determination of BD/DNC, as false-positive determinations could have major negative implications for the medical field and the public's trust in our ability to accurately declare death. In this Review, we review the changes that were introduced in the 2023 US BD/DNC guidelines and consider how these guidelines compare with those formulated in Canada and elsewhere in the world. We address controversies in BD/DNC determination, including neuroendocrine function, consent and accommodation of objections, summarize the legal status of BD/DNC internationally and discuss areas for further BD/DNC research.

Prenatal maternal glucocorticoid exposure modifies sperm miRNA profiles across multiple generations in the guinea-pig.

Maternal stress and glucocorticoid exposure during pregnancy have multigenerational effects on neuroendocrine function and behaviours in offspring. Importantly, effects are transmitted through the paternal lineage. Altered phenotypes are associated with profound differences in transcription and DNA methylation in the brain. In the present study, we hypothesized that maternal prenatal synthetic glucocorticoid (sGC) exposure in the F0 pregnancy will result in differences in miRNA levels in testes germ cells and sperm across multiple generations, and that these changes will associate with modified microRNA (miRNA) profiles and gene expression in the prefrontal cortex (PFC) of subsequent generations. Pregnant guinea-pigs (F0) were treated with multiple courses of the sGC betamethasone (Beta) (1mgkg-1; gestational days 40, 41, 50, 51, 60 and 61) in late gestation. miRNA levels were assessed in testes germ cells and in F2 PFC using the GeneChip miRNA 4.0 Array and candidate miRNA measured in epididymal sperm by quantitative real-time PCR. Maternal Beta exposure did not alter miRNA levels in germ cells derived from the testes of adult male offspring. However, there were significant differences in the levels of four candidate miRNAs in the sperm of F1 and F2 adult males. There were no changes in miRNA levels in the PFC of juvenile F2 female offspring. The present study has identified that maternal Beta exposure leads to altered miRNA levels in sperm that are apparent for at least two generations. The fact that differences were confined to epididymal sperm suggests that the intergenerational effects of Beta may target the epididymis. KEY POINTS: Paternal glucocorticoid exposure prior to conception leads to profound epigenetic changes in the brain and somatic tissues in offspring, and microRNAs (miRNAs) in sperm may mediate these changes. We show that there were significant differences in the miRNA profile of epididymal sperm in two generations following prenatal glucocorticoid exposure that were not observed in germ cells derived from the testes. The epididymis is a probable target for intergenerational programming. The effects of prenatal glucocorticoid treatment may span multiple generations.

Dopaminergic and serotoninergic systems as preferential targets of the pyrethroid tefluthrin exposure in the rat brain

The monoaminergic systems dopamine (DA) and serotonin (5-HT) play important roles in neuromodulation, such as motor control, cognitive, affective, and neuroendocrine functions. In the present research study, we addressed the hypothesis that exposure to Type I pyrethroid tefluthrin may specifically target the dopaminergic and serotoninergic systems. Tefluthrin could modify brain monoamine neurotransmitters, DA and 5-HT levels as well as dopaminergic and serotoninergic signaling pathways. Adult male Wistar rats were treated with tefluthrin [2.2, 4.4 and 5.5 mg/kg bw, equivalent to 1/10, 1/5 and 1/4 of the acute oral rat lethal dose 50 (LD50) value] by oral gavage, six days. After last dose of tefluthrin, DA and 5-HT and metabolites levels were determined in brain regions (striatum, hippocampus, prefrontal cortex and hypothalamus). Tefluthrin induced a decrease of DA, 5-HT and metabolites contents, in a brain regional- and dose-related manner. The major decreases in DA and 5-HT contents were observed in prefrontal cortex tissue. Here, we studied that in vivo exposure to tefluthrin may alter DA and 5-HT neurotransmission in prefrontal cortex. Transcripts related to (i) dopaminergic [dopamine transporter 1 (Dat1), tyrosine hydroxylase (TH), dopamine receptors (Drd1, Drd2)], (ii) serotoninergic [serotonin transporter (SERT), tryptophan hydroxylase 2 (TPH2), serotonin receptors (5-HT1A, 5-HT2A)] and (iii) DA and 5-HT degradation [monoamine oxidases (MAOA, MAOB)] signaling pathways were investigated. Results showed that tefluthrin induced down-regulation of transcripts responsible for the synthesis and action of DA (TH, Drd1, Drd2) and 5-HT (SERT, TPH2). In contrast, tefluthrin treatment induced up-regulation of genes involved in DA transporter (Dat1), 5-HT receptors (5-HT1A, 5-HT2A) and monoamine oxidases (MAOA, MAOB). Given the integral roles of mitochondrial dysfunction and dopaminergic and serotoninergic alterations as hallmarks of neurodegenerative diseases, our data suggest that tefluthrin may be a candidate for pesticides contributing to neurodegenerative disorders pathogenesis by causing damage to the DA and 5-HT systems.

Associations between Social Adversity and Biomarkers of Inflammation, Stress, and Aging in Children

BackgroundPrior work has found relationships between childhood social adversity and biomarkers of stress, but knowledge gaps remain. To help address these gaps, we explored associations between social adversity and biomarkers of inflammation (interleukin-1β [IL-1β], IL-6, IL-8, tumor necrosis factor-alpha [TNF-α], and salivary cytokine hierarchical “clusters” based on the three interleukins), neuroendocrine function (cortisol, cortisone, dehydroepiandrosterone, testosterone, and progesterone), neuromodulation (N-arachidonoylethanolamine, stearoylethanolamine, oleoylethanolamide, and palmitoylethanolamide), and epigenetic aging (Pediatric-Buccal-Epigenetic clock).MethodsWe collected biomarker samples of children ages 0–17 recruited from an acute care pediatrics clinic and examined their associations with caregiver-endorsed education, income, social risk factors, and cumulative adversity. We calculated regression-adjusted means for each biomarker and compared associations with social factors using Wald tests. We used logistic regression to predict being in the highest cytokine cluster based on social predictors.ResultsOur final sample included 537 children but varied based on each biomarker. Cumulative social adversity was significantly associated with having higher levels of all inflammatory markers and with cortisol, displaying a U-shaped distribution. There were no significant relationships between cumulative social adversity and cortisone, neuromodulation biomarkers or epigenetic aging.ConclusionOur findings support prior work suggesting that social stress exposures contribute to increased inflammation in children.ImpactOur study is one of the largest studies examining associations between childhood social adversity and biomarkers of inflammation, neuroendocrine function, neuromodulation, and epigenetic aging. It is one of the largest studies to link childhood social adversity to biomarkers of inflammation, and the first of which we are aware to link cumulative social adversity to cytokine clusters. It is also one of the largest studies to examine associations between steroids and epigenetic aging among children, and one of the only studies of which we are aware to examine associations between social adversity and endocannabinoids among children. Clinical Trial Registration: NCT02746393

Prenatal double-hit with aluminium and cadmium mediate testicular atrophy and hypothalamic hypoplasia: the role of oxido-nitrergic stress and endocrine perturbations.

There is limited experimental evidence on the biochemical consequences of aluminium (Al) and cadmium (Cd) co-exposures during pregnancy and postnatal life.This study investigated the impacts of perinatal Al chloride (AlCl3) and Cd chloride (CdCl2) co-exposures on neuroendocrine functions in mice offspring during postnatal life. The study comprised of four pregnant experimental groups. Group 1 received AlCl3 (10mg/kg), group 2 were administered CdCl2 (1.5mg/kg), while group 3 received both AlCl3 (10mg/kg) and CdCl2 (1.5mg/kg) (AlCl3+CdCl2), and group 4 received saline (10mL/kg) only and served as control group. All experimental animals were chemically exposed once daily from gestation days 7-20. Upon delivery, male pups were regrouped based on maternal chemical exposure on postnatal day 21 (PND 21) and allowed to grow to adulthood until PND 78, after which they were sacrificed for assessment of neuroendocrine markers and histological investigations. There was no statistical significance (p > 0.05) on follicle stimulating hormone, testosterone, estrogen and progesterone, thyroid stimulating hormone, thyroxine (T4) in all treatment groups relative to controls|. However, AlCl3 and AlCl3-CdCl2 significantly (p < 0.05) reduced triiodothyronine (T3) levels, with a profound increase in T3:T4 ratio by AlCl3, and AlCl3+CdCl2 compared to control. Furthermore, pups from pregnant mice treated with CdCl2 and AlCl3+CdCl2 demonstrated increased testicular malondialdehyde concentration with increased catalase activity relative to controls, suggesting oxidative imbalance. In addition, AlCl3, CdCl2, and AlCl3+CdCl2 exposures induced testicular and hypothalamic architectural disruption compared to controls, with marked architectural derangement in the AlCl3+CdCl2 group. Our findings suggest that prenatal co-exposures to Alcl3 and CdCl2 induce testicular and hypothalamic alterations in offspring via a testicular oxidative stress and thyrotoxicosis-dependent mechanisms.

Prenatal paternal anxiety symptoms predict child DHEA levels and internalizing symptoms during adrenarche.

This study examined (1) whether measures of paternal anxious and depressive symptoms collected prenatally and during a follow-up assessment when the child was in middle childhood, predict child neuroendocrine outcomes, and (2) whether neuroendocrine outcomes are intermediate factors between paternal mental health and child cognitive/behavioral outcomes. Middle childhood coincides with increased autonomy as the child transitions into grade school, and with adrenarche, as the maturing adrenal gland increases secretion of dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEA-S), hormones that are implicated in corticolimbic development which regulate emotions and cognition. Participants were recruited from a subsample of a large prospective birth cohort study (3D study). We conducted a follow-up study when children were 6-8 years old (N = 61 families, 36 boys, 25 girls). Parental symptoms of anxiety, stress and depression were assessed via validated self-report questionnaires: prenatally using an in-house anxiety questionnaire, the Perceived Stress Scale (PSS) and the Center for Epidemiologic Studies Depression (CES-D), and at the follow up, using the Beck Anxiety and Beck Depression Inventories. Children provided salivary hormone samples, and their pituitary gland volume was measured from structural Magnetic Resonance Imaging (MRI) scans. Child behaviors were measured using the Strengths and Difficulties Questionnaire and cognitive outcomes using the WISC-V. Multiple regression analyses were used to test whether paternal mental health symptoms assessed prenatally and during childhood are associated with child neuroendocrine outcomes, adjusting for maternal mental health and child sex. Indirect-effect models assessed whether neuroendocrine factors are important intermediates that link paternal mental health and cognitive/behavioral outcomes. (1) Fathers' prenatal anxiety symptoms predicted lower DHEA levels in the children, but not pituitary volume. (2) Higher prenatal paternal anxiety symptoms predicted higher child internalizing symptoms via an indirect pathway of lower child DHEA. No associations were detected between paternal anxiety symptoms measured in childhood, and neuroendocrine outcomes. No child sex differences were detected on any measure. These results highlight the often-overlooked role of paternal factors during pregnancy on child development, suggesting that paternal prenatal anxiety symptoms are associated with child neuroendocrine function and in turn internalizing symptoms that manifest at least up to middle childhood.

Bisphenol A Analogues Induce Neuroendocrine Disruption via Gut-Brain Regulation in Zebrafish.

There is epidemiological evidence in humans that exposure to endocrine-disrupting chemicals such as bisphenol A (BPA) is tied to abnormal neuroendocrine function with both behavioral and intestinal symptoms. However, the underlying mechanism of this effect, particularly the role of gut-brain regulation, is poorly understood. We exposed zebrafish embryos to a concentration series (including environmentally relevant levels) of BPA and its analogues. The analogue bisphenol G (BPG) yielded the strongest behavioral impact on zebrafish larvae and inhibited the largest number of neurotransmitters, with an effective concentration of 0.5 μg/L, followed by bisphenol AF (BPAF) and BPA. In neurod1:EGFP transgenic zebrafish, BPG and BPAF inhibited the distribution of enteroendocrine cells (EECs), which is associated with decreased neurotransmitters level and behavioral activity. Immune staining of ace-α-tubulin suggested that BPAF inhibited vagal neural development at 50 and 500 μg/L. Single-cell RNA-Seq demonstrated that BPG disrupted the neuroendocrine system by inducing inflammatory responses in intestinal epithelial cells via TNFα-trypsin-EEC signaling. BPAF exposure activated apoptosis and inhibited neural developmental pathways in vagal neurons, consistent with immunofluorescence imaging studies. These findings show that both BPG and BPAF affect the neuroendocrine system through the gut-brain axis but by different mechanisms, revealing new insights into the modes of bisphenol-mediated neuroendocrine disruption.

Hypothalamic CRF neurons facilitate brain reward function

Aversive stimuli activate corticotropin-releasing factor (CRF)-expressing neurons in the paraventricular nucleus of hypothalamus (PVNCRF neurons) and other brain stress systems to facilitate avoidance behaviors. Appetitive stimuli also engage the brain stress systems, but their contributions to reward-related behaviors are less well understood. Here, we show that mice work vigorously to optically activate PVNCRF neurons in an operant chamber, indicating a reinforcing nature of these neurons. The reinforcing property of these neurons is not mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis. We found that PVNCRF neurons send direct projections to the ventral tegmental area (VTA), and selective activation of these projections induced robust self-stimulation behaviors, without activation of the HPA axis. Similar to the PVNCRF cell bodies, self-stimulation of PVNCRF-VTA projection was dramatically attenuated by systemic pretreatment of CRF receptor 1 or dopamine D1 receptor (D1R) antagonist and augmented by corticosterone synthesis inhibitor metyrapone, but not altered by dopamine D2 receptor (D2R) antagonist. Furthermore, we found that activation of PVNCRF-VTA projections increased c-Fos expression in the VTA dopamine neurons and rapidly triggered dopamine release in the nucleus accumbens (NAc), and microinfusion of D1R or D2R antagonist into the NAc decreased the self-stimulation of these projections. Together, our findings reveal an unappreciated role of PVNCRF neurons and their VTA projections in driving reward-related behaviors, independent of their core neuroendocrine functions. As activation of PVNCRF neurons is the final common path for many stress systems, our study suggests a novel mechanism underlying the positive reinforcing effect of stressful stimuli.

Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia Pathogenesis.

Leptin plays a crucial role in regulating energy homoeostasis, neuroendocrine function, metabolism, and immune and inflammatory responses. The adipose tissue is a main source of leptin, but during pregnancy, leptin is also secreted primarily by the placenta. Circulating leptin levels peak during the second trimester of human pregnancy and fall after labor. Several studies indicated a strong association between elevated placental leptin levels and preeclampsia (PE) pathogenesis and elevated serum interleukin-6 (IL-6) levels in PE patients. Therefore, we hypothesized that a local increase in placental leptin production induces IL-6 production in Hofbauer cells (HBCs) to contribute to PE-associated inflammation. We first investigated HBCs-specific IL-6 and leptin receptor (LEPR) expression and compared their immunoreactivity in PE vs. gestational age-matched control placentas. Subsequently, we examined the in vitro regulation of IL-6 as well as the phosphorylation levels of intracellular signaling proteins STAT3, STAT5, NF-κB, and ERK1/2 by increasing recombinant human leptin concentrations (10 to 1000 ng/mL) in primary cultured HBCs. Lastly, HBC cultures were incubated with leptin ± specific inhibitors of STAT3 or STAT5, or p65 NF-κB or ERK1/2 MAPK signaling cascades to determine relevant cascade(s) involved in leptin-mediated IL-6 regulation. Immunohistochemistry revealed ~three- and ~five-fold increases in IL-6 and LEPR expression, respectively, in HBCs from PE placentas. In vitro analysis indicated that leptin treatment in HBCs stimulate IL-6 in a concentration-dependent manner both at the transcriptional and secretory levels (p < 0.05). Moreover, leptin-treated HBC cultures displayed significantly increased phosphorylation levels of STAT5, p65 NF-κB, and ERK1/2 MAPK and pre-incubation of HBCs with a specific ERK1/2 MAPK inhibitor blocked leptin-induced IL-6 expression. Our in situ results show that HBCs contribute to the pathogenesis of PE by elevating IL-6 expression, and in vitro results indicate that induction of IL-6 expression in HBCs is primarily leptin-mediated. While HBCs display an anti-inflammatory phenotype in normal placentas, elevated levels of leptin may transform HBCs into a pro-inflammatory phenotype by activating ERK1/2 MAPK to augment IL-6 expression.