Early life adversity and serotonin transporter gene variation interact at the level of the adrenal gland to affect the adult hypothalamo-pituitary-adrenal axis

The short allelic variant of the serotonin transporter (5-HTT) promoter-linked polymorphic region (5-HTTLPR) has been associated with the etiology of major depression by interaction with early life stress (ELS). Furthermore, 5-HTTLPR has been associated with abnormal functioning of the stress-responsive hypothalamo-pituitary-adrenal (HPA) axis. Here, we examined if, and at what level, the HPA-axis is affected in an animal model for ELS × 5-HTTLPR interactions. Heterozygous and homozygous 5-HTT knockout rats and their wild-type littermates were exposed daily at postnatal days 2–14 to 3 h of maternal separation. When grown to adulthood, plasma levels of adrenocorticotropic hormone (ACTH), and the major rat glucocorticoid, corticosterone (CORT), were measured. Furthermore, the gene expression of key HPA-axis players at the level of the hypothalamus, pituitary and adrenal glands was assessed. No 5-HTT genotype × ELS interaction effects on gene expression were observed at the level of the hypothalamus or pituitary. However, we found significant 5-HTT genotype × ELS interaction effects for plasma CORT levels and adrenal mRNA levels of the ACTH receptor, such that 5-HTT deficiency was associated under control conditions with increased, but after ELS with decreased basal HPA-axis activity. With the use of an in vitro adrenal assay, naïve 5-HTT knockout rats were furthermore shown to display increased adrenal ACTH sensitivity. Therefore, we conclude that basal HPA-axis activity is affected by the interaction of 5- HTT genotype and ELS, and is programmed, within the axis itself, predominantly at the level of the adrenal gland. This study therefore emphasizes the importance of the adrenal gland for HPA-related psychiatric disorders

The effects of COVID-19 on child mental health:Biannual assessments up to April 2022 in a clinical and two general population samples

BACKGROUND: The COVID-19 pandemic has had an acute impact on child mental and social health, but long-term effects are still unclear. We examined how child mental health has developed since the start of the COVID-19 pandemic up to 2 years into the pandemic (April 2022).METHODS: We included children (age 8-18) from two general population samples (N = 222-1333 per measurement and N = 2401-13,362 for pre-covid data) and one clinical sample receiving psychiatric care (N = 334-748). Behavioral questionnaire data were assessed five times from April 2020 till April 2022 and pre-pandemic data were available for both general population samples. We collected parent-reported data on internalizing and externalizing problems with the Brief Problem Monitor and self-reported data on Anxiety, Depressive symptoms, Sleep-related impairments, Anger, Global health, and Peer relations with the Patient-Reported Outcomes Measurement Information System (PROMIS®).RESULTS: In all samples, parents reported overall increased internalizing problems, but no increases in externalizing problems, in their children. Children from the general population self-reported increased mental health problems from before to during the pandemic on all six PROMIS domains, with generally worst scores in April 2021, and scores improving toward April 2022 but not to pre-pandemic norms. Children from the clinical sample reported increased mental health problems throughout the pandemic, with generally worst scores in April 2021 or April 2022 and no improvement. We found evidence of minor age effects and no sex effects.CONCLUSIONS: Child mental health in the general population has deteriorated during the first phase of the COVID-19 pandemic, has improved since April 2021, but has not yet returned to pre-pandemic levels. Children in psychiatric care show worsening of mental health problems during the pandemic, which has not improved since. Changes in child mental health should be monitored comprehensively to inform health care and policy.</p

Discovery of Novel Small Molecule Activators of β-Catenin Signaling

Wnt/β-catenin signaling plays a major role in embryonic development and adult stem cell maintenance. Reduced activation of the Wnt/β-catenin pathway underlies neurodegenerative disorders and aberrations in bone formation. Screening of a small molecule compound library with a β-galactosidase fragment complementation assay measuring β-catenin nuclear entry revealed bona fide activators of β-catenin signaling. The compounds stabilized cytoplasmic β-catenin and activated β–catenin-dependent reporter gene activity. Although the mechanism through which the compounds activate β-catenin signaling has yet to be determined, several key regulators of Wnt/β-catenin signaling, including glycogen synthase kinase 3 and Frizzled receptors, were excluded as the molecular target. The compounds displayed remarkable selectivity, as they only induced β-catenin signaling in a human osteosarcoma U2OS cell line and not in a variety of other cell lines examined. Our data indicate that differences in cellular Wnt/β-catenin signaling machinery can be exploited to identify cell type-specific activators of Wnt/β-catenin signaling

In vitro assessment of adsorbents aiming to prevent deoxynivalenol and zearalenone mycotoxicoses

The high prevalence of the Fusarium mycotoxins, deoxynivalenol (DON) and zearalenone (ZON) in animal feeds in mild climatic zones of Europe and North America results in considerable economic losses, as these toxins affect health and productivity particularly of pigs from all age groups. The use of mycotoxin adsorbents as feed additives is one of the most prominent approaches to reduce the risk for mycotoxicoses in farm animals, and to minimise carry-over of mycotoxins from contaminated feeds into foods of animal origin. Successful aflatoxin adsorption by means of different substances (phyllosilicate minerals, zeolites, activated charcoal, synthetic resins or yeast cell-wall-derived products) has been demonstrated in vivo and in vitro. However, attempts to adsorb DON and ZON have been less encouraging. Here we describe the adsorption capacity of a variety of potential binders, including compounds that have not been evaluated before, such as humic acids. All compounds were tested at realistic inclusion levels for their capacity to bind ZON and DON, using an in vitro method that resembles the different pH conditions in the gastro-intestinal tract of pigs. Mycotoxin adsorption was assessed by chemical methods and distinct bioassays, using specific markers of toxicity as endpoints of toxicity in cytological assays. Whereas none of the tested substances was able to bind DON in an appreciable percentage, some of the selected smectite clays, humic substances and yeast-wall derived products efficiently adsorbed ZON (>70%). Binding efficiency was indirectly confirmed by the reduction of toxicity in the in vitro bioassays. In conclusion, the presented test protocol allows the rapid screening of potential mycotoxin binders. Like other in vitro assays, the presented protocol combining chemical and biological assays cannot completely simulate the conditions of the gastro-intestinal tract, and hence in vivo experiments remain mandatory to assess the efficacy of mycotoxin binders under practical conditions

Induction of gut leakage in young broiler chickens fed a diet with low rye inclusion

The aim of the present study was to assess the absence of a non-starch polysaccharide (NSP) enzyme in a broiler diet containing a low level (10%) of rye inclusion. Two experimental groups with 40 Ross broilers each, were fed a diet containing 10% rye. One group was supplemented with a NSP enzyme, and the other was not supplemented with the enzyme to increase intestinal viscosity. The birds were fed the respective diets for 14 or 28 days. Intestinal sections were submitted to morphological, morphometric and mRNA-level gene expression analyses. To assess gut leakage, 150 min before euthanasia, broilers had no access to feed and received an oral gavage with fluorescein isothiocyanate-labelled dextran (FITC-d). Serum levels of FITC-d, D-lactate, tight-junction-associated protein 1 (TJAP1), citrulline and ovotransferrin were determined. A significant increase in FITC-d levels was observed in the 14-day-old birds fed the non-supplemented rye diet, and no other serum markers were affected. These birds presented a decreased villus height/crypt depth (VH:CD) ratio and an increased degree of damage in the jejunum. The ileum VH:CD increased, and the goblet cell number decreased in 28-day-old birds fed the non-supplemented rye diet. When broilers were fed the non-supplemented rye diet, the mRNA expression of the tight-junction zona occludens 1 (ZO1) was significantly decreased in the jejunum of 14-day-old broilers, whereas a significant decrease in jejunum mRNA expression of ZO2 and mucin-2 (MUC2) was observed in the jejunum of 28-day-old broilers. In contrast, a significant increase in the mRNA expression of ZO2 was observed in the ileum from 28-day-old broilers fed the non-supplemented rye diet. In conclusion, a 10% rye diet causes intestinal stress in young broiler chickens when the feed is not supplemented with a NSP enzyme. This study may be applied as experimental model of mild gut leakage of broiler chickens

Susceptibility of Broiler Chickens to Deoxynivalenol Exposure via Artificial or Natural Dietary Contamination

Multi-mycotoxin contamination of poultry diets is a recurrent problem, even if the mycotoxins levels are below EU recommendations. Deoxynivalenol (DON) is one of the main studied mycotoxins due to its risks to animal production and health. When evaluating the effects of DON, one must consider that under practical conditions diets will not be contaminated solely with this mycotoxin. In the present study, broiler chickens were fed diets with negligible mycotoxin levels or with naturally or artificially contaminated diets containing approximately 4000 μg/kg DON. Birds were sampled at D14 and D28. Naturally-contaminated diets caused the most harm to the birds, especially the young ones, which presented decreased jejunal villus height and increased lesions, down-regulation of a peptide transporter. At D28 broiler chickens seemed to have adapted to the dietary conditions, when no differences were observed in villus morphometry, together with up-regulation of a carbohydrate transporter. However, intestinal lesions remained present in these older birds

The effects of COVID-19 on child mental and social health: biannual assessments up to April 2022 in a clinical and two general population samples

Background The COVID-19 pandemic has had an acute impact on child mental and social health, but long-term effects are still unclear. We examined how child mental health has developed since the start of the COVID-19 pandemic up to two years into the pandemic (April 2022). Methods We included children (age 8-18) from two general population samples (N = 222-1,333 per measurement and N = 2,401-13,362 for pre-covid data) and one clinical sample receiving psychiatric care (N = 334-748). Behavioral questionnaire data were assessed five times from April 2020 till April 2022 and pre-pandemic data were available for both general population samples. We collected parent-reported data on internalizing and externalizing problems with the Brief Problem Monitor and self-reported data on Anxiety, Depressive symptoms, Sleep-related impairments, Anger, Global health, and Peer relations with the Patient-Reported Outcomes Measurement Information System (PROMIS®). Results In all samples, parents reported overall increased internalizing problems, but no increases in externalizing problems, in their children. Children from the general population self-reported increased mental health problems from before to during the pandemic on all six PROMIS domains, with generally worst scores in April 2021, and scores improving towards April 2022 but not to pre-pandemic norms. Children from the clinical sample reported increased mental health problems throughout the pandemic, with generally worst scores in April 2021 or April 2022 and no improvement. We found evidence of minor age effects and no sex effects. Conclusions Child mental health in the general population has deteriorated during the first phase of the COVID-19 pandemic, has improved since April 2021, but has not yet returned to pre-pandemic levels. Children in psychiatric care show worsening of mental health problems during the pandemic, which has not improved since. Changes in child mental health should be monitored comprehensively to inform health care and policy

Adaptive fitness; early life adversity improves adult stress coping in heterozygous serotonin transporter knockout rats

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