Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring

During pregnancy, women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring. This study investigated whether maternal androgen excess causes anxiety-like behavior in offspring mimicking anxiety disorders in PCOS. The PCOS phenotype was induced in rats following prenatal androgen (PNA) exposure. PNA offspring displayed anxiety-like behavior in the elevated plus maze, which was reversed by flutamide [androgen receptor (AR) blocker] and tamoxifen [selective estrogen receptor (ER) modulator]. Circulating sex steroids did not differ between groups at adult age. The expression of serotonergic and GABAergic genes associated with emotional regulation in the amygdala was consistent with anxiety-like behavior in female, and partly in male PNA offspring. Furthermore, AR expression in amygdala was reduced in female PNA offspring and also in females exposed to testosterone in adult age. To determine whether AR activation in amygdala affects anxiety-like behavior, female rats were given testosterone microinjections into amygdala, which resulted in anxiety-like behavior. Together, these data describe the anxiety-like behavior in PNA offspring and adult females with androgen excess, an impact that seems to occur during fetal life, and is mediated via AR in amygdala, together with changes in ERα, serotonergic, and GABAergic genes in amygdala and hippocampus. The anxiety-like behavior following testosterone microinjections into amygdala demonstrates a key role for AR activation in this brain area. These results suggest that maternal androgen excess may underpin the risk of developing anxiety disorders in daughters and sons of PCOS mothers.Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by excessive androgen secretion and abnormal insulin activity and affects up to 17% of women worldwide (1). Women with PCOS are at an increased risk of developing symptoms of anxiety and depression. In fact, over 60% of women with PCOS are diagnosed with at least one psychiatric disorder, such as depression, anxiety, or an eating disorder (2). Suicide attempts have also been shown to be seven times more common in women with PCOS than in healthy controls (3). The mechanisms underlying the development of PCOS are poorly understood. Although a genetic basis for PCOS has been suggested, the intrauterine milieu might also affect the reproductive/endocrine function of a child born to a PCOS mother in a manner that is independent of genetic inheritance or sex. It is also known that daughters of mothers with PCOS are at increased risk of developing the syndrome and that sons tend to suffer from obesity and insulin resistance (4). Thus, it has been proposed that PCOS originates during fetal development and that this might be, in part, a result of maternal androgen excess (5).Maternal testosterone levels in humans have been shown to affect brain morphology and function (6) and to be correlated to neural development and mental function (7). There is evidence for a crucial role of the hippocampus and the amygdala in the development of anxiety and depression, and that these neural circuits are affected by fluctuations in sex steroids in humans and in rodents (8). We have previously demonstrated that continuous exposure to dihydrotestosterone (DHT) from puberty until adulthood in female rats down-regulates androgen receptor (AR) expression in the hypothalamus and induces anxiety-like behavior in female rats (9). The increased rates of anxiety disorders and disruptive behavioral disorders among children with genetically induced hyperandrogenism further indicate that androgen excess may contribute to a higher risk of psychopathology (10).During pregnancy, androgens are metabolized to estrogens by the placenta in women and by the ovaries in rodents. Thus, the effects of testosterone on pregnancy are partly mediated by estrogen (11). Women with PCOS exhibit high circulating androgen levels during pregnancy, which hypothetically could be related to the increased risk of mood disorders in their offspring (12).Here, we tested the hypothesis that an excess of androgens in dams during pregnancy may cause anxiety-like behavior in adult female and male offspring. We used the prenatal androgen (PNA) model, which mimics the elevation of androgens in women with PCOS during pregnancy (13). The phenotype of the PNA model in mice (14) and in rats (12) reflects reproductive and metabolic characteristics of lean women with PCOS. However, whether it reflects symptoms of anxiety (2) is unknown. We demonstrated that female PNA offspring exhibited increased anxiety-like behavior, which was prevented by blocking the AR during pregnancy, implicating AR-mediated signaling in mediating the altered behavior of PNA offspring. To understand the neuroanatomical distribution of sites affected by the PNA treatment we evaluated the gene expression of key steroid receptors [Ar, estrogen receptor-α (Erα), Erβ, and G protein-coupled estrogen receptor (Gper)] in the hypothalamus, hippocampus, and amygdala, brain areas known to be involved in the regulation of mood behavior in female offspring. The expression of the AR gene was selectively altered in the amygdala of the PNA offspring. We further show that subchronic testosterone exposure in adult females also reduced Ar expression in the amygdala. Because the amygdala is known to be involved in the regulation of mood behavior, we hypothesized that testosterone exerts an anxiogenic effect in the amygdala. We obtained support for this hypothesis by demonstrating that intra-amygdala testosterone microinjections resulted in anxiety-like behavior.     

Clinical Trials of Potential Cognitive-Enhancing Drugs in Schizophrenia: What Have We Learned So Far?

In light of the number of studies conducted to examine the treatment of cognitive impairment associated with schizophrenia (CIAS), we critically reviewed recent CIAS trials. Trials were identified through searches of the website “www.clinicaltrials.gov” using the terms “schizophrenia AND cognition,” “schizophrenia AND neurocognition,” “schizophrenia AND neurocognitive tests,” “schizophrenia AND MATRICS,” “schizophrenia AND MCCB,” “schizophrenia AND BACS,” “schizophrenia AND COGSTATE,” and “schizophrenia AND CANTAB” and “first-episode schizophrenia AND cognition.” The cutoff date was 20 April 2011. Included trials were conducted in people with schizophrenia, the effects on cognition were either a primary or secondary outcome, and the effect of a pharmacologically active substance was examined. Drug challenge, pharmacokinetic, pharmacodynamic, or prodrome of psychosis studies were excluded. We identified 118 trials, with 62% using an add-on parallel group design. The large majority of completed trials were underpowered to detect moderate effect sizes, had ≤8 weeks duration, and were performed in samples of participants with chronic stable schizophrenia. The ongoing add-on trials are longer, have larger sample sizes (with a number of them being adequately powered to detect moderate effect sizes), and are more likely to use a widely accepted standardized cognitive battery (eg, the MATRICS Consensus Cognitive Battery) and MATRICS guidelines. Ongoing studies performed in subjects with recent onset schizophrenia may help elucidate which subjects are most likely to show an effect in cognition. New insights into the demands of CIAS trial design and methodology may help increase the probability of identifying treatments with beneficial effect on cognitive impairment in schizophrenia.     

Chronic rejection after liver transplantation: Opening the Pandora’s box

Chronic rejection (CR) of liver allografts causes damage to intrahepatic vessels and bile ducts and may lead to graft failure after liver transplantation. Although its prevalence has declined steadily with the introduction of potent immunosuppressive therapy, CR still represents an important cause of graft injury, which might be irreversible, leading to graft loss requiring re-transplantation. To date, we still do not fully appreciate the mechanisms underlying this process. In addition to T cell-mediated CR, which was initially the only recognized type of CR, recently a new form of liver allograft CR, antibody-mediated CR, has been identified. This has indeed opened an era of thriving research and renewed interest in the field. Liver biopsy is needed for a definitive diagnosis of CR, but current research is aiming to identify new non-invasive tools for predicting patients at risk for CR after liver transplantation. Moreover, the minimization or withdrawal of immunosuppressive therapy might influence the establishment of subclinical CR-related injury, which should not be disregarded. Therapies for CR may only be effective in the “early” phases, and a tailored management of the immunosuppression regimen is essential for preventing irreversible liver damage. Herein, we provide an overview of the current knowledge and research on CR, focusing on early detection, identification of non-invasive biomarkers, immunosuppressive management, re-transplantation and future perspectives of CR.     

Evaluation of SNPs in miR-196-a2, miR-27a and miR-146a as risk factors of colorectal cancer

AIM: To investigate whether selected single nucleotide polymorphisms (SNPs) in miR-196a2, miR-27a and miR-146a genes are associated with sporadic colorectal cancer (CRC).METHODS: In order to investigate the effect of these SNPs in CRC, we performed a case-control study of 197 cases of sporadic CRC and 212 cancer-free controls originating from the Central-European Caucasian population using TaqMan Real-Time polymerase chain reaction and allelic discrimination analysis.RESULTS: The genotype and allele frequencies of SNPs were compared between the cases and the controls. None of the performed analysis showed any statistically significant results.CONCLUSION: Our data suggest a lack of association between rs11614913, rs895819 and rs2910164 and colorectal cancer risk in the Central-European Caucasian population, a population with an extremely high incidence of sporadic colorectal cancer.