Impaired Dopamine-Dependent Locomotory Behavior of C. elegans Neuroligin Mutants Depends on the Catechol-O-Methyltransferase COMT-4.

Neurexins and neuroligins are neuronal membrane adhesion molecules that have been involved in neuropsychiatric and neurodevelopmental disorders. The nrx-1 and nlg-1 genes of Caenorhabditis elegans encode NRX-1 and NLG-1, orthologue proteins of human neurexins and neuroligins, respectively. Dopaminergic and serotoninergic signalling control the locomotory rate of the nematode. When well-fed animals are transferred to a plate with food (bacterial lawn), they reduce the locomotory rate. This behavior, which depends on dopamine, is known as basal slowing response (BSR). Alternatively, when food-deprived animals are moved to a plate with a bacterial lawn, further decrease their locomotory rate. This behavior, known as enhanced slowing response (ESR), is serotonin dependent. C. elegans nlg-1-deficient mutants are impaired in BSR and ESR. Here we report that nrx-1-deficient mutants were defective in ESR, but not in BSR. The nrx-1;nlg-1 double mutant was impaired in both behaviors. Interestingly, the nlg-1 mutants upregulate the expression of comt-4 which encodes an enzyme with putative catechol-O-methyltransferase activity involved in dopamine degradation. Our study also shows that comt-4(RNAi) in nlg-1-deficient mutants rescues the wild type phenotypes of BSR and ESR. On the other hand, comt-4(RNAi) in nlg-1-deficient mutants also recovers, at least partially, the gentle touch response and the pharyngeal pumping rate that were impaired in these mutants. These latter behaviors are dopamine and serotonin dependent, respectively. Based on these results we propose a model for the neuroligin function in modulating the dopamine-dependent locomotory behavior in the nematode.

Emotional stability is related to 2D:4D and social desirability in women: Possible implications on subjective well-being and psychopathology.

Emotional stability-Neuroticism is a complex construct influenced by genetics and environmental factors. Women tend to exhibit higher neuroticism scores than men, which may be associated with an increased risk of suffering from some common mental conditions. Some authors have pointed out the influence of sex hormones, since they induce sexual differentiation of the brain that can lead to sex-specific behaviors. 2D:4D digit ratio is commonly used as a marker of prenatal sex hormones. In this study we analyzed whether there was an association between 2D:4D and personality measured through the BFQ in a homogeneous sample of 101 young women college students. We found a positive association between 2D:4D and emotional stability, as well as with its subdimensions emotion control and impulse control. This association could be quadratic and nonlinear. However, no association was found with the other four dimensions. We also measured anxiety, depression and global life satisfaction, variables related to neuroticism. We observed that emotional stability is positively associated to social desirability and global life satisfaction, and negatively related to anxiety and depression. On the other hand, we did not find any association between 2D:4D and anxiety, depression, and global life satisfaction. These results can be linked to other aspects such as subjective well-being and psychopathological symptoms. This study may help to better understand how these constructs are related and could lead to future projects to elucidated how these variables influence personality.

Flavonoid Phloretin Inhibits Adipogenesis and Increases OPG Expression in Adipocytes Derived from Human Bone-Marrow Mesenchymal Stromal-Cells.

Phloretin (a flavonoid abundant in apple), has antioxidant, anti-inflammatory, and glucose-transporter inhibitory properties. Thus, it has interesting pharmacological and nutraceutical potential. Bone-marrow mesenchymal stem cells (MSC) have high differentiation capacity, being essential for maintaining homeostasis and regenerative capacity in the organism. Yet, they preferentially differentiate into adipocytes instead of osteoblasts with aging. This has a negative impact on bone turnover, remodeling, and formation. We have evaluated the effects of phloretin on human adipogenesis, analyzing MSC induced to differentiate into adipocytes. Expression of adipogenic genes, as well as genes encoding OPG and RANKL (involved in osteoclastogenesis), protein synthesis, lipid-droplets formation, and apoptosis, were studied. Results showed that 10 and 20 µM phloretin inhibited adipogenesis. This effect was mediated by increasing beta-catenin, as well as increasing apoptosis in adipocytes, at late stages of differentiation. In addition, this chemical increased OPG gene expression and OPG/RANKL ratio in adipocytes. These results suggest that this flavonoid (including phloretin-rich foods) has interesting potential for clinical and regenerative-medicine applications. Thus, such chemicals could be used to counteract obesity and prevent bone-marrow adiposity. That is particularly useful to protect bone mass and treat diseases like osteoporosis, which is an epidemic worldwide.

Emotional stability is associated with the MAOA promoter uVNTR polymorphism in women.

BACKGROUND: Neuroticism is associated with low emotional stability, and it is characterized by a tendency to perceive ordinary situations as threatening and difficult to manage. This personality trait has been associated with psychological distress and predicts some mental disorders. Previous studies have shown that women tend to be more neurotic than men and, in general, females have also a higher incidence of anxious and depressive disorders. METHODS: We analyzed in a sample of 99 female university students (from 18 to 26 years old) if emotional stability, measured using the Big Five Questionnaire, was linked to polymorphic variants in candidate genes related to dopaminergic and serotonergic systems, and other personality variables. RESULTS: We found that emotional stability and its subdimensions are genetically associated with MAOA-uVNTR polymorphism. Thus, women carriers of the 3-repeat allele (lower MAO-A expression) showed higher levels of emotional stability. No associations were found with other polymorphisms analyzed, including COMT Val158 Met, 5-HTTLPR, and DAT 3'UTR VNTR. Furthermore, our results showed a negative correlation between emotional stability and depression, state anxiety, and trait anxiety. In fact, MAOA-uVNTR and trait anxiety also explained emotional stability and its subdimensions. We also found that other genetic characteristic, phenylthiocarbamide tasting, explained impulsivity, specifically tasters controlled impulses better than nontasters. CONCLUSION: Our results indicate that neuroticism might be regulated by MAOA and could be a common factor between different phenotypes, such as aggressive behaviors or personality disorders, observed in women with higher activity genotype who had been exposed to negative environments during childhood. This study could lead to a better understanding of the basis of emotional stability and could lead to future projects for this purpose.

Behavioral Mechanisms That Depend on Dopamine and Serotonin in Caenorhabditis elegans Interact With the Antipsychotics Risperidone and Aripiprazole.

The neurotransmitters dopamine and serotonin participate in specific behavioral neuromuscular mechanisms in the nematode Caenorhabditis elegans. Dopamine is involved in the gentle touch response and serotonin in the pharyngeal pumping rate. In its genome, the worm presents genes encoding dopamine and serotonin receptors orthologous to those of human genes. Risperidone and aripiprazole are a class of drugs known as atypical antipsychotics commonly used to treat schizophrenia, bipolar disorder, and irritability associated with autism. Risperidone is an antagonist of the dopamine D2 and serotonin 5-HT2A receptors. Aripiprazole functions as a partial agonist of the dopamine D2 receptor and as a partial agonist and antagonist of 5-HT1A and 5-HT2A serotonin receptors, respectively. Our results show that risperidone and aripiprazole alter the touch response and pharyngeal pumping in wild-type worm animals. Furthermore, in the presence of the drugs, both behaviors change to varying degrees in dopamine (dop-1, dop-2, and dop-3), serotonin (ser-1), and tyramine (ser-2) receptor-deficient mutants. This variation in response reveals specific targets for these antipsychotics in the nematode. Interestingly, their effect on behavior persisted to some extent in successive generations, indicating that they might induce epigenetic changes throughout development. Sodium butyrate, a histone deacetylase inhibitor, eliminated the consecutive generation effect of both drugs. In addition, these transgenerational effects were also abolished after the dauer stage. These observations suggest that risperidone and aripiprazole, in addition to interacting with specific receptors impairing the function of the nervous system of the nematode, may lead to the deposition of long-lasting epigenetic marks.