Long-term drug-induced alterations in CNS gene expression may be responsible for some therapeutic effects, such as antidepressant action, as well as for psychopathological conditions, such as drug ...addiction and abuse. Transcription factors called “clock” genes can be affected by psychotropic drugs and may modify the expression pattern of other genes. In this study in mice, we investigated the delayed effects of single and repeated (i.e. 14 days) administration of the antidepressant fluoxetine and the psychostimulant cocaine on the brain expression of clock genes
Period1,
Period2,
Period3,
Clock,
Bmal1,
Cryptochrome1,
Cryptochrome2, and
NPAS2 (neuronal PAS domain protein 2), and their putative target gene, serotonin
N-acetyltransferase. Mice were treated at ZT05 (lights on at 5:00 am; ZT00). Brain samples (i.e. hippocampus, striatum, and prefrontal cortex) were processed for a semi-quantitative mRNA assay. Repeated but not single treatment with either drug increased serotonin
N-acetyltransferase expression in all areas tested. On the other hand, the expression of clock genes was differentially affected depending on the drug (i.e. fluoxetine and cocaine), treatment schedule (i.e. single and repeated), and brain area (i.e. hippocampus and striatum) tested. More pronounced changes were induced by repeated rather than single administrations of fluoxetine or cocaine. We propose that the effects of psychoactive drugs on clock transcription factors may mediate long-term drug-induced changes, possibly by regulating the expression of a second set of genes (i.e. clock-controlled genes).
Abstract Using a transgenic mice model (i.e. “clock” knockouts), clock transcription factors have been suggested as critical regulators of dopaminergic behaviors induced by drugs of abuse. Moreover, ...it has been shown that systemic administration of psychostimulants, such as cocaine and methamphetamine regulates the striatal expression of clock genes. However, it is not known whether dopamine receptors mediate these regulatory effects of psychostimulants at the cellular level. Primary striatal neurons in culture express dopamine receptors as well as clock genes and have been successfully used in studying dopamine receptor functioning. Therefore, we investigated the role of dopamine receptors on neuronal clock gene expression in this model using specific receptor agonists. We found an inhibitory effect on the expression of mClock and mPer1 genes with the D2-class (i.e. D2/D3) receptor agonist quinpirole. We also found a generalized stimulatory effect on the expression of clock genes mPer1 , mClock , mNPAS2 (neuronal PAS domain protein 2), and mBmal1 with the D1-class (i.e. D1) receptor agonist SKF38393. Further, we tested whether systemic administration of dopamine receptor agonists causes similar changes in striatal clock gene expression in vivo . We found quinpirole-induced alterations in mPER1 protein levels in the mouse striatum (i.e. rhythm shift). Collectively, our results indicate that the dopamine receptor system may mediate psychostimulant-induced changes in clock gene expression. Using striatal neurons in culture as a model, further research is needed to better understand how dopamine signaling modulates the expression dynamics of clock genes (i.e. intracellular signaling pathways) and thereby influences neuronal gene expression, neuronal transmission, and brain functioning.
•Binge-watching is defined as “watching multiple episodes of TV series in a single session”.•This behaviour provides instant gratification, leading a person to lose self-control.•The affective ...temperaments play a significant role impulsivity and decision-making.•The results of a multivariate regression analysis show that anxious and cyclothymic temperaments are highly significant.•The irritable temperament is significant for the avoidance and dependency dimensions.
Binge-watching is a new type of behaviour that has started to gain popularity since 2013 and is defined as “watching multiple episodes of TV series (at least two to six) in a single session”. Binge-watching is a phenomenon that affects the general population up to over 65 years of age, with a trend in the 18–39 age group. It is plausible to think that affective temperament dimensions may have an impact on the excessive use of watching serious TV. The affective temperaments play a significant role on motivated behaviour, impulsivity, and decision-making of binge watching. This behaviour provides instant gratification, leading a person to lose self-control.
The aim of the present study is to learn about the possible role of affective temperaments on motivated behaviour, impulsivity, and decision-making of binge watching in the general Italian population.
The sample consisted of 1,701 subject belonging Italian population. Data were collected by an online survey including the Binge-Watching Addiction Questionnaire (BWAQ) and the short form of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A) questionnaire. A multivariate regression analysis, in which the BWAQ variables (Anticipation, Avoidance, Craving, Dependency) were considered dependent variables and all the TEMPS-A factors were included in the equation, was performed to assess what kind of temperamental dimension could play the role of specific predictor towards the different aspects of binge watching.
Anxious and cyclothymic temperaments are highly significant. The factors that have a weaker impact on the dependent variables (significance at the 5 % level) are depressive and hyperthymic temperaments on the craving and avoidance dimensions, respectively. The irritable temperament is significant at the 5 % level for the models associated with the avoidance and dependency dimensions.
In summary, the results of multivariate regression analysis show that subjects with anxious and cyclothymic temperaments have a higher risk of engaging in binge-watching behaviour. It is important to obtain further knowledge on the psychological consequences of this phenomenon for future diagnosis, prevention and therapeutic implementations.
•The affective temperaments are subclinical manifestations of affective disorders and is important to consider their possible role on the development, clinical expression, course and prognosis of the ...diseas.•In particulary, the irritable temperament was associated with a range of negative affect, including irritability, anger and worry.•The irritability was found to be a significant predictor of depression and anxiety disorders.•The results of the linear regression analysis show that the Cyclothymic and Irritable temperaments significantly predicted “Irritability”.•The present study confirms the role of affective temperaments as possible risk factors in the manifestations psychopatological.
The affective temperaments are defined as the fundamental predisposition from which normal affective states originate or as the constitutional core of personality. Recently, researchers have started considering the role of affective temperament on the clinical expression of affective disorders. The aim of the study is to learn more about the role of affective temperaments on irritability, anxiety and depression symptoms.
748 subjects belonging to Italian population were included. Data were collected through an online survey including IDAS and TEMPS-A questionnaire. Two correlation analysis were performed to assess sex differences in the affective patterns. A linear regression analysis was performed to assess how age, sex and temperamental dimensions could play a role as predictors of depression, anxiety and irritability symptoms.
The correlation analysis shows that "Cyclothymic," "Depressive," "Irritable", and "Anxious" temperaments, in both genders, positively correlate with Anxiety, Depression, and Irritability. Hyperthymic temperament, instead, negatively correlates with Depression in men and with both Anxiety and Depression in women. Linear regression show that Cyclothymic, depressive and anxious temperaments are significant predictors of anxiety symptoms while depressive and cyclothymic temperaments are predictors of depressive symptoms. The irritability was found to be a significant predictor of depression and anxiety disorders. The results of the linear regression analysis show that the Cyclothymic and Irritable temperaments significantly predicted “Irritability”. Finally, female sex was found to be a predictor of anxiety (β = 0.090, t = 2.906, p = <0.004)
The present study confirms the role of affective temperaments as possible risk factors in psychopathological manifestations. Further studies would be necessary in order to investigate the mechanisms of these observed associations.
First-episode psychosis (FEP) is a major life event and can have an adverse impact on the diagnosed individual and their families. The importance of intervening early and providing optimal treatments ...is widely acknowledged. In comparison to patient groups, literature is scarce on identifying treatment predictors and moderators of caregiver outcomes. This study aimed to identify pre-treatment characteristics predicting and/or moderating carer outcomes, based on data from a multi-element psychosocial intervention to FEP patients and carers (GET-UP PIANO trial).
Carer demography, type of family relationship, patient contact hours, pre-treatment carer burden, patient perceptions of parental caregiving and expressed emotion (EE) were selected, a priori, as potential predictors/moderators of carer burden and emotional distress at 9 months post treatment. Outcomes were analysed separately in mixed-effects random regression models.
Analyses were performed on 260 carers. Only patient perceptions of early maternal criticism predicted reports of lower carer burden at follow-up. However, multiple imputation analysis failed to confirm this result. For treatment moderators: higher levels of carer burden at baseline yielded greater reductions in carer emotional distress at follow-up in the experimental group compared with treatment as usual (TAU). Higher levels of perceived EE moderated greater reductions in carer reports of tension in experimental group, compared with TAU, at follow-up. In younger caregivers (<51 years old), there were greater reductions in levels of worry during the baseline to follow-up period, within the experimental group compared with TAU.
The study failed to identify significant treatment predictors of FEP carer outcomes. However, our preliminary findings suggest that optimal treatment outcomes for carers at first episode might be moderated by younger carer age, and carers reporting higher baseline levels of burden, and where patients perceive higher levels of negative effect from caregivers.
Synthesis of terpolymer coatings composed of hyperbranched fluoropolymers cross-linked with bisamino-propyl poly(ethylene glycol) and bisamino-propyl polydimethylsiloxane (PDMS) was performed to ...generate antibiofouling surfaces. Nanoscale imaging and surface spectroscopy confirmed that this system possessed complex surface topographies and chemical compositions. Surface complexity was determined to be due to molecular interactions, phase segregation, and compositional gradients arising between the three components. A clear difference in surface behavior was observable before and after exposure to water. Antibiofouling characteristics were investigated by bovine serum albumin (BSA) adsorption studies; the terpolymer coating displayed a 60% greater resistance to protein adsorption in comparison to the fouling of a commercial antibiofouling silicone coating. The unique surface topography, topology, and chemical heterogeneity expressed at a variety of scales provide a robust regime for the generation of hardy, complex surfaces known to incorporate characteristics appropriate for antibiofouling applications. Thorough assessment of thermal responses and mechanical properties in relevant environments demonstrated a formulation platform immediately appropriate for consideration in marine and in vivo applications.
A series of thiol-ene generated amphiphilic cross-linked networks was prepared by reaction of alkene-modified Boltorn polyesters (Boltorn-ene) with varying weight percent of 4-armed poly(ethylene ...glycol) (PEG) tetrathiol (0–25 wt %) and varying equivalents of pentaerythritol tetrakis(3-mercaptopropionate) (PETMP) (0–64 wt %). These materials were designed to present complex surface topographies and morphologies, with heterogeneity of surface composition and properties and robust mechanical properties, to serve as nontoxic antibiofouling coatings that are amenable to large-scale production for application in the marine environment. Therefore, a two-dimensional matrix of materials compositions was prepared to study the physical and mechanical properties, over which the compositions spanned from 0 to 25 wt % PEG tetrathiol and 0–64 wt % PETMP (the overall thiol/alkene (SH/ene) ratios ranged from 0.00 to 1.00 equiv), with both cross-linker weight percentages calculated with respect to the weight of Boltorn-ene. The Boltorn-ene components were prepared through the esterification of commercially available Boltorn H30 with 3-butenoic acid. The subsequent cross-linking of the Boltorn-PEG-PETMP films was monitored using IR spectroscopy, where it was found that near-complete consumption of both thiol and alkene groups occurred when the stoichiometry was ca. 48 wt % PETMP (0.75 equiv SH/ene, independent of PEG amount). The thermal properties of the films showed an increase in T g with an increase in 4-armed PEG-tetrathiol wt %, regardless of the PETMP concentration. Investigation of the bulk mechanical properties in dry and wet states found that the Young’s modulus was the greatest at 48 wt % PETMP (0.75 equiv of SH/ene). The ultimate tensile strength increased when PETMP was constant and the PEG concentration was increased. The Young’s modulus was slightly lower for wet films at constant PEG or constant PETMP amounts, than for the dry samples. The nanoscopic surface features were probed using atomic force microscopy (AFM), where it was observed that the surface of the amphiphilic films became increasingly rough with increasing PEG wt %. On the basis of the physicochemical data from the diverse sample matrix, a focused compositional profile was then investigated further to determine the antifouling performance of the cross-linked Boltorn-PEG-PETMP networks. For these studies, a low, constant PETMP concentration of 16 wt % was maintained with variation in the PEG wt % (0–35 wt %). Antifouling and fouling-release activities were tested against the marine alga Ulva. Spore settlement densities were low on these films, compared to that on standards of polydimethylsiloxane and glass.
Abstract 5-Lipoxygenase (5-Lox), an enzyme involved in the metabolism of arachidonic acid participates in the modulation of the proliferation and differentiation of neural stem cells and cerebellar ...granule cell (CGC) precursors. Since epigenetic mechanisms including DNA methylation regulate 5-LOX expression and have been suggested as possible modulators of stem cell differentiation and aging, using primary cultures of mouse CGC (1, 5, 10, 14, 30 days in vitro ; DIV), we studied DNA methylation patterns of the 5-LOX promoter and 5-LOX mRNA levels. We also measured the mRNA and protein content of the DNA methyltransferases DNMT1 and DNMT3a. 5-LOX, DNMT1, and DNMT3a mRNA levels were measured by real-time PCR. We observed that 5-LOX expression and the expression of maintenance DNMT1 is maximal at 1 DIV (proliferating neuronal precursors), whereas the expression of the de novo DNA methyltransferase DNMT3a mRNA increased in aging cultures. We analyzed the methylation status of the 5-LOX promoter using the methylation-sensitive restriction endonucleases AciI, BstUI, HpaII, and HinP1I, which digest unmethylated CpGs while leaving methylated CpGs intact. The 5-LOX DNA methylation increased with the age of the cells. Taken together, our data show that as cultured CGC mature and age in vitro , a decrease in 5-LOX mRNA content is accompanied by an increase in the methylation of the gene DNA. In addition, an increase in DNMT3a but not DNMT1 expression accompanies an increase of 5-LOX methylation during in vitro maturation.
Abstract The melatonin receptors MT1 and MT2 take part in the regulation of the activity (i.e. phosphorylation) of extracellular-signal-regulated kinase (ERK1/2), an enzyme involved in ...neuroplasticity. Primary cultures of mouse and rat cerebellar granule cells (CGC), which express both MT1 and MT2 receptors, have been widely used as an in vitro model to study neuronal ERK1/2. A novel MT1/MT2 agonist, ramelteon, has recently become clinically available. In this study, we characterized its action on neuronal ERK1/2. We used CGC cultures prepared from the cerebella of wild-type mice (MT1/MT2 CGC) and MT1- and MT2-knockout (KO) mice (MT1 KO CGC and MT2 KO CGC, respectively), and we employed a Western blot assay to evaluate ERK1/2 phosphorylation. Ramelteon increased ERK1/2 phosphorylation not only in MT1/MT2 CGC but also in CGC expressing only one of the two melatonin receptors. In the MT1 KO CGC, the stimulatory effect of ramelteon was blocked by an MT2 antagonist, 4P-PDOT, whereas in the MT2 KO CGC, this effect of ramelteon was blocked by luzindole. Pertussis toxin treatment did not prevent ramelteon from activating ERK1/2 but pretreatment with a tyrosine kinase (Trk) inhibitor, K252a, did, suggesting that an activation of Trk may mediate melatonin-receptor dependent ERK1/2 activation. In conclusion, we showed for the first time that a clinically used MT1/MT2 agonist, ramelteon, is capable of activating neuronal ERK1/2.
The strategy of decorating antibiofouling hyperbranched fluoropolymer–poly(ethylene glycol) (HBFP-PEG) networks with a settlement sensory deterrent, noradrenaline (NA), and the results of biofouling ...assays are presented. This example of a dual-mode surface, which combines both passive and active modes of antibiofouling, works in synergy to improve the overall antibiofouling efficiency against barnacle cyprids. The HBFP-PEG polymer surface, prior to modification with NA, was analyzed by atomic force microscopy, and a significant distribution of topographical features was observed, with a nanoscopic roughness measurement of 110 ± 8 nm. NA attachment to the surface was probed by secondary ion mass spectrometry to quantify the extent of polymer chain-end substitution with NA, where a 3- to 4-fold increase in intensity for a fragment ion associated with NA was observed and 39% of the available sites for attachment were substituted. Cytoskeletal assays confirmed the activity of tethered NA on adhering oyster hemocytes. Settlement assays showed deterrence toward barnacle cyprid settlement, while not compromising the passive biofouling resistance of the surface. This robust strategy demonstrates a methodology for the incorporation of actively antibiofouling moieties onto a passively antibiofouling network.
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