Anxiety-related Traits Research Articles

The Persian COVID stress scales (Persian-CSS) and COVID-19-related stress reactions in patients with obsessive-compulsive and anxiety disorders

The COVID Stress Scales (CSS) were designed to assess stress related to the COVID-19 pandemic. Emerging evidence indicates that people with anxiety disorders (ADs) and obsessive-compulsive disorder (OCD) may be more negatively impacted by COVID-19 than those with mood disorders or healthy individuals. Accordingly, this study sought to validate the Persian CSS (Persian-CSS) and to compare COVID-19-related stress reactions among patients with specific ADs and OCD. Patients with OCD (n = 300) and ADs (n = 310) completed the Persian-CSS and other scales developed to assess anxiety-related traits and COVID-19-related distress. The Persian-CSS replicated a five-factor structure similar to the original CSS in OCD and ADs. The total CSS and its scales had good reliability and validity. Patients with generalized anxiety disorder, panic disorder, and OCD had higher COVID-19 stress reactions than patients with social anxiety disorder and specific phobia. Patients with panic disorder had higher danger and contamination fears and xenophobia than patients with OCD. The study suggests that the Persian-CSS is a valid scale to be used in patients with OCD and ADs, each of whom differs in their specific patterns of COVID-19-related stress reactions.

Unified Behavioral Scoring for Preclinical Models.

Preclinical mental health research relies upon animal models, and whilst many encouraging advances are being made, reproducibility and translational relevance may be limited by sub-optimal testing or model choices. Animal behaviors are complex and test batteries should be designed to include their multifaceted nature. However, multiple behavioral testing is often avoided due to cost, availability or statistical rigor. Additionally, despite the disparity in the incidence of mental health problems between the sexes, a move toward reducing animal numbers could be a deterrent to including both male and female animals. The current study introduces a unified scoring system for specific behavioral traits with the aim of maximizing the use of all data generated whilst reducing the incidence of statistical errors. Female and male mice from two common background strains were tested on behavior batteries designed to probe multiple aspects of anxiety-related and social behavioral traits. Results for every outcome measure were normalized to generate scores for each test and combined to give each mouse a single unified score for each behavioral trait. The unified behavioral scores revealed clear differences in the anxiety and stress-related, and sociability traits of mice. Principle component analysis of data demonstrated significant clustering of animals into their experimental groups. In contrast, individual tests returned an ambiguous mixture of non-significant trends and significant effects for various outcome measures. Utilizing a range of behavioral measures and combining all outcome measure data to produce unified scores provides a useful tool for detecting subtle behavioral traits in preclinical models.

Impulsivity and anxiety-related dimensions in adults with bulimic-spectrum disorders differentially relate to eating disordered behaviors

While facets of both anxiety and impulsivity appear central to the development and maintenance of bulimia nervosa (BN), specific BN behaviors may be propagated by differing profiles of risk. The current study examined associations between dimensions of anxiety and impulsivity and BN symptoms (binge eating, vomiting, laxative misuse, driven exercise), both in terms of the presence of such behaviors and their frequency. Two hundred and four women (Mage = 25.7 years) who met DSM-IV criteria for full or subthreshold BN completed self-report measures of perfectionism (Frost Multidimensional Perfectionism Scale), anxiety (Spielberger Trait Anxiety Inventory), impulsivity (Barratt Impulsiveness Scale–11; Impulsive Behavior Scale), eating disordered behaviors (Eating Disorder Examination – Questionnaire), and associated psychiatric symptoms (Michigan Assessment Screening Test/Alcohol-Drug; Maudsley Obsessive-Compulsive Inventory). Factor analysis revealed multidimensional impulsive and anxiety-related traits (5 anxiety-related factors; 7 impulsivity-related factors). In zero-sensitive regression models, different facets of impulsivity evidenced association with the presence of binge eating (risk taking), laxative misuse (impulsive spending), and fasting (difficulty concentrating), along with the frequency of vomiting (long-term planning difficulties). In contrast, anxiety-related dimensions were only associated with driven exercise (high standards) and fasting (concern over mistakes, high standards, parental expectations). Overall, impulsive and anxiety-related factors and symptoms showed distinct associations with specific eating disorder behaviors, even among those with the same diagnosis.

Prevalence, comorbidity, and breed differences in canine anxiety in 13,700 Finnish pet dogs

Behaviour problems and anxieties in dogs decrease their quality of life and may lead to relinquishment or euthanasia. Considering the large number of pet dogs and the commonness of these problematic behaviours, a better understanding of the epidemiology and related molecular and environmental factors is needed. We have here studied the prevalence, comorbidity, and breed specificity of seven canine anxiety-like traits: noise sensitivity, fearfulness, fear of surfaces and heights, inattention/impulsivity, compulsion, separation related behaviour and aggression with an online behaviour questionnaire answered by dog owners. Our results show that noise sensitivity is the most common anxiety-related trait with a prevalence of 32% in 13,700 Finnish pet dogs. Due to the high prevalence of noise sensitivity and fear, they were the most common comorbidities. However, when comparing the relative risk, the largest risk ratios were seen between hyperactivity/inattention, separation related behaviour and compulsion, and between fear and aggression. Furthermore, dog breeds showed large differences in prevalence of all anxiety-related traits, suggesting a strong genetic contribution. As a result, selective breeding focusing on behaviour may reduce the prevalence of canine anxieties. Anxious animals may suffer from chronic stress and thus, modified breeding policies could improve the welfare of our companion dogs.

Serotonin (5-HT) neuron-specific inactivation of Cadherin-13 impacts 5-HT system formation and cognitive function

Genome-wide screening approaches identified the cell adhesion molecule Cadherin-13 (CDH13) as a risk factor for neurodevelopmental disorders, nevertheless the contribution of CDH13 to the disease mechanism remains obscure. CDH13 is involved in neurite outgrowth and axon guidance during early brain development and we previously provided evidence that constitutive CDH13 deficiency influences the formation of the raphe serotonin (5-HT) system by modifying neuron-radial glia interaction.Here, we dissect the specific impact of CDH13 on 5-HT system development and function using a 5-HT neuron-specific Cdh13 knockout mouse model (conditional Cdh13 knockout, Cdh13 cKO).Our results show that exclusive inactivation of CDH13 in 5-HT neurons selectively increases 5-HT neuron density in the embryonic dorsal raphe, with persistence into adulthood, and serotonergic innervation of the developing prefrontal cortex. At the behavioral level, adult Cdh13 cKO mice display delayed acquisition of several learning tasks and a subtle impulsive-like phenotype, with decreased latency in a sociability paradigm alongside with deficits in visuospatial memory. Anxiety-related traits were not observed in Cdh13 cKO mice.Our findings further support the critical role of CDH13 in the development of dorsal raphe 5-HT circuitries, a mechanism that may underlie specific clinical features observed in neurodevelopmental disorders.

Brain and blood biomarkers of tauopathy and neuronal injury in humans and rats with neurobehavioral syndromes following blast exposure

Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). CTE may be suspected when behavior, cognition, and/or memory deteriorate following repetitive mTBI. Exposure to blast overpressure from improvised explosive devices (IEDs) has been implicated as a potential antecedent for CTE amongst Iraq and Afghanistan Warfighters. In this study, we identified biomarker signatures in rats exposed to repetitive low-level blast that develop chronic anxiety-related traits and in human veterans exposed to IED blasts in theater with behavioral, cognitive, and/or memory complaints. Rats exposed to repetitive low-level blasts accumulated abnormal hyperphosphorylated tau in neuronal perikarya and perivascular astroglial processes. Using positron emission tomography (PET) and the [18F]AV1451 (flortaucipir) tau ligand, we found that five of 10 veterans exhibited excessive retention of [18F]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions, a typical localization of CTE tauopathy. We also observed elevated levels of neurofilament light (NfL) chain protein in the plasma of veterans displaying excess [18F]AV1451 retention. These findings suggest an association linking blast injury, tauopathy, and neuronal injury. Further study is required to determine whether clinical, neuroimaging, and/or fluid biomarker signatures can improve the diagnosis of long-term neuropsychiatric sequelae of mTBI.

Individual differences of conflict monitoring and feedback processing during reinforcement learning in a mock forensic context

This study investigated individual differences of conflict monitoring (N2 component), feedback processing (feedback negativity component), and reinforcement learning in a discrimination learning task using a mock (fictitious) forensic scenario to set participants in a semantic task context. We investigated individual differences of anxiety-related, impulsivity-related traits and reasoning ability during trial-and-error learning of mock suspect and nonsuspect faces. Thereby, we asked how the differential investment of cognitive-motivational processes facilitates learning in a mock forensic context. As learning can be studied by means of time-on-task effects (i.e., variations of cognitive processes across task blocks), we investigated the differential investment of cognitive-motivational processes block-wise in N = 100 participants. By performing structural equation modeling, we demonstrate that conflict monitoring decreased across task blocks, whereas the percentage of correct responses increased across task blocks. Individuals with higher reasoning scores and higher impulsivity-related traits relied rather on feedback processing (i.e., external indicators) during reinforcement learning. Individuals with higher anxiety-related traits intensified their conflict monitoring throughout the task to learn successfully. Observation by relevant others intensified conflict monitoring more than nonobservation. Our data highlight that individual differences and social context modulate the intensity of information processing in a discrimination learning task using a mock forensic task scenario. We discuss our data with regard to recent cognitive-motivational approaches and in terms of reinforcement learning.

Polygenic risk score models based on anxiety-related traits as endophenotypes to predict unipolar depression and suicidal behavior

The present study included the construction of polygenic risk score (PRS) models of individual differences in anxiety level, which increased values represent the endophenotype of depression and suicidal behavior, to predict these psychopathologies based on genotyping of 63 SNPs of serotoninergic, hypothalamicpituitary-adrenal and neurotrophic factors systems together with the relative leukocyte telomere length. According to logistic regression analysis, PRS models of individual differences in Neuroticism (EPI) level (P<0,2) predicted decreased risk of unipolar depression (P0.2=0,033, β=-5,24, r2=0,78) in women, which points to the necessity to consider sex during polygenic risk score analysis.

High- and Low-conditioned Behavioral effects of midazolam in Carioca high- and low-conditioned freezing rats in an ethologically based test

The selective breeding of laboratory rodents with different anxiety-related traits is the subject of growing interest. The present study compared the effects of the benzodiazepine midazolam in the elevated plus maze (EPM) test of anxiety in two lines of Wistar rats that were selectively bred in our laboratory for either high or low anxiety-like traits based on a contextual freezing conditioning paradigm. After phenotyping anxiety-like traits (i.e., conditioned freezing behavior), Carioca High-Freezing [CHF], Carioca Low-Freezing [CLF]) and control rats were intraperitoneally injected (1.0 ml/kg) with .9 % saline or midazolam (.25, .5, .75, and 1.0 mg/kg) and subjected to the EPM 30 min later. After the saline injection, the CHF and CLF groups exhibited lower and higher open-arm exploration in the EPM, respectively, compared with control rats. These results indicate that anxiety-related traits previously selected from an associative learning paradigm can also be phenotypically expressed in an ethologically based animal model of anxiety. All midazolam doses significantly increased open-arm exploration in both CHF and control animals, but this anxiolytic-like effect in CLF rats was only observed at the lowest dose tested (.25 mg/kg). The present findings indicate that these two breeding lines of rats are a useful model for studying anxiety, and the anxiolytic effect of midazolam depends on genetic variability that is associated with basal reactions to threatening situations.

Anxious anticipation prolongs emotional interference for rapid visual detection.

When we view emotionally arousing images, our perception of stimuli that follow soon afterward is transiently impaired-a phenomenon known as emotion-induced blindness. Previous studies have demonstrated that the magnitude and time course of this visual processing impairment is exaggerated by the presence of psychopathology and anxiety-related traits. Here, we tested whether emotional interference on a primary task can be modulated on a more dynamic basis, by the anticipation of unpredictable electric shock. We embedded naturalistic scenes in a 10-Hz rapid serial visual presentation (RSVP) stream, while varying the hedonic content of distractor images (aversive or neutral) and their temporal position (200, 400, and 700 ms) with respect to landscape targets. In Experiment 1, we found that, under typical conditions, aversive distractors induced a temporary visual performance decrement that exhibited a full rebound following a 400-ms distractor-target lag. In Experiment 2, subjects performed an identical RSVP task while under continuous threat of electric shock. We found that threat of unpredictable electric shock prolonged the duration of the emotional interference out to 400 ms and 700 ms, without affecting the overall magnitude of the performance impairment. In Experiment 3, the prolonged emotional interference under threat of unpredictable electric shock persisted at the 400-ms lag despite observed practice effects within subjects. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Heritable natural variation of light/dark preference in an outbred zebrafish population

Anxiety is a fear-like response to stimuli perceived to be threatening. Excessive or uncontrollable anxiety is a debilitating psychiatric disorder which affects many people throughout their lifetime. In unravelling the complex genetic and environmental regulations of anxiety-like phenotypes, models measuring the natural dark avoidance of larval zebrafish have shed light on the individual variation and heritability of this anxiety-related trait. Using the light/dark choice paradigm and selective breeding, this study aims to validate previous findings of the variable (VDA) and strong dark aversion (SDA) heritability in AB-WT larval zebrafish using the outbred zebrafish strain EK, which offers more genetic diversity to aid in future molecular mapping efforts. 190 larvae (6 days post fertilization [dpf] and 7 dpf) were tested across four trials and divided into variable (VDA), medium (MDA) and strong (SDA) dark aversion for further in-crosses. VDA and MDA larvae became more explorative with time, whereas SDA larvae rarely left the preferred light zone. The SDA and VDA in-crosses significantly increased the respective phenotypes in the second generation of larvae, whereas VDA × MDA inter-crosses did not. For the second-generation SDA cohort, dark aversion correlated with increased thigmotaxis, which reinforces SDA as an anxiety-like phenotype. Our finding that the dark aversion trait and SDA and VDA phenotypes are heritable in an outbred zebrafish population lays an important foundation for future studies of genetic underpinnings using whole-genome mapping methods. This conserved fear/anxiety-like response in a highly accessible model organism also allows for further pharmacological and behavioral studies to elucidate the etiology of anxiety and the search for novel therapeutics for anxiety disorders.

Anxiety-related Endophenotypes and Hazardous Alcohol Use in Young Adults are Associated with a Functional Polymorphism in the SLC6A4 Gene

Background:A functional polymorphism (5-HTTLPR, rs4795541) in the serotonin transporter (SLC6A4) gene has been shown as an important candidate for several psychiatric and behavioral traits.Objective:The objective of this study was to examine the possible interaction of this polymorphism with physical neglect in childhood on the presentation of anxiety traits and hazardous alcohol consumption in young Colombian subjects.Methods:272 young adults (mean age: 21.3 years) were evaluated with the Childhood Trauma Questionnaire, the Zung Self-rating Anxiety Scale, the Big Five Inventory, the Cohen’s Perceived Stress Scale, the Alcohol, Smoking, Substance Involvement Screening Test and the Alcohol Use Disorders Identification Test. Genotyping for the 5-HTTLPR polymorphism was carried out using conventional PCR. A linear regression model, corrected by age and gender, was used.Results:We found that individuals with the L/L genotype showed higher scores on physical neglect (p=0.0047), anxiety symptoms (p=0.028), neuroticism (p=0.019) and perceived stress (p=0.035). L/L genotype was a risk factor for hazardous alcohol use in young adults (OR=3.06,p=0.0003). No GxE interactions were observed in our data.Conclusion:Our results provide novel evidence for the role of a functional polymorphism in theSLC6A4gene on the relationship of childhood trauma, anxiety-related traits and risky consumption of alcohol.

Reference Trait Analysis Reveals Correlations Between Gene Expression and Quantitative Traits in Disjoint Samples.

Systems genetic analysis of complex traits involves the integrated analysis of genetic, genomic, and disease-related measures. However, these data are often collected separately across multiple study populations, rendering direct correlation of molecular features to complex traits impossible. Recent transcriptome-wide association studies (TWAS) have harnessed gene expression quantitative trait loci (eQTL) to associate unmeasured gene expression with a complex trait in genotyped individuals, but this approach relies primarily on strong eQTL. We propose a simple and powerful alternative strategy for correlating independently obtained sets of complex traits and molecular features. In contrast to TWAS, our approach gains precision by correlating complex traits through a common set of continuous phenotypes instead of genetic predictors, and can identify transcript-trait correlations for which the regulation is not genetic. In our approach, a set of multiple quantitative "reference" traits is measured across all individuals, while measures of the complex trait of interest and transcriptional profiles are obtained in disjoint subsamples. A conventional multivariate statistical method, canonical correlation analysis, is used to relate the reference traits and traits of interest to identify gene expression correlates. We evaluate power and sample size requirements of this methodology, as well as performance relative to other methods, via extensive simulation and analysis of a behavioral genetics experiment in 258 Diversity Outbred mice involving two independent sets of anxiety-related behaviors and hippocampal gene expression. After splitting the data set and hiding one set of anxiety-related traits in half the samples, we identified transcripts correlated with the hidden traits using the other set of anxiety-related traits and exploiting the highest canonical correlation (R = 0.69) between the trait data sets. We demonstrate that this approach outperforms TWAS in identifying associated transcripts. Together, these results demonstrate the validity, reliability, and power of reference trait analysis for identifying relations between complex traits and their molecular substrates.

Distinct Stress Response and Altered Striatal Transcriptome in Alpha-Synuclein Overexpressing Mice.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder with motor symptoms and a plethora of non-motor and neuropsychiatric features that accompany the disease from prodromal to advanced stages. While several genetic defects have been identified in familial forms of PD, the predominance of cases are sporadic and result from a complex interplay of genetic and non-genetic factors. Clinical evidence, moreover, indicates a role of environmental stress in PD, supported by analogies between stress-induced pathological consequences and neuronal deterioration observed in PD. From this perspective, we set out to investigate the effects of chronic stress exposure in the context of PD by using a genetic mouse model that overexpresses human wildtype SNCA. Mimicking chronic stress was achieved by adapting a chronic unpredictable mild stress protocol (CUMS) comprising eight different stressors that were applied randomly over a period of eight weeks starting at an age of four months. A distinctive stress response with an impact on anxiety-related behavior was observed upon SNCA overexpression and CUMS exposure. SNCA-overexpressing mice showed prolonged elevation of cortisol metabolites during CUMS exposure, altered anxiety-related traits, and declined motor skills surfacing with advanced age. To relate our phenotypic observations to molecular events, we profiled the striatal and hippocampal transcriptome and used a 2 × 2 factorial design opposing genotype and environment to determine differentially expressed genes. Disturbed striatal gene expression and minor hippocampal gene expression changes were observed in SNCA-overexpressing mice at six months of age. Irrespective of the CUMS-exposure, genes attributed to the terms neuroinflammation, Parkinson’s signaling, and plasticity of synapses were altered in the striatum of SNCA-overexpressing mice.

Evidence for the effect of serotoninergic and dopaminergic gene variants on stress levels in horses participating in dressage and harness racing

Eye temperature assessed with infrared thermography is an adequate tool for stress level assessment in sport horses’ competitions having a moderate heritability. Serotonin and dopamine signal transduction-linked gene variants have been associated with anxiety-related traits in several species. In this study we examined the association between 10 gene variants in BDNF, COMT, HTR1A, TPH2 and SLC6A4 genes (and the haplotypes at SLC6A4 gene) with stress level (measured with eye temperature and heart rate) in 270 animals, 135 Spanish Trotter Horses (STH) participating in trotting races and 135 ‘Pura Raza Español’ (PRE) horses in dressage. Association analyses were performed using a unified mixed model (counting for population structure and individual relatedness) for the whole population and for each horse breed. The g.43865600G > A intronic gene variant located 11.0 kb downstream from the transcription start site of SLC6A4 gene was associated with an increase in eye temperature before competition with a relative contribution of this gene variant of 38.8% (P = 0.001), 31.8% just after (P = 0.001) and 29.8% 2 h after the competition (P = 0.003). In STH, the g.43865600G > A gene variant showed the same association with eye temperature before (P = 0.001, contribution 27.2%), just after (P = 0.0003, 29.0%) and after the competition (P = 0.002, 17.5%); and the c.*111G > A gene variant located at the 3′UTR region of COMT gene was associated with eye temperature 2 h after the competition (P = 0.001, 22.3%). These results showed that SLC6A4 and COMT gene variants are associated with stress level measured as eye temperature increase during competitions, and may be promising tools for genetic testing against resistance at high stress levels in trotter horses.

HrQoL in hair loss-affected patients with alopecia areata, androgenetic alopecia and telogen effluvium: the role of personality traits and psychosocial anxiety.

Illness impact on HrQoL has been widely studied in hair loss-affected patients, yet no study has addressed whether individual differences modulate HrQoL in patients with alopecia areata (AA), androgenetic alopecia (AGA) and telogen effluvium (TE). To identify the personality dimensions most predictive of the impact of disease on HrQoL. A single-site cross-sectional study was carried out in the Dermatology Unit of Sant'Orsola-Malpighi Hospital, Bologna between September 2016 and September 2017. The study included 143 patients (105 females, ages 18-60years) diagnosed with AA (n=27), AGA (n=80) and TE (n=36). Illness severity, alopecia type, age, gender, education and civil status were documented. Health-related quality of life (HrQoL), personality traits, trait anxiety, emotional intelligence, social anxiety and social phobia were also measured. AA, AGA and TE groups differed significantly for illness severity with most severe patients falling in AA type. For HrQoL, Gender×Group interaction resulted significant with AGA females reporting a higher impact of hair loss on quality of life than males, while TE males were more impacted by hair loss than AA and AGA males. Lower scores were obtained by AGA females than males on emotional intelligence while no significant differences were evidenced on other groups. A significant Gender × Group interaction was also found for trait anxiety, social phobia and social anxiety: consistently, AGA females reported higher scores than AGA males in all three measures. Finally, discriminant analysis evidenced that anxiety-related traits can contribute to reliably predict hair loss impact on HrQoL, regardless of illness severity and alopecia type. We recommend that gender and individual differences in anxiety-related dimensions be considered as key factors in gaining a deeper understanding of hair loss impact on quality of life as well as in reducing the burden of illness in alopecia-affected patients.

The Relationship between Plasma Oxytocin Levels and Social Anxiety Symptoms.

ObjectiveThe pathophysiology of social anxiety disorder (SAD) is not yet well understood, but previous research has suggested that oxytocin is associated with social behavior and may play a role in human anxiety states and anxiety-related traits. The aim of this study was to investigate the possible relationship between social anxiety symptoms and plasma oxytocin levels. MethodsTwenty-three male patients with SAD and 28 healthy male controls participated in this study. All participants were assessed using the Mini International Neuropsychiatric Interview (MINI) and the Liebowitz Social Anxiety Scale (LSAS). Multivariate regression analysis was performed to identify associations between plasma oxytocin levels and SAD. ResultsIn multiple regression models, after controlling for age and years of education, we found that higher oxytocin levels were significantly associated with higher total LSAS scores (R2=0.157, coefficient=0.145, 95% CI=-0.0005–0.291, p=0.051) and fear subscale scores (R2=0.134, coefficient=0.083, 95% CI=0.007–0.159, p=0.034) in the SAD group. ConclusionIn this study, increased plasma oxytocin levels were associated with higher social anxiety symptoms among SAD patients, but not among controls. This might be because among SAD patients, higher oxytocin (OT) secretion is an insufficient compensatory attempt to reduce social anxiety symptoms.

Failure to Replicate the Association Between Fractional Anisotropy and the Serotonin Transporter Gene (5-HTTLPR, rs25531).

Recent work underlines the importance of alterations in white matter (e.g., measured by fractional anisotropy (FA)) as a neural vulnerability marker for psychiatric disorders. In this context, the uncinate fasciculus (UF), which connects the limbic system with prefrontal areas, has repeatedly been linked to psychiatric disorders, fear processing, and anxiety-related traits. Individual differences in FA may partly be genetically determined. Variation in the promoter region of the serotonin transporter gene (serotonin transporter-linked polymorphic region [5-HTTLPR]) is a particularly promising candidate in this context, which has been linked to psychiatric disorders as well as to limbic and prefrontal reactivity. However, findings on the association between the 5-HTTLPR and FA within the UF-tract have been heterogeneous. The present study investigated this relationship and extended previous work by considering different genetic classification approaches as well as sex effects in a human sample (n = 114). All participants were genotyped for the 5-HTTLPR and the rs25531 polymorphism. As a main result, we did not find any significant relationship between the 5-HTTLPR and FA in the UF-tract although power analyses showed an adequate power. In addition, genotype effects were neither found when different classification approaches were used nor when analyses were carried out in males or females only. The present findings suggest that the association of the 5-HTTLPR and FA seems to be a more labile phenomenon than previously assumed. Possible explanations and limitations are discussed.

A Protein Aggregation Inhibitor, Leuco-Methylthioninium Bis(Hydromethanesulfonate), Decreases α-Synuclein Inclusions in a Transgenic Mouse Model of Synucleinopathy.

α-Synuclein (α-Syn) aggregation is a pathological feature of synucleinopathies, neurodegenerative disorders that include Parkinson’s disease (PD). We have tested whether N,N,N′,N′-tetramethyl-10H-phenothiazine-3,7-diaminium bis(hydromethanesulfonate) (leuco-methylthioninium bis(hydromethanesulfonate); LMTM), a tau aggregation inhibitor, affects α-Syn aggregation in vitro and in vivo. Both cellular and transgenic models in which the expression of full-length human α-Syn (h-α-Syn) fused with a signal sequence peptide to promote α-Syn aggregation were used. Aggregated α-Syn was observed following differentiation of N1E-115 neuroblastoma cells transfected with h-α-Syn. The appearance of aggregated α-Syn was inhibited by LMTM, with an EC50 of 1.1 μM, with minimal effect on h-α-Syn mRNA levels being observed. Two independent lines of mice (L58 and L62) transgenic for the same fusion protein accumulated neuronal h-α-Syn that, with aging, developed into fibrillary inclusions characterized by both resistance to proteinase K (PK)-cleavage and their ability to bind thiazin red. There was a significant decrease in α-Syn-positive neurons in multiple brain regions following oral treatment of male and female mice with LMTM administered daily for 6 weeks at 5 and 15 mg MT/kg. The early aggregates of α-Syn and the late-stage fibrillar inclusions were both susceptible to inhibition by LMTM, a treatment that also resulted in the rescue of movement and anxiety-related traits in these mice. The results suggest that LMTM may provide a potential disease modification therapy in PD and other synucleinopathies through the inhibition of α-Syn aggregation.

Home-cage anxiety levels in a transgenic rat model for Spinocerebellar ataxia type 17 measured by an approach-avoidance task: The light spot test

BackgroundMeasuring anxiety in a reliable manner is essential for behavioural phenotyping of rodent models such as the rat model for Spinocerebellar ataxia type 17 (SCA17) where anxiety is reported in patients. An automated tool for assessing anxiety within the home cage can minimize human intervention, stress of handling, transportation and novelty. New methodWe applied the anxiety test “light spot” (LS) (white led directed at the food-hopper) to our transgenic SCA17 rat model in the PhenoTyper 4500® to extend the knowledge of this automated tool for behavioural phenotyping and to verify an anxiety-like phenotype at three different disease stages for use in future therapeutic studies. ResultsLocomotor activity was increased in SCA17 rats at 6 and 9 months during the first 15min of the LS, potentially reflecting increased risk assessment. Both genotypes responded to the test with lower duration in the LS zone and higher time spent inside the shelter compared to baseline. Comparison with existing methodsWe present the first data of a rat model subjected to the LS. The LS can be considered more biologically relevant than a traditional test as it measures anxiety in a familiar situation. ConclusionsThe LS successfully evoked avoidance and shelter-seeking in rats. SCA17 rats showed a stronger approach-avoidance conflict reflected by increased activity in the area outside the LS. This home cage test, continuously monitoring pre- and post-effects, provides the opportunity for in-depth analysis, making it a potentially useful tool for detecting subtle or complex anxiety-related traits in rodents.