Deciphering the reward-related impulsivity domains in rats: The big data study of historical control

Impulsivity is a lack of ability to control own impulses, and encompasses many subdomains. The variable-delay-to-signal (VDS) paradigm is behavioral procedure for assessing motor impulsivity and delay intolerance in rats, but it was unclear whether all parameters contributed to these domains. Therefore, the aim of this study was to uncover the relationship between impulsivity parameters in a large cohort. VDS adapted to a touchscreen environment was used to assess impulsivity in adult Sprague-Dawley rats. After 1 week of training, animals were tested in a 3-stage testing protocol. The first stage included 20 trials with 6s inter-trial interval (ITI6si) that suggested motor impulsivity. The second stage, with 60 randomly distributed trials of ITI9s or 15s, was interpreted as delay intolerance, whereas for the last stage (ITI6sf), which is similar to the first stage, it was unclear to which type of impulsivity it was associated. Principal component analysis (PCA) was used to determine the different behavioral domains. The results of 132 controls from 11 independent VDS experiments were analyzed. Based on the cumulative variance explained, scree plot, and eigenvalues, the main components were extracted whereby varimax rotation was used on factor loadings to extract the components. PCA with varimax rotation was performed in R studio. PCA revealed that 96.45% of the variance could be explained by 3 principal components (PCs). After varimax rotation, loadings for ITI9s and ITI15s were 0.8189 and 0.9419, respectively, for rotated PC1 (RC1), loading for ITI6sf was 0.9482 for RC2, and loading for 6si was 0.9183 for RC3. In the VDS paradigm, 3 different impulsivity domains could be determined. In addition to motor impulsivity and delay intolerance, it is suggested that reflection impulsivity can also be assessed as learning-based impulsivity.Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 202

Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats

Introduction: Impulsivity is an umbrella term that encompasses many subdomains, most of which rely on the decision-making processes. It is reported that in the process of healthy aging, the two dimensions of impulse control, cognition and motivation, are preserved or even improved. On the other hand, the attentive efficiency seems to decrease with age. Therefore, we aimed to investigate the effects of healthy aging on impulsivity in rats and the influence of food deprivation on impulsivity in aged rats as a strategy to enhance motivation. Additionally, we wanted to assess the gene expression for the alpha5 GABAA receptor subunit during aging, which plays a role in cognitive processes. Methodology: The variable-delay-to-signal (VDS) paradigm adapted to a touchscreen environment was used to assess impulsivity and attention in Sprague-Dawley rats at 2, 3, 5, 8, and 14 months of age. After one week of training, animals were tested at different ages in 3-stage testing protocol. Additionally, prior to testing, animals were fed a restricted diet (16 g/animal). The first stage included 20 trials with inter-trial interval of 6s (ITI6si) that reflected motor impulsivity. The second stage, with 60 randomly distributed trials of ITI9s or 15s, was related to delay intolerance, while the final stage (ITI6sf), similar to the first, was related to reflection impulsivity. The strict 3-day restriction diet (24h food deprivation followed by 10g/day/animal and 8g/day/animal) was applied to 14-month-old animals before testing. Gabra5 expression in the hippocampus was determined by qPCR. Results were analyzed by one-way ANOVA with or without repeated measures, followed by Sidak post-hoc test for impulsivity and attention parameters and by t-test for PCR parameters. Results: Animals aged 8 and 14 months had reduced motor impulsivity (p<0.01 for both groups) and delay intolerance (p<0.05 for both groups) and higher number of omissions (p<0.05 for both groups) compared to animals aged 2, 3 and 5 months of age. In addition, half of the animals were unable to successfully complete a task after 14 months. After rigorous food restriction in 14-month-old animals, the level of impulsivity (ITI9s and ITI15s) and attention (number of omissions) returned to the control level (2 and 3 months of age) compared to the performance of 14-month-old animals prior to rigorous food restriction (p<0.05). Further, the peak of reflection impulsivity (ITI6sf) was reached at 5 months compared to all other groups (p<0.01). No changes in Gabra5 expression in hippocampus were detected in 14-month-old compared to 3-month-old animals. Conclusion: From 8 months of age onwards, rats showed reduced impulsivity in the VDS stages where motor impulsivity and delay intolerance were tested, followed by attention deficits. After strict food restriction in 14-month-old animals, delay intolerance and attention were restored, suggesting the prominent role of motivation in controlling these processes, independently of Gabra5 expression levels in the hippocampus. Since the VDS paradigm aims to assess reward-related impulsivity based on cognition and motivation, it is suspected that results related to impaired cognition in older animals in other cognitive tests should be interpreted with caution, and with additional observation of motivation

Deciphering ciprofloxacin-induced neurotoxicity: behavioral and molecular profiling of ciprofloxacin treatment in rats

Introduction: Ciprofloxacin is a fluoroquinolone antibiotic commonly used to treat various bacterial infections, with a potential to induce adverse mood effects in patients. Since the molecular mechanism of ciprofloxacin-induced neurotoxicity is poorly understood, we aimed to identify behavioral changes and corresponding neurotransmitter pattern after its prolonged administration in rats. We screened for untoward effects of ciprofloxacin on locomotor activity, despair, anhedonia, object recognition memory, and anxiety, as behavioral domains affected in various psychiatric diseases. Methodology: Three-month old male Sprague-Dawley rats were orally gavaged with ciprofloxacin (20 or 100 mg/kg) or solvent (0.5% methyl cellulose solution) each day for 4 weeks (n=80). One group of animals (n=40) passed the open field (OF), novel object recognition test (NORT), and forced swimming test (FST). Another group (n=40) underwent elevated plus maze (EPM) and sucrose preference test (SPT). After the completion of behavioral battery, the prefrontal cortex and cerebrospinal fluid (CSF) were collected. The neurotransmitters and metabolites of the kynurenine pathway were determined in the prefrontal cortex (PFC) through HPLC-MS/MS. Additionally, levels of interleukin-2 (IL-2) in CSF were quantified with Luminex. Behavioral and molecular parameters were analyzed by one-way ANOVA followed by Dunnett post hoc test in GraphPad Prism 9. Results: In FST, the treatment with high dose of ciprofloxacin decreased the swim time compared to control, which could be related to induction of despair-like behavior (p<0.05). The ciprofloxacin treatment did not affect object memory in NORT. In OF, the distance travelled and the number of rotations were not changed after treatment with ciprofloxacin compared to the control group. Further, animals treated with ciprofloxacin did not show changes in parameters in EPM and SPT. The acetylcholine levels in PFC were increased after ciprofloxacin treatment (p<0.05) in comparison with controls, which could be associated with depressed mood states. In line with that, high dose of ciprofloxacin treatment showed the tendency to decrease and increase levels of GABA and dopamine, respectively, but without reaching the statistical significance (p=0.07 and p=0.06). No changes in kynurenine pathway were observed after the treatment. The IL-2 concentration in CSF was increased after prolonged administration of low dose of ciprofloxacin treatment compared to the control levels (p<0.05), which could imply immunological stimulation of T lymphocytes and potential neuroinflammation. Conclusion: The despair behavior after treatment with high dose of ciprofloxacin was accompanied by increased levels of acetylcholine in PFC. Furthermore, the high dose of ciprofloxacin treatment showed tendency to decrease GABA levels, and increase dopamine levels in PFC, which could be connected to psychiatric adverse effects. Nonetheless, further studies are essential to confirm these neurotransmitter changes. On the other hand, the low dose of ciprofloxacin treatment elicited the increase of IL-2, which could be a marker of neuroinflammation-related neurotoxicity. In the future, efforts should be made to examine the role of IL-2 in the interaction of the immune system and the central nervous system, as its potential significance as a biomarker

Dietary Intake, Body Composition and Performance of Professional Football Athletes in Slovenia

This is the first study to examine the nutritional status of professional Slovenian football players. This study aimed to analyze the dietary intake of elite football players during their preparation phase of the season and to investigate whether there is a relationship between energy and macronutrient intake with body composition and physical performance. Twenty-three footballers completed a three-day dietary and physical activity diary and underwent body composition measurements via bioelectrical impedance vector analysis (BIVA). Fifteen participants also took part in the Cooper treadmill test to assess their physical performance in correlation with their nutritional intake. Football players had an energy intake that was significantly too low for their needs, reflecting low energy availability. The average carbohydrate (CHO) intake was below the Union of European Football Associations (UEFA) recommendations, i.e., <4 g CHO/kg body weight (BW). Additionally, players had adequate intakes of protein and fat, and inadequate intakes of saturated fat, fiber, calcium and vitamin D. There was a positive correlation between protein intake and lean body mass. Additionally, a negative correlation was observed between body fat mass and carbohydrate intake as well as between performance with the percentage of energy intake from fat. Results of this study highlight what aspects of nutrition might be improved upon in professional football players to maximize performance, longevity and body composition of athletes, as well as the necessity of a nutritionist role in this process

Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations

Background: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations. Objective: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts. Methods: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered. Results: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years. Conclusions: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations. (J Allergy Clin Immunol 2021;148:1332-41.