Cell-nanoparticle stickiness and dose delivery in a multi-model in silico platform: DosiGUI.

BACKGROUND: It is well-known that nanoparticles sediment, diffuse and aggregate when dispersed in a fluid. Once they approach a cell monolayer, depending on the affinity or "stickiness" between cells and nanoparticles, they may adsorb instantaneously, settle slowly - in a time- and concentration-dependent manner - or even encounter steric hindrance and rebound. Therefore, the dose perceived by cells in culture may not necessarily be that initially administered. Methods for quantifying delivered dose are difficult to implement, as they require precise characterization of nanoparticles and exposure scenarios, as well as complex mathematical operations to handle the equations governing the system dynamics. Here we present a pipeline and a graphical user interface, DosiGUI, for application to the accurate nano-dosimetry of engineered nanoparticles on cell monolayers, which also includes methods for determining the parameters characterising nanoparticle-cell stickiness. RESULTS: We evaluated the stickiness for 3 industrial nanoparticles (TiO2 - NM-105, CeO2 - NM-212 and BaSO4 - NM-220) administered to 3 cell lines (HepG2, A549 and Caco-2) and subsequently estimated corresponding delivered doses. Our results confirm that stickiness is a function of both nanoparticle and cell type, with the stickiest combination being BaSO4 and Caco-2 cells. The results also underline that accurate estimations of the delivered dose cannot prescind from a rigorous evaluation of the affinity between the cell type and nanoparticle under investigation. CONCLUSION: Accurate nanoparticle dose estimation in vitro is crucial for in vivo extrapolation, allowing for their safe use in medical and other applications. This study provides a computational platform - DosiGUI - for more reliable dose-response characterization. It also highlights the importance of cell-nanoparticle stickiness for better risk assessment of engineered nanomaterials.

Enhancing shear strength and handleability of dewatered clay-rich coal tailings for dry-stacking.

Mineral tailings dams pose high pollution risks to the environment and catastrophic failures. Dry stacking has been identified as a promising alternative to mitigate these risks and offers various benefits to the mining industry but lacks systematic research outcomes. To facilitate dry stacking, coal tailings slurries were dewatered using either filtration or centrifugation methods, resulting in a semi-solid form (cake) that can be safely disposed of. The handleability and disposability of these cakes are greatly influenced by the selection of chemical aids (such as polymer flocculants) and the mechanical dewatering technique employed. The effects of polyacrylamide (PAM) flocculants with a range of molecular weight, charge, and charge density are presented. Coal tailings samples with differences in clay mineralogy were dewatered using press filtration, solid bowl centrifugation, and natural air drying. Handleability and disposability of the tailings were assessed by their rheological properties, including yield stress, adhesive and cohesive stresses, and stickiness. Residue moisture, type of polymer flocculants, and clay mineralogy were found to be crucial factors affecting the handleability and disposability of the dewatered cakes. The tailing yield stress (shear strength) increased as the solid concentration increased. In the semi-solid regime (above 60 wt% solids), the tailings displayed stiff exponential growth. Similar trends were observed for stickiness and adhesive/cohesive energy of the tailings with a steel (truck) surface. Adding polymer flocculants increased the shear strength of the dewatered tailings by 10-15%, thus favouring disposability. However, the polymer selection for coal tailing handling and processing is a trade-off between its disposability and handleability, which requires a multi-criteria decision-making process. The current results also suggested that cationic PAM could be most suitable for dewatering by press filtration, while anionic PAM should be selected for dewatering by solid bowl centrifugation.

Solidification of concentrated pea protein-pectin mixtures as potential binder.

BACKGROUND: Binders in plant-based meat analogues allow different components, such as extrudate and fat particles, to stick together. Typically, binders then are solidified to transform the mass into a non-sticky, solid product. As an option for a clean-label binder possessing such properties, the solidification behavior of pea protein-pectin mixtures (250 g kg-1 , r = 2:1, pH 6) was investigated upon heating, and upon addition of calcium, transglutaminase, and laccase, or by combinations thereof. RESULTS: Mixtures of (homogenized) pea protein and apple pectin had higher elastic moduli and consistency coefficients and lower frequency dependencies upon calcium addition. This indicated that calcium physically cross-linked pectin chains that formed the continuous phase in the biopolymer matrix. The highest degree of solidification was obtained with a mixture of pea protein and sugar beet pectin upon addition of laccase that covalently cross-linked both biopolymers involved. All solidified mixtures lost their stickiness. A mixture of soluble pea protein and apple pectin solidified only slightly through calcium and transglutaminase, probably due to differences in the microstructural arrangement of the biopolymers. CONCLUSION: The chemical makeup of the biopolymers and their spatial distribution determines solidification behavior in concentrated biopolymer mixtures. In general, pea protein-pectin mixtures can solidify and therefore have the potential to act as binders in meat analogues. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

N,N-Diethyl-3-toluamide Formulation Based on Ethanol Containing 0.1% 2-Hydroxypropyl-ß-cyclodextrin Attenuates the Drug's Skin Penetration and Prolongs the Repellent Effect without Stickiness.

N,N-diethyl-3-toluamide (DEET) is one of the most widely used insect repellents in the world. It was reported that a solution containing 6-30% cyclodextrin (CD) as a solvent instead of ethanol (EtOH) provided an enhancement of the repellent action time duration of the DEET formulation, although the high-dose CD caused stickiness. In order to overcome this shortcoming, we attempted to prepare a 10% DEET formulation using EtOH containing low-dose CDs (ß-CD, 2-hydroxypropyl-ß-CD (HPßCD), methyl-ß-CD, and sulfobutylether-ß-CD) as solvents (DEET/EtOH/CD formulations). We determined the CD concentration to be 0.1% in the DEET/EtOH/CD formulations, since the stickiness of 0.1% CDs was not felt (approximately 8 × 10-3 N). The DEET residue on the skin superficial layers was prolonged, and the drug penetration into the skin tissue was decreased by the addition of 0.1% CD. In particular, the retention time and attenuated penetration of DEET on the rat skin treated with the DEET/EtOH/HPßCD formulation was significantly higher in comparison with that of the DEET/EtOH formulation without CD. Moreover, the repellent effect of DEET was more sustained by the addition of 0.1% HPßCD in the study using Aedes albopictus. In conclusion, we found that the DEET/EtOH/HPßCD formulations reduced the skin penetration of DEET and prolonged the repellent action without stickiness.

Online prices and inflation during the nationwide COVID-19 quarantine period: Evidence from 107 Chinese websites.

Given the lack of activity in China's offline economy during the COVID-19 quarantine period, online prices provide new insights for analyzing the impacts of the pandemic on the economy. Using online prices from 107 websites in China and the DiD method to remove the Spring Festival effect, we show that the pandemic leads to a 0.4% surge in the overall inflation rate, a 20% decrease in the price change probability, and a 1% decline in the size of absolute price changes. Moreover, the pandemic had heterogeneous impacts on different sectors, leading to significant structural changes in inflation. Specifically, the pandemic hindered the price correction behavior after Spring Festival, and whether products could be consumed while customers stayed at home was an important factor affecting price adjustment and inflation dynamics.

Understanding stickiness in sugar-rich food systems: A review of mechanisms, analyses, and solutions of adhesion.

Stickinessis an inherent textural property in many sugar-rich foods, which can be problematic to the processing of confectionery products. The adhesion between foods and contact surfaces during processing and consumption has not been well understood in academia or industry. The theories of adhesion were discovered by scientists in the adhesive field of study, some of which can explain the stickiness phenomenon of confections. This work reviewed these theories in the context of sugar-rich foods, followed by a survey on the sensory and instrumental analyses of stickiness. Furthermore, the contributions of ingredients, temperature, compression, and contact surfaces to sugar-rich food adhesion are highlighted.

Brief communication: rapid elimination of egg stickiness using sodium hypochlorite in wels catfish Silurus glanis.

The wels catfish Silurus glanis is valuable fish for aquaculture. Its production relies mainly on artificial reproduction. One of the crucial steps determining success of the reproduction is elimination of egg stickiness after fertilization. To date, the catfish egg de-adhesion is usually carried out using proteolytic enzymes. Here, we prove a novel method based on oxidation of the egg surface by means of sodium hypochlorite. An effect of different exposure times and concentrations on the egg adhesiveness and damage was tested in the first trial. The selected concentration of sodium hypochlorite 0.3 mg · l-1 with exposure time 40 s was used for comparison with the conventical de-adhesion method using alcalase treatment. The fertilization and hatching rates reached very satisfactory outcome in both treatments (98.3 ± 0.7% vs 97.5 ± 2.2% and 86.6 ± 8.3% vs 91.3 ± 8.5% in alcalase- and sodium hypochlorite-treated embryos, respectively) without any statistical differences. Thus, the de-adhesion method using sodium hypochlorite can be recommended as a suitable method for wels catfish eggs. The method is simple, cheap, very fast, and the treated eggs are disinfected.

Study of the Human Stickiness Perception of Wet Fabric on the Volar Forearm via Two Contact Modes: Friction and Adhesion-Separation.

Wet fabric clinging to human skin may cause stickiness perception and facilitate wearing discomfort. This study aims to investigate the stickiness perception of wet fabrics via two contact modes (friction and adhesion-separation) as well as the influences of fabric properties and contact features on stickiness perception. A set of dynamic contact devices was developed to drive the samples to move horizontally or vertically on volar forearms. According to the magnitude estimation approach, 12 subjects were asked to assess the stickiness perceptions caused by 64 types of contact stimuli. The results showed that the water absorption capacity had a significant and negative correlation with stickiness perception under the two contact modes. However, the surface roughness was neither related to stickiness perception under the friction mode nor to stickiness perception under the adhesion-separation mode. There was an interaction between contact pressure and sliding velocity. The sliding velocity at medium or high pressure had a significant effect on stickiness perception, but the separating velocity had no significant effect. Stickiness perception under the friction mode is higher than that under the adhesion-separation mode in most cases. Consequently, the friction mode was considered the main contact mode that evokes stickiness perception.

[Physiochemical property variation in traditional Chinese medicine decoction before or after precipitation in alcohol and its relationship with wall stickiness in spray drying].

To explore the relationship between the variations of the physiochemical properties of traditional Chinese medicine(TCM) decoction before or after precipitation in alcohol and the wall stickiness in spray drying. In this study, widely used TCMs in clinic were selected to determine the physiochemical properties of TCM decoction before or after precipitation in alcohol separately.Afterwards, the principle component analysis(PCA),Hierarchical cluster analysis(HCA),and orthogonal partial least squares-discriminate analysis(OPLS-DA) were used to evaluate the relationship between the variations of those liquid before or after precipitation in alcohol and hot-melt stickiness in spray drying.Three types of statistical analysis methods all indicated that ethanol precipitation affected physiochemical properties of TCM decoction, and the variations of physical properties showed significant association with hot-melt stickiness in spray drying.The results of PCA-X and HCA suggested that the dynamic surface tension(DST) was impacted most by the alcohol deposition treatment,at the same time,the other 5 physiochemical properties were also affected.OPLS-DA verified that PCA-X and HCA results, and revealed that DST,equilibrium surface tension(EST) and pH were significantly affected by alcohol deposition treatment,and the order of the affecting factors from high to low was DST,EST and pH.Therefore,the downward trend of DST and pH were the important factors that directly affected the hot-melt stickiness of TCM after precipitation in alcohol,which would be probably caused by losing macromolecules alcoholic insoluble components and increasing relative proportions of organic acid and small molecule sugar.

Cadmium toxicity and its relationship with disturbances in the cytoskeleton, cell cycle and chromosome stability.

This study aimed to investigate the mode of action of cadmium (Cd) toxicity at cell level, especially at early stages of plant exposure. Tomato seedlings were cultivated in growth media containing from 0.1 to 70 µM CdCl2 for 24 h. Mitotic index, chromosome abnormality, DNA integrity and organization of tubulin-based structures were assessed in root cells. As higher the Cd concentration in the growth media, higher was the DNA damage intensity and the occurrence of chromosomal abnormalities that included chromosome lost, bridges, stickiness, C-metaphase and polyploidy. The profile of chromosomal aberrations also varied with elevated Cd concentration, being observed increases in the frequency of chromosome stickiness. The mitotic index was reduced at the lowest Cd concentration, but such reduction was statistically similar to that detected at the highest concentration, suggesting that mitotic depression is a rapid outcome and, at same time, a Cd-induced effect that is limited at the first 24 h of direct root exposure to this metal. Under exposure to 20 µM CdCl2, heterogenous distribution of the spindle fibers, formation of two spindle complexes in both of the cell poles, absence of centrosome center, polarization of the spindle fibers during cell division, and non-uniform tubulin deposition in microtubule and phragmoplast were noticed. The results indicate that the tubulin-dependent components of cytoskeleton are Cd targets, and the sensitivity of tubulin-based structures to Cd exposure depends on cell cycle phase. Moreover, DNA damage intensity and chromosomal abnormality profile can be employed as markers of Cd toxicity level.

Diet-induced co-variation between architectural and physicochemical plasticity in an extended phenotype.

The adaptive benefits of extended phenotypic plasticity are imprecisely defined due to a paucity of experiments examining traits that are manipulable and measurable across environments. Spider webs are often used as models to explore the adaptive benefits of variations in extended phenotypes across environments. Nonetheless, our understanding of the adaptive nature of the plastic responses of spider webs is impeded when web architectures and silk physicochemical properties appear to co-vary. An opportunity to examine this co-variation is presented by modifying prey items while measuring web architectures and silk physiochemical properties. Here, we performed two experiments to assess the nature of the association between web architectures and gluey silk properties when the orb web spider Argiope keyserlingi was fed a diet that varied in either mass and energy or prey size and feeding frequency. We found web architectures and gluey silk physicochemical properties to co-vary across treatments in both experiments. Specifically, web capture area co-varied with gluey droplet morphometrics, thread stickiness and salt concentrations when prey mass and energy were manipulated, and spiral spacing co-varied with gluey silk salt concentrations when prey size and feeding frequency were manipulated. We explained our results as A. keyserlingi plastically shifting its foraging strategy as multiple prey parameters simultaneously varied. We confirmed and extended previous work by showing that spiders use a variety of prey cues to concurrently adjust web and silk traits across different feeding regimes.

The paradox of falling job satisfaction with rising job stickiness in the German nursing workforce between 1990 and 2013.

BACKGROUND: Literature reports a direct relation between nurses' job satisfaction and their job retention (stickiness). The proper planning and management of the nursing labor market necessitates the understanding of job satisfaction and retention trends. The objectives of the study are to identify trends in, and the interrelation between, the job satisfaction and job stickiness of German nurses in the 1990-2013 period using a flexible specification for job satisfaction that includes different time periods and to also identify the main determinants of nurse job stickiness in Germany and test whether these determinants have changed over the last two decades. METHODS: The development of job stickiness in Germany is depicted by a subset of data from the German Socio-Economic Panel (1990-2013), with each survey respondent assigned a unique identifier used to calculate the year-to-year transition probability of remaining in the current position. The changing association between job satisfaction and job stickiness is measured using job satisfaction data and multivariate regressions assessing whether certain job stickiness determinants have changed over the study period. RESULTS: Between 1990 and 2013, the job stickiness of German nurses increased from 83 to 91%, while their job satisfaction underwent a steady and gradual decline, dropping by 7.5%. We attribute this paradoxical result to the changing association between job satisfaction and job stickiness; that is, for a given level of job (dis)satisfaction, nurses show a higher stickiness rate in more recent years than in the past, which might be partially explained by the rise in part-time employment during this period. The main determinants of stickiness, whose importance has not changed in the past two decades, are wages, tenure, personal health, and household structure. CONCLUSIONS: The paradoxical relation between job satisfaction and job stickiness in the German nursing context could be explained by historical downsizing trends in hospitals, an East-West German nurse compensation gap, and an increase in the proportion of nurses employed on a part-time basis. A clearer analysis of each of these trends is thus essential for the development of evidence-based policies that enhance the job satisfaction and efficiency of the German nursing workforce.

Lactose in dairy ingredients: Effect on processing and storage stability.

Lactose is the main carbohydrate in the milk of most species. It is present in virtually all dry dairy ingredients, with levels ranging from <2% (e.g., caseinates, milk protein isolates) to 100% in lactose powders. The presence of lactose has a strong effect on ingredient processing and stability. Lactose can negatively influence powder properties and lead to undesirable effects, such as the stickiness of powder resulting in fouling during drying, or caking and related phenomena during storage. In addition, being a reducing carbohydrate, lactose can also participate in the Maillard reaction with free amino groups of proteins, peptides, and free AA. In this review, the influence of the presence (or absence) of lactose on physiochemical properties of dairy ingredients is reviewed, with particular emphasis on behavior during processing and storage. Particularly important features in this respect are whether lactose is in the (glassy) amorphous phase or in the crystalline phase, which is strongly affected by precrystallization conditions (e.g., in lactose, permeate, and whey powders) and by drying conditions. Furthermore, the moisture content and water activity of the ingredients are important parameters to consider, as they determine both mobility and reactivity, influencing Maillard reactions and concomitant browning, the crystallization of amorphous lactose during storage of dairy ingredients, glass transitions temperatures, and associated stickiness and caking phenomena. For the stickiness and caking, a crucial aspect to take into account is powder particle surface composition in relation to the bulk powder. Lactose is typically underrepresented at the powder surface, as a result of which deviations between observed lactose-induced caking and stickiness temperatures, and determined glass transition temperatures arise. By considering lactose as an integral part of ingredient composition along with all other compositional and environmental properties, lactose behavior in dairy ingredients can be understood, controlled, and optimized. Routes to achieve this are outlined in this review paper.

DSPMP: Discriminating secretory proteins of malaria parasite by hybridizing different descriptors of Chou's pseudo amino acid patterns.

Identification of the proteins secreted by the malaria parasite is important for developing effective drugs and vaccines against infection. Therefore, we developed an improved predictor called "DSPMP" (Discriminating Secretory Proteins of Malaria Parasite) to identify the secretory proteins of the malaria parasite by integrating several vector features using support vector machine-based methods. DSPMP achieved an overall predictive accuracy of 98.61%, which is superior to that of the existing predictors in this field. We show that our method is capable of identifying the secretory proteins of the malaria parasite and found that the amino acid composition for buried and exposed sequences, denoted by AAC(b/e), was the most important feature for constructing the predictor. This article not only introduces a novel method for detecting the important features of sample proteins related to the malaria parasite but also provides a useful tool for tackling general protein-related problems. The DSPMP webserver is freely available at http://202.207.14.87:8032/fuwu/DSPMP/index.asp.

Tablet formulation of an active pharmaceutical ingredient with a sticking and filming problem: direct compression and dry granulation evaluations.

OBJECTIVE: To develop a tablet formulation for an active pharmaceutical ingredient for which sticking and filming problems occurred during tablet punching. METHODS: Direct compression and dry granulation tableting techniques were evaluated using factorial experimental design. The effects of chrome-coated punch tips, filler types and active percent in the tablet formulation by direct compression were evaluated. Similarly, for dry granulation using the roller compaction technique, three formulation factors - roller compaction pressure, intragranular filler percent and filler type - were studied. Tablets prepared by both techniques were characterized in regard to their compressibility index, tablet hardness, disintegration time, friability index and stickiness-filming index (an arbitrary index). Ten formulations were prepared by each technique. Using multiple response optimizations and estimated response surface plots, the data were analyzed to identify optimum levels for the formulation factors. RESULTS: Compressibility index values for all the formulations prepared by direct compression exceeded 25%, unlike the blends prepared by dry granulation. Both tablet hardness and disintegration time for direct compression formulations were significantly lower than for dry granulation formulations. The friability index values were significantly higher for direct compression formulations than for dry granulation formulations. All the direct compression formulations, unlike the dry granulation formulations, had a high stickiness-filming index. CONCLUSION: Statistical analysis helped in identifying the optimum levels of formulation factors, as well as the method for eliminating sticking and filming. Unlike the direct compression technique, dry granulation yielded tablets for which sticking and filming were completely eliminated.

Roller milled black gram (Phaseolus mungo) semolina and its influence on the quality characteristics of high protein pasta.

Black gram (Phaseolus mungo) was roller milled into semolina (BGS) and was substituted at 25, 50 and 75 % levels in vermicelli making in this investigation. There was an increase in ash and protein content as the inclusion of BGS in blends increased. The quality characteristics of pasta showed marginal increase in cooking loss up to 50 % level of BGS. The firmness value did not change much up to 50 % BGS in pasta. At 75 % level of BGS, the cooking loss and stickiness value were highest (6.10 % and 0. 90 N) whereas firmness value and overall quality score were lowest (4 N and 27.5/40) indicating that the pasta had mushy, indiscrete, sticky strands and had a prominent beany odour making it unacceptable. Hence 50 % BGS was considered optimum in vermicelli. The pasta made with 50 % BGS inclusion had a protein and dietary fiber content of 15.30 % and 8 % as against the control value of 11.30 and 4.20 % respectively.

Neurobehavioral Precursors of Compulsive Cocaine Seeking in Dual Frontostriatal Circuits.

Background: Only some individuals who use drugs recreationally eventually develop a substance use disorder, characterized in part by the rigid engagement in drug foraging behavior (drug seeking), which is often maintained in the face of adverse consequences (i.e., is compulsive). The neurobehavioral determinants of this individual vulnerability have not been fully elucidated. Methods: Using a prospective longitudinal study involving 39 male rats, we combined multidimensional characterization of behavioral traits of vulnerability to stimulant use disorder (impulsivity and stickiness) and resilience (sign tracking and sensation seeking/locomotor reactivity to novelty) with magnetic resonance imaging to identify the structural and functional brain correlates of the later emergence of compulsive drug seeking in drug-naïve subjects. We developed a novel behavioral procedure to investigate the individual tendency to persist in drug-seeking behavior in the face of punishment in a drug-free state in subjects with a prolonged history of cocaine seeking under the control of the conditioned reinforcing properties of a drug-paired Pavlovian conditioned stimulus. Results: In drug-naïve rats, the tendency to develop compulsive cocaine seeking was characterized by behavioral stickiness-related functional hypoconnectivity between the prefrontal cortex and posterior dorsomedial striatum in combination with impulsivity-related structural alterations in the infralimbic cortex, anterior insula, and nucleus accumbens. Conclusions: These findings show that the vulnerability to developing compulsive cocaine-seeking behavior stems from preexisting structural or functional changes in two distinct corticostriatal systems that underlie deficits in impulse control and goal-directed behavior.

The texture of potato mashes is impacted by blanching induced changes in their extracellular starch fractions.

The texture of potato mash significantly influences consumer satisfaction. We here investigated the impact of blanching and different methods thereof on the texture and extractable extracellular fractions (EEFs) of potato mash when extracted with water or with dimethyl sulfoxide (DMSO) to seek determining factors of potato mash texture. Mashes prepared from potatoes blanched in 2.04 mM CaCl2 (CaB-M) exhibited hardness (24.9 N) and stickiness (1.0 N·s) readings intermediate to those from potatoes that were not blanched (NB-M, 19.2 N and 1.2 N·s), or blanched in deionized water (WaB-M, 30.5 N and 0.6 N·s), which aligned with their levels of intact cells. Starch was the main constituent (57.2 % - 64.4 %, w/w) in all EEFs and more starch was present in (1) NB-M and (2) the DMSO extracts. The chain length distributions of DMSO-extracted extracellular starch (DEES) revealed that the amylopectin content increased in the order WaB-M (46.3 %), CaB-M (55.1 %), and NB-M (76.6 %), which was attributed to more intracellular amylopectin being released to the extracellular phase of mashes. The relative contents of shorter chain amylose (degree of polymerization 110-1000) and the DEES yield were significantly correlated to the hardness while the yield of DEEFs was positively correlated with the stickiness.

Social pressures and their impact on smartphone use stickiness and use habit among adolescents.

Excessive smartphone use has become a growing issue among adolescents as they develop mentally and socially. While researchers have examined individual and technological predictors of smartphone addiction, few studies consider broader societal influences. This study explored how social pressures such as mimicry, coercion, and norms impact persistent conscious smartphone use (use stickiness) and unconscious smartphone use (use habit). A survey was administered in two phases to 309 college students at a university in Southern China to gather data on perceptions of social influences and their degree of smartphone overuse. The relationships were analysed using a structural equation model. The study confirms the impact of three social pressures - mimetic, coercive and normative - on adolescents' degree of smartphone overuse (use stickiness and use habit). The mimetic pressure positively impacted use stickiness but not use habit. The coercive pressure positively impacted both the use stickiness and the use habit. The normative pressure positively impacted use habit but not use stickiness. This study provides a novel perspective on overlooked social drivers of problematic smartphone tendencies among youth. Our study also provides insights for educators, parents, and policymakers to more effectively intervene in adolescent smartphone overuse.

5-HT 2A and 5-HT 2C receptor antagonism differentially modulate reinforcement learning and cognitive flexibility: behavioural and computational evidence.

RATIONALE: Cognitive flexibility, the ability to adapt behaviour in response to a changing environment, is disrupted in several neuropsychiatric disorders, including obsessive-compulsive disorder and major depressive disorder. Evidence suggests that flexibility, which can be operationalised using reversal learning tasks, is modulated by serotonergic transmission. However, how exactly flexible behaviour and associated reinforcement learning (RL) processes are modulated by 5-HT action on specific receptors is unknown. OBJECTIVES: We investigated the effects of 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) antagonism on flexibility and underlying RL mechanisms. METHODS: Thirty-six male Lister hooded rats were trained on a touchscreen visual discrimination and reversal task. We evaluated the effects of systemic treatments with the 5-HT2AR and 5-HT2CR antagonists M100907 and SB-242084, respectively, on reversal learning and performance on probe trials where correct and incorrect stimuli were presented with a third, probabilistically rewarded, stimulus. Computational models were fitted to task choice data to extract RL parameters, including a novel model designed specifically for this task. RESULTS: 5-HT2AR antagonism impaired reversal learning only after an initial perseverative phase, during a period of random choice and then new learning. 5-HT2CR antagonism, on the other hand, impaired learning from positive feedback. RL models further differentiated these effects. 5-HT2AR antagonism decreased punishment learning rate (i.e. negative feedback) at high and low doses. The low dose also decreased reinforcement sensitivity (beta) and increased stimulus and side stickiness (i.e., the tendency to repeat a choice regardless of outcome). 5-HT2CR antagonism also decreased beta, but reduced side stickiness. CONCLUSIONS: These data indicate that 5-HT2A and 5-HT2CRs both modulate different aspects of flexibility, with 5-HT2ARs modulating learning from negative feedback as measured using RL parameters and 5-HT2CRs for learning from positive feedback assessed through conventional measures.