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Reduced sensitivity to both positive and negative reinforcement in mice over-expressing the 5-hydroxytryptamine transporter.

ABSTRACT: The 5-hydroxytryptamine (5-HT) transporter (5-HTT) is believed to play a key role in both normal and pathological psychological states. Much previous data suggest that the s allele of the polymorphic regulatory region of the 5-HTT gene promoter is associated with reduced 5-HTT expression and vulnerability to psychiatric disorders, including anxiety and depression. In comparison, the l allele, which increases 5-HTT expression, is generally considered protective. However, recent data link this allele to both abnormal 5-HT signalling and psychopathic traits. Here, we studied the processing of aversive and rewarding cues in transgenic mice that over-express the 5-HTT (5-HTTOE mice). Compared with wild-type mice, 5-HTTOE mice froze less in response to both a tone that had previously been paired with footshock, and the conditioning context. In addition, on a decision-making T-maze task, 5-HTTOE mice displayed reduced preference for a larger, delayed reward and increased preference for a smaller, immediate reward, suggesting increased impulsiveness compared with wild-type mice. However, further inspection of the data revealed that 5-HTTOE mice displayed a relative insensitivity to reward magnitude, irrespective of delay. In contrast, 5-HTTOE mice appeared normal on tests of spatial working and reference memory, which required an absolute choice between options associated with either reward or no reward. Overall, the present findings suggest that 5-HTT over-expression results in a reduced sensitivity to both positive and negative reinforcers. Thus, these data show that increased 5-HTT expression has some maladaptive effects, supporting recent suggestions that l allele homozygosity may be a potential risk factor for disabling psychiatric traits.

SUBMITTER: Line SJ

PROVIDER: S-EPMC4737229 | biostudies-other | 2014 Dec

REPOSITORIES: biostudies-other

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Project description:Positive self-beliefs are important for well-being, and are influenced by how others evaluate us during social interactions. Mechanistic accounts of self-beliefs have mostly relied on associative learning models. These account for choice behaviour but not for the explicit beliefs that trouble socially anxious patients. Neither do they speak to self-schemas, which underpin vulnerability according to psychological research. Here, we compared belief-based and associative computational models of social-evaluation, in individuals that varied in fear of negative evaluation (FNE), a core symptom of social anxiety. We used a novel analytic approach, 'clinically informed model-fitting', to determine the influence of FNE symptom scores on model parameters. We found that high-FNE participants learn more easily from negative feedback about themselves, manifesting in greater self-negative learning rates. Crucially, we provide evidence that this bias is underpinned by an overall reduced belief about self-positive attributes. The study population could be characterized equally well by belief-based or associative models, however large individual differences in model likelihood indicated that some individuals relied more on an associative (model-free), while others more on a belief-guided strategy. Our findings have therapeutic importance, as positive belief activation may be used to specifically modulate learning.Author summaryUnderstanding how we form and maintain positive self-beliefs is crucial to understanding how things go awry in disorders such as social anxiety. The loss of positive self-belief in social anxiety, especially in inter-personal contexts, is thought to be related to how we integrate evaluative information that we receive from others. We frame this social information integration as a learning problem and ask how people learn whether someone approves of them or not. We thus elucidate why the decrease in positive evaluations manifests only for the self, but not for an unknown other, given the same information. We investigated the mechanics of this learning using a novel computational modelling approach, comparing models that treat the learning process as series of stimulusresponse associations with models that treat learning as updating of beliefs about the self (or another). We show that both models characterise the process well and that individuals higher in symptoms of social anxiety learn more from negative information specifically about the self. Crucially, we provide evidence that this originates from a reduction in the amount of positive attributes that are activated when the individual is placed in a social evaluative context.

Project description:OBJECTIVES:Among critically ill patients with acute kidney injury, exposure to positive fluid balance, compared with negative fluid balance, has been associated with mortality and impaired renal recovery. However, it is unclear whether positive and negative fluid balances are associated with poor outcome compared to patients with even fluid balance (euvolemia). In this study, we examined the association between exposure to positive or negative fluid balance, compared with even fluid balance, on 1-year mortality and renal recovery. DESIGN:Retrospective cohort study. SETTING:Eight medical-surgical ICUs at the University of Pittsburgh Medical Center, Pittsburgh, PA. PATIENTS:Critically ill patients admitted between July 2000 and October 2008. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Among 18,084 patients, fluid balance was categorized as negative (< 0%), even (0% to < 5%), or positive (? 5%). Following propensity matching, positive fluid balance, compared with even or negative fluid balance, was associated with increased mortality (30.3% vs 21.1% vs 22%, respectively; p < 0.001). Using Gray's model, negative fluid balance, compared with even fluid balance, was associated with lower short-term mortality (adjusted hazard ratio range, 0.81; 95% CI, 0.68-0.96) but higher long-term mortality (adjusted hazard ratio range, 1.16-1.22; p = 0.004). Conversely, positive fluid balance was associated with higher mortality throughout 1-year (adjusted hazard ratio range, 1.30-1.92; p < 0.001), which was attenuated in those who received renal replacement therapy (positive fluid balance × renal replacement therapy interaction (adjusted hazard ratio range, 0.43-0.89; p < 0.001). Of patients receiving renal replacement therapy, neither positive (adjusted odds ratio, 0.98; 95% CI, 0.68-1.4) nor negative (adjusted odds ratio, 0.81; 95% CI, 0.43-1.55) fluid balance was associated with renal recovery. CONCLUSIONS:Among critically ill patients, exposure to positive or negative fluid balance, compared with even fluid balance, was associated with higher 1-year mortality. This mortality risk associated with positive fluid balance, however, was attenuated by use of renal replacement therapy. We found no association between fluid balance and renal recovery.

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Reduced sensitivity to both positive and negative reinforcement in mice over-expressing the 5-hydroxytryptamine transporter.

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