Associative learning theories regard the probability of reinforcement as the critical factor determining responding. However, the role of this factor in instrumental conditioning is not completely clear. In fact, free-operant experiments show that participants respond at a higher rate on variable ratio than on variable interval schedules even though the reinforcement probability is matched between the schedules. This difference has been attributed to the differential reinforcement of long inter-response times (IRTs) by interval schedules, which acts to slow responding. In the present study, we used a novel experimental design to investigate human responding under random ratio (RR) and regulated probability interval (RPI) schedules, a type of interval schedule that sets a reinforcement probability independently of the IRT duration. Participants responded on each type of schedule before a final choice test in which they distributed responding between two schedules similar to those experienced during training. Although response rates did not differ during training, the participants responded at a lower rate on the RPI schedule than on the matched RR schedule during the choice test. This preference cannot be attributed to a higher probability of reinforcement for long IRTs and questions the idea that similar associative processes underlie classical and instrumental conditioning. ARTICLE HISTORY

Impaired cognitive flexibility in visual reversal-learning tasks has been observed in a wide range of neurological and neuropsychiatric disorders. Although both human and animal studies have implicated striatal D 2-like and D 1-like receptors (D2R; D1R) in this form of flexibility, less is known about the contribution they make within distinct sub-regions of the striatum and the different phases of visual reversal learning. The present study investigated the involvement of D2R and D1R during the early (perseverative) phase of reversal learning as well as in the intermediate and late stages (new learning) after microinfusions of D2R and D1R antagonists into the nucleus accumbens core and shell (NAcC; NAcS), the anterior and posterior dorsomedial striatum (DMS) and the dorsolateral striatum (DLS) on a touchscreen visual serial reversal-learning task. Reversal learning was improved after dopamine receptor blockade in the nucleus accumbens; the D1R antagonist, SCH23390, in the NAcS and the D2R antagonist, raclopride, in the NAcC selectively reduced early, perseverative errors. In contrast, reversal learning was impaired by D2R antagonism, but not D1R antagonism, in the dorsal striatum: raclopride increased errors in the intermediate phase after DMS infusions, and increased errors across phases after DLS infusions. These findings indicate that D1R and D2R modulate different stages of reversal learning through effects localised to different sub-regions of the striatum. Thus, deficits in behavioral flexibility observed in disorders linked to dopamine perturbations may be attributable to specific D1R and D2R dysfunction in distinct striatal sub-regions.

Addiction is regarded as a disorder of inflexible choice with behavior dominated by immediate positive rewards over longer-term negative outcomes. However, the psychological mechanisms underlying the effects of self-administered drugs on behavioral flexibility are not well understood. To investigate whether drug exposure causes asymmetric effects on positive and negative outcomes we used a reversal learning procedure to assess how reward contingencies are utilized to guide behavior in rats previously exposed to intravenous cocaine self-administration (SA). Twenty-four rats were screened for anxiety in an open field prior to acquisition of cocaine SA over six daily sessions with subsequent long-access cocaine SA for 7 days. Control rats (n = 24) were trained to lever-press for food under a yoked schedule of reinforcement. Higher rates of cocaine SA were predicted by increased anxiety and preceded impaired reversal learning, expressed by a decrease in lose-shift as opposed to win-stay probability. A model-free reinforcement learning algorithm revealed that rats with high, but not low cocaine escalation failed to exploit previous reward learning and were more likely to repeat the same response as the previous trial. Eight-day withdrawal from high cocaine escalation was associated, respectively, with increased and decreased dopamine receptor D2 (DRD2) and serotonin receptor 2C (HTR2C) expression in the ventral striatum compared with controls. Dopamine receptor D1 (DRD1) expression was also significantly reduced in the orbitofrontal cortex of high cocaine-escalating rats. These findings indicate that withdrawal from escalated cocaine SA disrupts how negative feedback is used to guide goal-directed behavior for natural reinforcers and that trait anxiety may be a latent variable underlying this interaction.

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BackgroundIncreased access to transportation and information has led to the emergence of more diverse patient choice and new forms of health care consumption, such as medical travel. In order for health care providers to effectively attract patients, more knowledge is needed on the mechanisms underlying decision-making of potential travelers from different countries. A particularly promising method of studying the travelers’ motives is collecting data on social media.ObjectivesThe aim of this study was to test what factors influence decision-making of potential medical travelers and how these factors interact. Based on existing literature, the factors analyzed included quality, cost, and waiting time for 2 procedures varying in invasiveness across 12 different destination countries.MethodsDecision-making patterns were examined using a pilot questionnaire that generated a large amount of data from over 800 participants in 40 countries. Participants indicated their willingness to travel given different scenarios. Each scenario consisted of a combination of several factors. Additionally, participants were asked to indicate the reasons for their choice.ResultsIndividuals display high willingness to travel for medical care when combining all participants and scenarios, travel for care was chosen 66.9% of the time. Among the factors influencing their decisions, quality of the medical procedure abroad was considered most important, and cost was least important as shown by chi-square tests and corresponding odds ratios. Log-linear analyses revealed an interaction between time waiting in the local health care system and type of procedure, whereby time pressure increased the odds of agreeing to travel for the more invasive procedure. The odds of traveling to Europe and the USA were by far the highest, although participants indicated that under certain conditions they might be willing to travel to other medical destinations, such as Asia.ConclusionOur measurements yielded several reliable insights into the factors driving medical decision-making. An essential next step would be to expand these findings with a more encompassing sample and more elaborate statistical modeling.

RationaleImpairments in behavioral flexibility lie at the core of anxiety and obsessive-compulsive disorders. Few studies, however, have investigated the neural substrates of natural variation in behavioral flexibility and whether inflexible behavior is linked to anxiety and peripheral markers of stress and monoamine function.ObjectiveThe objective of the study was to investigate peripheral and central markers associated with perseverative behavior on a spatial-discrimination serial reversal learning task.MethodsRats were trained on a reversal learning task prior to blood sampling, anxiety assessment, and the behavioral evaluation of selective monoamine oxidase-A (MAO-A) and MAO-B inhibitors, which block the degradation of serotonin (5-HT), dopamine (DA), and noradrenaline (NA).ResultsPerseveration correlated positively with 5-HT levels in blood plasma and inversely with trait anxiety, as measured on the elevated plus maze. No significant relationships were found between perseveration and the stress hormone corticosterone or the 5-HT precursor tryptophan. Reversal learning was significantly improved by systemic administration of the MAO-A inhibitor moclobemide but not by the MAO-B inhibitor lazabemide. Moclobemide also increased latencies to initiate a new trial following an incorrect response suggesting a possible role in modulating behavioral inhibition to negative feedback. MAO-A but not MAO-B inhibition resulted in pronounced increases in 5-HT and NA content in the orbitofrontal cortex and dorsal raphé nuclei and increased 5-HT and DA content in the basolateral amygdala and dorsomedial striatum.ConclusionsThese findings indicate that central and peripheral monoaminergic mechanisms underlie inter-individual variation in behavioral flexibility, which overlaps with trait anxiety and depends on functional MAO-A activity.

Despite a growing focus on neuroimmune mechanisms of Alzheimer’s disease (AD), the role of peripheral monocytes remains largely unknown. Circulating monocytes communicate with the brain’s resident myeloid cells, microglia, via chemical signaling and can directly infiltrate the brain parenchyma.1 Thus, molecular signatures of monocytes may serve as indicators of neuropathological events unfolding in the CNS.2–5 However, no studies have yet directly tested the association of monocyte gene expression on longitudinal cognitive decline or postmortem neuropathology and brain gene expression in aging. Here we present a resource of RNA sequencing of purified CD14+ human monocytes - including an eQTL map - from over 200 elderly individuals, most with accompanying bulk brain RNA sequencing profiles, longitudinal cognitive assessments, and detailed postmortem neuropathological examinations. We tested the direct correlation of gene expression between monocytes and bulk brain tissue, finding very few significant signals driven largely by genetic variation. However, we did identify sets of monocyte-expressed genes that were highly predictive of postmortem microglial activation, diffuse amyloid plaque deposition, and cerebrovascular disease. Our findings prioritize potential blood-based molecular biomarkers for AD; they also reveal the previously unknown architecture of shared gene expression between the CNS and peripheral immune system in aging.

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