Associations and hallucinations in mice and men

Powers et al. (2017, Science, 357(6351), 596–600) report that Pavlovian conditioning can result in the perception of a stimulus in its absence, and that this effect is related to hallucinations outside the laboratory. Considered alongside similar studies in animals, this suggests that associatively produced perceptual processing offers a means to study hallucination-like behaviour in the animal laboratory

Conditioned hedonic responses elicited by contextual cues paired with nausea or with internal pain

Pairing a taste with either internal pain or nausea, despite equivalent effects on voluntary consumption, has dissociable effects on hedonic responses: Only pairing with nausea results in the production of disgust reactions, while pairing with internal pain results in conditioned fear as indicated by immobility. Here, we use orofacial reactions to examine the hedonic responses elicited by contextual, nonflavor, cues paired with nausea produced by injection of lithium chloride (LiCl) or internal pain caused by injection of hypertonic saline. In Experiment 1, aversive orofacial responses were the specific context-elicited behaviors in the rats injected with LiCl, whereas immobility was seen in the animals injected with hypertonic saline. In Experiment 2, rats first received discriminative training with two contexts, where one context was paired with LiCl or hypertonic saline, and the other context with isotonic saline. After this, rats were intraorally infused with a flavor (conditioned stimulus (CS) +) in the paired context, and with a different flavor (CS−) in the unpaired context. Second-order conditioning was then examined in a test conducted in the unpaired context. The infusion of the CS + flavor produced aversive orofacial responses in the rats injected with LiCl but immobility in the subjects injected with hypertonic saline. The results suggest that nonflavor cues support conditioned hedonic responses in the same way as flavor cues, which implies that the quality of aversion learning (conditioned nausea vs. fear) is primarily determined by the nature of the aversive event and not the type of conditioned cue

Wistar Kyoto Rats display anhedonia in consumption but retain some sensitivity to the anticipation of palatable solutions

The Wistar Kyoto (WKY) rat has been proposed as a model of depression-like symptoms. However, anhedonia—a reduction in the response to normatively rewarding events—as a central depression symptom has yet to be fully assessed in this model. We compared WKY rats and Wistar controls, with stress-susceptibility examined by applying mild unpredictable stress to a subset of each group. Anhedonia-like behavior was assessed using microstructural analysis of licking behavior, where mean lick cluster size reflects hedonic responses. This was combined with tests of anticipatory contrast, where the consumption of a moderately palatable solution (4% sucrose) is suppressed in anticipation of a more palatable solution (32% sucrose). WKY rats displayed greatly attenuated hedonic reactions to sucrose overall, although their reactions retained some sensitivity to differences in sucrose concentration. They displayed normal reductions in consumption in anticipatory contrast, although the effect of contrast on hedonic reactions was greatly blunted. Mild stress produced overall reductions in sucrose consumption, but this was not exacerbated in WKY rats. Moreover, mild stress did not affect hedonic reactions or the effects of contrast. These results confirm that the WKY substrain expresses a direct behavioral analog of anhedonia, which may have utility for increasing mechanistic understanding of depression symptoms

Affective biases and their interaction with other reward-related deficits in rodent models of psychiatric disorders

Major depressive disorder (MDD) is one of the leading global causes of disability. Symptoms of MDD can vary person to person, and current treatments often fail to alleviate the poor quality of life that patients experience. One of the two core diagnostic criteria for MDD is the loss of interest in previously pleasurable activities, which suggests a link between the disease aetiology and reward processing. Cognitive impairments are also common in patients with MDD, and more recently, emotional processing deficits known as affective biases have been recognised as a key feature of the disorder. Studies in animals have found similar affective biases related to reward. In this review we consider these affective biases in the context of other reward-related deficits and examine how affective biases associated with learning and memory may interact with the wider behavioural symptoms seen in MDD. We discuss recent developments in how analogues of affective biases and other aspects of reward processing can be assessed in rodents, as well as how these behaviours are influenced in models of MDD. We subsequently discuss evidence for the neurobiological mechanisms contributing to one or more reward-related deficits in preclinical models of MDD, identified using these behavioural assays. We consider how the relationships between these selective behavioural assays and the neurobiological mechanisms for affective bias and reward processing could be used to identify potential treatment strategies

Reward adaptation and the mechanisms of learning: contrast changes reward value in rats and drives learning

Formal theories of learning suggest that associations between events are determined by the internal representations of those events. Thus, learning should depend on perceived reward value—even when perceptions differ from objective values. We examined this prediction in flavor-preference learning in rats. In two experiments, simultaneous contrast either increased perceived reward value, which was paired with a distinctive flavor cue (the positive conditioned stimulus, CS+), or decreased the perceived value of the same reward, which was then paired with a second flavor (the negative conditioned stimulus, CS–). Even though the CS+ and CS– were paired with the same objective reward, there was a preference for the CS+ in subsequent tests. Moreover, the size of contrast-produced changes in reward value during training predicted the preference for the CS+ at test. This contrast-produced learning effect illustrates the mechanisms by which associations, which normally track veridical relationships between events in the world, are formed

Blocking of flavor-nausea learning by non-flavor cues: assessment through orofacial reactivity responses

We investigated, using orofacial reactivity assessment, whether nonflavor context cues can elicit conditioned aversive reactions, and also whether context cues interfere, through blocking, with the reduction in taste palatability during taste aversion conditioning. Experiment 1 showed that a context previously paired with LiCl evoked aversive orofacial reactions, and also attenuated the reduction in palatability of a saccharin solution which was paired with LiCl in that context. In Experiment 2, this blocking effect was abolished when the rats were given nonreinforced exposure to the previously LiCl-paired context (context extinction) before aversive conditioning of the saccharin in compound with the context. These results confirm that context stimuli can elicit conditioned aversive reactions in the absence of any flavor component, and demonstrate that context cues can interfere with the affective aspects of taste aversion learning. Thus nonflavor cues appear to engage the same processes as taste cues in aversion learning. These results are consistent with the idea that taste aversion learning is governed by general associative mechanisms and the special properties of nausea, rather than by a selective mechanism for poison-avoidance

Differential Cellular Distribution of HIV-1 Drug Resistance in Vivo: Evidence for Infection of CD8+ T Cells during HAART

AbstractThis study presents a detailed analysis of HIV-1 populations isolated from total PBMC, plasma, CD4+ T cells, CD8+ T cells, and monocytes/macrophages in 13 patients receiving HAART. Sequence analysis of the reverse transcriptase and protease genes indicated that viral strains isolated from different blood leukocytes were genetically distinct in each subject. Notably, HIV variants isolated from CD8+ T cells were distantly related to strains derived from other blood cell types, providing evidence for the strain-specific infection of CD8+ T cells in vivo. Compartmentalization of drug resistance mutations in specific blood cell types was observed in approximately 50% of patients. The prevalence of resistance mutations was higher in either CD4+ T cells or monocytes/macrophages in these subjects. However, CD8+ T cells showed markedly lower levels of viral drug resistance in these patients, indicating a lack of viral replication in this compartment. This study is the first to demonstrate the differential distribution of HIV drug resistance in different blood cell types during HAART and provides new insights into the infection of CD8+ T cells in vivo

Individual differences in the nature of conditioned behavior across a conditioned stimulus: adaptation and application of a model

Pavlovian conditioning procedures produce marked individual differences in the form of conditioned behavior. For example, when rats are given conditioning trials in which the temporary insertion of a lever into an operant chamber (the conditioned stimulus, CS) is paired with the delivery of food (the unconditioned stimulus, US), they exhibit knowledge of the leverfood relationship in different ways. For some rats (known as sign-trackers) interactions with the lever dominate, while for others (goal-trackers) approaching the food well dominates. A formal model of Pavlovian conditioning (HeiDI) attributes such individual differences in behavior to variations in the perceived salience of the CS and US. An application of the model in which the perceived salience of the CS declines (i.e., adapts) across its duration, predicts changes in these individual differences within the presentation of the CS: The sign-tracking bias is predicted to decline and goal-tracking bias is predicted to increase across the presentation of a lever. The accuracy of these predictions was confirmed though analysis of archival data from female and male rats

Elaboration of a model of Pavlovian learning and performance: HeiDI

The model elaborated here adapts the influential pooled error term, first described by Allan R. Wagner and his colleague Robert A. Rescorla, to govern the formation of reciprocal associations between any pair of stimuli that are presented on a given trial. In the context of Pavlovian conditioning, these stimuli include various conditioned and unconditioned stimuli. This elaboration enables the model to deal with cue competition phenomena, including the relative validity effect, and evidence implicating separate error terms and attentional processes in association formation. The model also includes a performance rule, which provides a natural basis for (individual) variation in the strength and nature of conditioned behaviors that are observed in Pavlovian conditioning procedures. The new model thereby begins to address theoretical and empirical issues that were apparent when the Rescorla-Wagner model was first described, together with research inspired by the model over ensuing 50 years

individualized diagnostic and prognostic models for patients with psychosis risk syndromes a meta analytic view on the state of the art

Abstract Background The Clinical High Risk(CHR) paradigm has facilitated research into the underpinnings of help-seeking individuals at risk for developing psychosis, aiming at predicting and possibly preventing transition to the overt disorder. Statistical methods like machine learning(ML) and Cox regression have provided the methodological basis for this research by enabling the construction of diagnostic, i.e., distinguishing CHR from healthy individuals, and prognostic models, i.e., predicting a future outcome, based on different data modalities, including clinical, neurocognitive, and neurobiological data. However, their translation to clinical practice is still hindered by the high heterogeneity both of CHR populations and methodologies applied. Methods We systematically reviewed the literature on diagnostic and prognostic models built on Cox regression and ML. Furthermore, we conducted a meta-analysis on prediction performances investigating heterogeneity of methodological approaches and data modality. Results Forty-four articles were included covering 3707 individuals for prognostic and 1052 for diagnostic studies(572 CHR and 480 healthy controls). CHR patients could be classified against healthy controls with 78% sensitivity and 77% specificity. Across prognostic models, sensitivity reached 67% and specificity 78%. ML models outperformed those applying Cox regression by 10% sensitivity. There was a publication bias for prognostic studies, yet no other moderator effects. Conclusions Our results may be driven by substantial clinical and methodological heterogeneity currently affecting several aspects of the CHR field and limiting the clinical implementability of the proposed models. We discuss conceptual and methodological harmonization strategies to facilitate more reliable and generalizable models for future clinical practice