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To study individual recognition in animals, discrimination tasks are often conducted by presenting 2D images of real conspecifics. However, animals may discriminate the images merely as visual stimulus combinations without establishing referential relationships to the individuals depicted. In the current study, we investigated whether goats are able to discriminate photos of familiar and unfamiliar conspecifics, whether they not only process the photos as visual stimuli, but also understand them as virtual copies of real conspecifics and whether they grasp the concept of familiarity. Using a computer-controlled learning device, in three tests, goats of two experimental groups (A and B) had to discriminate portrait (Te1), profile (Te2) or headless body photos (Te3) of conspecifics. Tests were presented as 4-choice tasks, with one photo from Group A (rewarded) plus three photos from Group B (distractors). That is, the rewarded photo was familiar to Group A, but unfamiliar to Group B. Finally, in a reversal test (Te4) we reversed this principle. The goats learned the discriminations in Te1 to Te3 within two (Te1 and Te2) and three training days (Te3), respectively, and they needed between 91 [CL (66, 126)] and 174 [CL (126, 241)] trials to reach the learning criterion, with no statistically significant differences between the groups. In Te4, in contrast, the animals took 403 [Group A; CL (291, 557)] and 385 [Group B; CL (286, 519)] trials, respectively, to learn the task. The lack of spontaneous preferences for the photo of the familiar conspecific in the pretests of Te1 to Te3 in Group A, as well as the lack of differences in the number of trials to learn the discriminations between both groups, do not at first glance suggest that the goats established a correspondence between real conspecifics and their 2D representations. However, the higher number of trials in Te4 suggests that both groups formed the learning rule of choosing either the known (Group A) or the unknown goat (Group B) over the course of Te1 to Te3 and then failed after the rule was reversed, providing evidence that goats can associate 2D photos of conspecifics with real animals. [ABSTRACT FROM AUTHOR]

A higher incidence of multiple psychiatric disorders occurs in people born in late winter/early spring. Reduced light exposure/activity level impacts adult rodent behavior and neural mechanisms, yet few studies have investigated such light exposure on gestating fetuses. A dysfunctional dopamine system is implicated in most psychiatric disorders, and genetic polymorphisms reducing expression of the dopamine transporter (DAT) are associated with some conditions. Furthermore, adult mice with reduced DAT expression (DAT-HT) were hypersensitive to short active (SA; 19:5 L:D) photoperiod exposure versus their wildtype (WT) littermates. Effects of SA photoperiod exposure during gestation in these mice have not been examined. We confirmed adult females exhibit a heightened corticosterone response when in SA photoperiod. We then tested DAT-HT mice and WT littermates in psychiatry-relevant behavioral tests after SA or normal active (NA; 12:12 L:D) photoperiod exposure during gestation and early life. SA-born WT mice exhibited sensorimotor gating deficits (males), increased reward preference, less immobility, open arm avoidance (females), less motivation to obtain a reward, and reversal learning deficits, vs. NA-born WT mice. DAT-HT mice were largely resilient to these effects, however. Future studies will determine the mechanism(s) by which SA photoperiod exposure influences brain development to predispose toward emergence of psychiatry-relevant behaviors.

BackgroundForced alcohol (ethanol, EtOH) exposure has been shown to cause significant impairments on reversal learning, a widely-used assay of cognitive flexibility, specifically on fully-predictive, deterministic versions of this task. However, previous studies have not adequately considered voluntary EtOH consumption and sex effects on probabilistic reversal learning. The present study aimed to fill this gap in the literature.MethodsMale and female Long-Evans rats underwent either 10 weeks of voluntary intermittent 20% EtOH access or water only (H2O) access. Rats were then pretrained to initiate trials and learn stimulus-reward associations via touchscreen response, and subsequently required to select between two visual stimuli, rewarded with probability 0.70 or 0.30. In the final phase, reinforcement contingencies were reversed.ResultsWe found significant sex differences on several EtOH-drinking variables, with females reaching a higher maximum EtOH consumption, exhibiting more high-drinking days, and escalating their EtOH at a quicker rate compared to males. During early abstinence, EtOH drinkers (and particularly EtOH-drinking females) made more initiation omissions and were slower to initiate trials than H2O drinking controls, especially during pretraining. A similar pattern in trial initiations was also observed in discrimination, but not in reversal learning. EtOH drinking rats were unaffected in their reward collection and stimulus response times, indicating intact motivation and motor responding. Although there were sex differences in discrimination and reversal phases, performance improved over time. We also observed sex-independent drinking group differences in win-stay and lose-shift strategies specific to the reversal phase.ConclusionsFemales exhibit increased vulnerability to EtOH effects in early learning: there were sex-dependent EtOH effects on attentional measures during pretraining and discrimination phases. We also found sex-independent EtOH effects on exploration strategies during reversal. Future studies should aim to uncover the neural mechanisms for changes in attention and exploration in both acute and prolonged EtOH withdrawal.

Abstract Background A core symptom of autism spectrum disorder (ASD) is repetitive and restrictive patterns of behavior. Cognitive inflexibility has been proposed as a potential basis for these symptoms of ASD. More generally, behavioral inflexibility has been proposed to underlie repetitive and restrictive behavior in ASD. Here, we investigated whether and how behavioral flexibility is compromised in a widely used animal model of ASD. Methods We compared the behavioral performance of Shank2-knockout mice and wild-type littermates in reversal learning employing a probabilistic classical trace conditioning paradigm. A conditioned stimulus (odor) was paired with an unconditioned appetitive (water, 6 µl) or aversive (air puff) stimulus in a probabilistic manner. We also compared air puff-induced eye closure responses of Shank2-knockout and wild-type mice. Results Male, but not female, Shank2-knockout mice showed impaired reversal learning when the expected outcomes consisted of a water reward and a strong air puff. Moreover, male, but not female, Shank2-knockout mice showed stronger anticipatory eye closure responses to the air puff compared to wild-type littermates, raising the possibility that the impairment might reflect enhanced fear. In support of this contention, male Shank2-knockout mice showed intact reversal learning when the strong air puff was replaced with a mild air puff and when the expected outcomes consisted of only rewards. Limitations We examined behavioral flexibility in one behavioral task (reversal learning in a probabilistic classical trace conditioning paradigm) using one ASD mouse model (Shank2-knockout mice). Thus, future work is needed to clarify the extent to which our findings (that enhanced fear limits behavioral flexibility in ASD) can explain the behavioral inflexibility associated with ASD. Also, we examined only the relationship between fear and behavioral flexibility, leaving open the question of whether abnormalities in processes other than fear contribute to behavioral inflexibility in ASD. Finally, the neurobiological mechanisms linking Shank2-knockout and enhanced fear remain to be elucidated. Conclusions Our results indicate that enhanced fear suppresses reversal learning in the presence of an intact capability to learn cue-outcome contingency changes in Shank2-knockout mice. Our findings suggest that behavioral flexibility might be seriously limited by abnormal emotional responses in ASD.

Abstract Our world is full of uncertainty. Animals, including humans, need to behave flexibly to adjust to ever-changing environments. Reversal learning tasks have been used to assess behavioral flexibility in many species. However, there are some limitations in the traditional free-moving methodology, including (1) sessions to train the animals, (2) within-session number of trials associated with reversals, (3) factors of physical movement unrelated to the task in the maze or operant box, and (4) incompatibility with techniques, such as two-photon imaging. Therefore, to address these limitations, we established a novel spatiotemporal Pavlovian head-fixed reversal learning task for mice. Six experimentally naive adult C57BL/6J mice were used in this study. First, we trained head-fixed mice on a fixed-time schedule task. Sucrose solution was delivered every 10 s with a single drinking spout placed within the licking distance of the mice. After the mice showed anticipatory licking toward the timing of sucrose solution delivery, we began training the mice on the fixed-time schedule reversal learning task with two licking spouts. In this task, sucrose solution was delivered through one of the two drinking spouts. The rewarding spout was switched every 10 trials. Mice quickly learned to switch anticipatory licking to the rewarding side of the spouts, suggesting that they learned this head-fixed reversal learning task. Using the head-fixed experimental design, behavioral measures can be simplified by eliminating the complex behavioral sequences observed in free-moving animals. This novel head-fixed reversal learning task is a useful assay for studying the neurobiological mechanism of behavioral flexibility that is impaired in various psychopathological conditions.

Since ecology influences the expression of cognitive traits, intra-specific variation in ecological demands can drive differences in cognition. This is often the case, for instance, when sexes face different ecological challenges. However, so far, most studies have focused on few cognitive domains (i.e., spatial cognition), which limits our understanding of the evolution of sexually dimorphic cognition in animals. Endangered Southern ground-hornbills (Bucorvus leadbeateri), for example, show sex-specific ecological differences in age at dispersal, where females disperse from their natal group earlier than males. Based on this potential sex-specific source of selection, females and males may differ in their capacity to behave flexibly. Here, we used the reversal-learning paradigm in ten Southern ground-hornbills in two conditions: spatial and colour. During the pre-test (learning phase), regardless the sex, all subjects were faster at associating the food reward with spatial rather than with colour cues. Similarly, during the test (reversal-learning phase), both sexes learned the new association quicker with spatial cues. There were no sex differences in learning or reversal learning during both experimental phases. This possibility, however, requires further observation and experimentation. We hope our study will provide the impetus to assess further the cognitive capacities of this still overlooked species. [ABSTRACT FROM AUTHOR]

This study evaluates, through artificial neural network (NN) simulations, the roles of amygdala (AMG) and orbitofrontal cortex (OFC) in reversal learning as responsible for assigning and updating incentive values, respectively, by taking into account some of its physiological characteristics and its connections with mesolimbic system structures. An architecture was built which contained modules of nodes representing OFC, amygdala (AMG), ventral tegmental area (VTA) and nucleus accumbens (NACC). Simulations were based on experimental responses of rats during a discrimination and reversal learning task in a T -maze. During simulations, intact NN responded similar to control rats. OFC showed retarded encoding in afferent connections as comparing with AMG nodes and an increase in the recruitment of neural nodes during reversal tasks. Activity of neural nodes plausibly emulates reinforcer preference during discriminations and reversals in AMG, COF and NACC. All these findings were disrupted by OFC's inactivation. NN with OFC nodes inactivated (RN), just like rats with OFC inactivated, achieved discrimination learning although its reversal was impaired. As with rats, perseveration of incorrect responses was not found because subjects stop responding after a few incorrect trials. These findings are in accordance with the hypotheses of AMG as key in encoding novel predicting-outcome cues and OFC as critical for incentive value updating and the crucial role this prefrontal region plays for correct performance in discrimination tasks. [ABSTRACT FROM AUTHOR]

The simultaneous matching‐to‐sample procedures that are widely used to study stimulus equivalence in human participants have generally been unsuccessful in animals. However, functional equivalence classes have been demonstrated in pigeons and sea lions using a concurrent repeated reversal discrimination procedure. In this procedure, responding to one set of stimuli is reinforced but responding to a different set is not and the set associated with reinforcement is changed with multiple reversals during the experiment. The experiments reported here were designed to assess whether functional equivalence classes could be demonstrated in rats using similar techniques. Rats were initially trained with two sets of olfactory stimuli (six odors/set). Following many reversals, probe reversal sessions were conducted in which rats were exposed to a subset of the members of each set and, later in the session, the withheld stimuli were introduced. Responding to these delayed probe trials in accord with the reversed contingencies constituted transfer of function. There was some evidence of transfer in Experiment 1, but the effects were relatively weak and variable. Experiment 2 introduced procedural changes and found strong evidence of transfer of function consistent with the formation of functional equivalence classes. These procedures offer a promising strategy to study symbolic behavior in rodents. [ABSTRACT FROM AUTHOR]

IntroductionThe Somatic Marker Hypothesis (SMH) posits that in experience-based choice, people develop physiological reactions that mark options as either positive or negative. These somatic markers aid decision making because they differentiate between “good” and “bad” options during pre-choice deliberation.MethodsWe examined this proposed role for somatic states in two decision-from-experience tasks (each N = 36) in which participants selected repeatedly with full feedback (i.e., for obtained and forgone outcomes) between two unlabeled options that returned wins or losses, with half receiving an additional summary of past outcomes. The probabilities of good and bad outcomes changed at an unannounced point. Participants completed a 100-trial game with a switch in the optimal option after trial 40 (Study 1) or a 200-trial game with switch points after trial 40 and trial 120 (Study 2). Skin conductance (SC) was measured continuously as an index of emotional intensity, from which we extracted measures of anticipatory SC (pre-choice) and outcome SC (post-choice).ResultsParticipants reliably selected the optimal option prior to any switches. They also altered their choices appropriately when the payoffs changed, though optimal play following payoff switches was reduced. Losses resulted in a greater outcome SC than wins, but only in Study 1, as did the finding that the outcome SC was greater when the forgone outcome was positive. Anticipatory SC did not reliably predict optimal play in either study.DiscussionThese results provide little support for the SMH. Our studies point to the importance of using diverse tasks and measures and very large sample sizes when testing the role of somatic states in decision making.

Anorexia nervosa has among the highest mortality rates of any psychiatric disorder and is characterized by cognitive inflexibility that persists after weight recovery and contributes to the chronic nature of the condition. What remains unknown is whether cognitive inflexibility predisposes individuals to anorexia nervosa, a question that is difficult to address in human studies. Our previous work using the most well-established animal model of anorexia nervosa, known as activity-based anorexia (ABA) identified a neurobiological link between cognitive inflexibility and susceptibility to pathological weight loss in female rats. However, testing flexible learning prior to exposure to ABA in the same animals has been thus far impossible due to the length of training required and the necessity of daily handling, which can itself influence the development of ABA. Here, we describe experiments that validate and optimize the first fully-automated and experimenter-free touchscreen cognitive testing system for rats and use this novel system to examine the reciprocal links between reversal learning (an assay of cognitive flexibility) and weight loss in the ABA model. First, we show substantially reduced testing time and increased throughput compared to conventional touchscreen testing methods because animals engage in test sessions at their own direction and can complete multiple sessions per day without experimenter involvement. We also show that, contrary to expectations, cognitive inflexibility measured by this reversal learning task does not predispose rats to pathological weight loss in ABA. Instead, rats that were predisposed to weight loss in ABA were more quickly able to learn this reversal task prior to ABA exposure. Intriguingly, we show reciprocal links between ABA exposure and cognitive flexibility, with ABA-exposed (but weight-recovered) rats performing much worse than ABA naïve rats on the reversal learning task, an impairment that did not occur to the same extent in rats exposed to food restriction conditions alone. On the other hand, animals that had been trained on reversal learning were better able to resist weight loss upon subsequent exposure to the ABA model. We also uncovered some stable behavioral differences between ABA susceptible versus resistant rats during touchscreen test sessions using machine learning tools that highlight possible predictors of anorectic phenotypes. These findings shed new light on the relationship between cognitive inflexibility and pathological weight loss and provide targets for future studies using the ABA model to investigate potential novel pharmacotherapies for anorexia nervosa.

Research on fish cognition provides strong evidence that fish are endowed with high level cognitive skills. However, most studies on cognitive flexibility and generalization abilities, two key adaptive traits for captive animals, focused on model species, and farmed fish received too little attention. Environmental enrichment was shown to improve learning abilities in various fish species, but its influence on cognitive flexibility and generalization abilities is still unknown. We studied farmed rainbow trout (Oncorhynchus mykiss) as an aquaculture model to study how environmental enrichment impacts their cognitive abilities. Using an operant conditioning device, allowing the expression of a motivated choice, we measured fish cognitive flexibility with serial reversal learning tests, after a successful acquisition phase based on two colors discrimination (2-alternative forced choice, 2-AFC), and their ability to generalize a rewarded color to any shape. Eight fish were divided into two groups: Condition E (fish reared from fry stages under enriched conditions with plants, rocks and pipes for ~9 months); Condition B (standard barren conditions). Only one fish (condition E) failed in the habituation phase of the device and one fish (condition B) failed in the 2-AFC task. We showed that after a successful acquisition phase in which the fish correctly discriminated two colors, they all succeeded in four reversal learnings, supporting evidence for cognitive flexibility in rainbow trout. They were all successful in the generalization task. Interestingly, fish reared in an enriched environment performed better in the acquisition phase and in the reversal learning (as evidenced by fewer trials needed to reach the learning criterion), but not in the generalization task. We assume that color-based generalization may be a simpler cognitive process than discriminative learning and cognitive flexibility, and does not seem to be influenced by environmental conditions. Given the small number of individuals tested, our results may be considered as first insights into cognitive flexibility in farmed fish using an operant conditioning device, but they pave the way for future studies. We conclude that farming conditions should take into account the cognitive abilities of fish, in particular their cognitive flexibility, by allowing them to live in an enriched environment.

The relationship between intestinal microbiota and cognitive function has been investigated as one of the major topics within the intestinal microbiota–gut–brain axis. Although an increasing number of studies have demonstrated an improvement in learning and memory when using probiotics or prebiotics, to date, there are no studies that target the cognitive flexibility observed in the early stages of several neuropsychiatric diseases, including dementia. We have recently developed a novel behavioral task using the touchscreen operant system to assess cognitive flexibility. We found that the disruption of the intestinal microbiota in mice induced a decline in cognitive flexibility. In the present study, we investigated the effects of treatments consisting of Bifidobacterium animalis subsp. lactis and arginine (Bifal + Arg), which promote the production of intestinal bacterial polyamine, on cognitive flexibility in the mouse model. Male C57BL6 mice orally treated with Bifal + Arg three times a week gradually decreased the 1st-choice incorrect diagonal rate with repeated reversals compared with the control group. Furthermore, in serial reversal phases, Bifal + Arg-treated mice shifted to the behavior of choosing a new correct spot more quickly after the reversal, and this was faster with repeated reversals. These results indicate that this treatment adapts to change and improves cognitive flexibility. This is the first report to show that intestinal environmental control, including probiotics and prebiotics, improves cognitive flexibility in mice.

The subjective sense of certainty, or confidence, in ambiguous sensory cues can alter the interpretation of reward feedback and facilitate learning. We trained rats to report the orientation of ambiguous visual stimuli according to a spatial stimulus-response rule that must be learned. Following choice, rats could wait a self-timed delay for reward or initiate a new trial. Waiting times increase with discrimination accuracy, demonstrating that this measure can be used as a proxy for confidence. Chemogenetic silencing of BLA shortens waiting times overall whereas ACC inhibition renders waiting times insensitive to confidence-modulating attributes of visual stimuli, suggesting contribution of ACC but not BLA to confidence computations. Subsequent reversal learning is enhanced by confidence. Both ACC and BLA inhibition block this enhancement but via differential adjustments in learning strategies and consistent use of learned rules. Altogether, we demonstrate dissociable roles for ACC and BLA in transmitting confidence and learning under uncertainty.

The production of behavioural flexibility requires the coordination and integration of information from across the brain, by the dorsal striatum. In particular, the striatal cholinergic system is thought to be important for the modulation of striatal activity. Research from animal literature has shown that chemical inactivation of the dorsal striatum leads to impairments in reversal learning. Furthermore, proton magnetic resonance spectroscopy work has shown that the striatal cholinergic system is also important for reversal learning in humans. Here, we aim to assess whether the state of the dorsal striatal cholinergic system at rest is related to serial reversal learning in humans. We provide preliminary results showing that variability in choline in the dorsal striatum is significantly related to both the number of perseverative and regressive errors that participants make, and their rate of learning from positive and negative prediction errors. These findings, in line with previous work, suggest the resting state of dorsal striatal cholinergic system has important implications for producing flexible behaviour. However, these results also suggest the system may have heterogeneous functionality across different types of tasks measuring behavioural flexibility. These findings provide a starting point for further interrogation into understanding the functional role of the striatal cholinergic system in flexibility.

To study individual recognition in animals, discrimination tasks are often conducted by presenting 2D images of real conspecifics. However, animals may discriminate the images merely as visual stimulus combinations without establishing referential relationships to the individuals depicted. In the current study, we investigated whether goats are able to discriminate photos of familiar and unfamiliar conspecifics, whether they not only process the photos as visual stimuli, but also understand them as virtual copies of real conspecifics and whether they grasp the concept of familiarity. Using a computer-controlled learning device, in three tests, goats of two experimental groups (A and B) had to discriminate portrait (Te1), profile (Te2) or headless body photos (Te3) of conspecifics. Tests were presented as 4-choice tasks, with one photo from Group A (rewarded) plus three photos from Group B (distractors). That is, the rewarded photo was familiar to Group A, but unfamiliar to Group B. Finally, in a reversal test (Te4) we reversed this principle. The goats learned the discriminations in Te1 to Te3 within two (Te1 and Te2) and three training days (Te3), respectively, and they needed between 91 [CL (66, 126)] and 174 [CL (126, 241)] trials to reach the learning criterion, with no statistically significant differences between the groups. In Te4, in contrast, the animals took 403 [Group A; CL (291, 557)] and 385 [Group B; CL (286, 519)] trials, respectively, to learn the task. The lack of spontaneous preferences for the photo of the familiar conspecific in the pretests of Te1 to Te3 in Group A, as well as the lack of differences in the number of trials to learn the discriminations between both groups, do not at first glance suggest that the goats established a correspondence between real conspecifics and their 2D representations. However, the higher number of trials in Te4 suggests that both groups formed the learning rule of choosing either the known (Group A) or the unknown goat (Group B) over the course of Te1 to Te3 and then failed after the rule was reversed, providing evidence that goats can associate 2D photos of conspecifics with real animals.

Early life adversity (ELA) is a major health burden in the United States, with 62% of adults reporting at least one adverse childhood experience. These experiences during critical stages of brain development can perturb the development of neural circuits that mediate sensory cue processing and behavioral regulation. Recent studies have reported that ELA impaired the maturation of dendritic spines on neurons in the dorsolateral striatum (DLS) but not in the dorsomedial striatum (DMS). The DMS and DLS are part of two distinct corticostriatal circuits that have been extensively implicated in behavioral flexibility by regulating and integrating action selection with the reward value of those actions. To date, no studies have investigated the multifaceted effects of ELA on aspects of behavioral flexibility that require alternating between different action selection strategies or higher-order cognitive processes, and the underlying synaptic transmission in corticostriatal circuitries. To address this, we employed whole-cell patch-clamp electrophysiology to assess the effects of ELA on synaptic transmission in the DMS and DLS. We also investigated the effects of ELA on the ability to update action control in response to outcome devaluation in an instrumental learning paradigm and reversal of action-outcome contingency in a water T-maze paradigm. At the circuit level, ELA decreased corticostriatal glutamate transmission in male but not in female mice. Interestingly, in DMS, glutamate transmission is decreased in male ELA mice, but increased in female ELA mice. ELA impaired the ability to update action control in response to reward devaluation in a context that promotes goal-directedness in male mice and induced deficits in reversal learning. Overall, our findings demonstrate the sex- and region-dependent effects of ELA on behavioral flexibility and underlying corticostriatal glutamate transmission. By establishing a link between ELA and circuit mechanisms underlying behavioral flexibility, our findings will begin to identify novel molecular mechanisms that can represent strategies for treating behavioral inflexibility in individuals who experienced early life traumatic incidents.

Precisely charting the maturation of core neurocognitive functions such as reinforcement learning (RL) and flexible adaptation to changing action-outcome contingencies is key for developmental neuroscience and adjacent fields like developmental psychiatry. However, research in this area is both sparse and conflicted, especially regarding potentially asymmetric development of learning for different motives (obtain wins vs avoid losses) and learning from valenced feedback (positive vs negative). In the current study, we investigated the development of RL from adolescence to adulthood, using a probabilistic reversal learning task modified to experimentally separate motivational context and feedback valence, in a sample of 95 healthy participants between 12 and 45. We show that adolescence is characterized by enhanced novelty seeking and response shifting especially after negative feedback, which leads to poorer returns when reward contingencies are stable. Computationally, this is accounted for by reduced impact of positive feedback on behavior. We also show, using fMRI, that activity of the medial frontopolar cortex reflecting choice probability is attenuated in adolescence. We argue that this can be interpreted as reflecting diminished confidence in upcoming choices. Interestingly, we find no age-related differences between learning in win and loss contexts.

The orbital cortex (ORB) of the rat consists of five divisions: the medial (MO), ventral (VO), ventrolateral (VLO), lateral (LO), and dorsolateral (DLO) orbital cortices. No previous report has comprehensively examined and compared projections from each division of the ORB to the thalamus. Using the anterograde anatomical tracer, Phaseolus vulgaris leucoagglutinin, we describe the efferent projections from the five divisions of the ORB to the thalamus in the rat. We demonstrated that, with some overlap, each division of the ORB distributed in a distinct (and unique) manner to nuclei of the thalamus. Overall, ORB projected to a relatively restricted number of sites in the thalamus, and strikingly distributed entirely to structures of the medial/midline thalamus, while completely avoiding lateral regions or principal nuclei of the thalamus. The main termination sites in the thalamus were the paratenial nucleus (PT) and nucleus reuniens (RE) of the midline thalamus, the medial (MDm) and central (MDc) divisions of the mediodorsal nucleus, the intermediodorsal nucleus, the central lateral, paracentral, and central medial nuclei of the rostral intralaminar complex and the submedial nucleus (SM). With some exceptions, medial divisions of the ORB (MO, VO) mainly targeted "limbic‐associated" nuclei such as PT, RE, and MDm, whereas lateral division (VLO, LO, DLO) primarily distributed to "sensorimotor‐associated" nuclei including MDc, SM, and the rostral intralaminar complex. As discussed herein, the medial/midline thalamus may represent an important link (or bridge) between the orbital cortex and the hippocampus and between the ORB and medial prefrontal cortex. In summary, the present results demonstrate that each division of the orbital cortex projects in a distinct manner to nuclei of the thalamus which suggests unique functions for each division of the orbital cortex. [ABSTRACT FROM AUTHOR]

Serial reversal-learning procedures are simple preparations that allow for a better understanding of how animals learn about environmental changes, including flexibly shifting responding to adapt to changing reinforcement contingencies. The present study examined serial reversal learning with humans by arranging both midsession and variable contingency reversals across two experiments. We also examined the effects of extinction by adding nonreinforced trials at the end of later sessions and provided the first evaluation of effects of win-stay/lose-shift versus counting strategies on accuracy and response latency of humans' reversal-learning performance. In each experiment, responding tracked contingency reversals, primarily with participants using either win-stay/lose-shift or counting strategies. Introducing variable reversal points in the second experiment resulted in near-exclusive win-stay/lose-shift responding among participants and eliminated counting of trials. Each experiment also revealed an immediate shift from S2 to S1 after experiencing extinction during the initial test trial, indicating resurgence of the initial response through a win-stay/lose-shift response pattern. Therefore, the present study replicates and extends prior findings of a win-stay/lose shift response pattern in situations of greater uncertainty. These findings suggest that differences in environmental certainty induce qualitatively different decision-making strategies. [ABSTRACT FROM AUTHOR]

Learning theories of depression propose that negative thinking is acquired through subsequent rewarding experiences and is often resistant to change even when it becomes associated with punishment. We examined whether this persistency of negative thinking is related to current and future levels of depressive symptoms among adolescents. Persistency of negative self-referent thinking was assessed by means of a decision-making task, namely the emotional reversal learning task. This task offers participants the choice between thinking about negative and positive self-related aspects. Their choice for negative self-referent thinking is initially rewarded but is later punished. Therefore, participants were expected to efficiently switch between negative and positive self-referent thinking, and to internally update their reward expectancy for these thinking options. Results showed that persistency of negative self-referent thinking was related to concurrent levels of depressive symptoms, replicating earlier findings in adults. However, persistency of negative thinking was unrelated to future levels of depressive symptoms. These findings suggest that adolescents with depressive symptoms tend to hold on to the belief that negative self-referent thinking has beneficial consequences, even when it is no longer being rewarded. This tendency should be seen as a concurrent feature of depression, as the predictive value is still in question.

IntroductionCognitive flexibility is the ability of an individual to make behavioral adjustments in response to internal and/or external changes. While it has been reported in a wide variety of species, established paradigms to assess cognitive flexibility vary between humans and non-human animals, making systematic comparisons difficult to interpret.MethodsWe developed a computer-based paradigm to assess cognitive flexibility in humans and non-human primates. Our paradigm (1) uses a classical reversal learning structure in combination with a set-shifting approach (4 stimuli and 3 rules) to assess flexibility at various levels; (2) it employs the use of motion as one of three possible contextual rules; (3) it comprises elements that allow a foraging-like and random interaction, i.e., instances where the animals operate the task without following a strategy, to potentially minimize frustration in favor of a more positive engagement.Results and DiscussionWe show that motion can be used as a feature dimension (in addition to commonly used shape and color) to assess cognitive flexibility. Due to the way motion is processed in the primate brain, we argue that this dimension is an ideal candidate in situations where a non-binary rule set is needed and where participants might not be able to fully grasp other visual information of the stimulus (e.g., quantity in Wisconsin Card Sorting Test). All participants in our experiment flexibly shifted to and from motion-based rules as well as color- and shape-based rules, but did so with different proficiencies. Overall, we believe that with such approach it is possible to better characterize the evolution of cognitive flexibility in primates, as well as to develop more efficient tools to diagnose and treat various executive function deficits.

Impulsive behavior and impulsivity are heritable phenotypes that are strongly associated with risk for substance use disorders. Identifying the neurogenetic mechanisms that influence impulsivity may also reveal novel biological insights into addiction vulnerability. Our past studies using the BXD and Collaborative Cross (CC) recombinant inbred mouse panels have revealed that behavioral indicators of impulsivity measured in a reversal-learning task are heritable and are genetically correlated with aspects of intravenous cocaine self-administration. Genome-wide linkage studies in the BXD panel revealed a quantitative trait locus (QTL) on chromosome 10, but we expect to identify additional QTL by testing in a population with more genetic diversity. To this end, we turned to Diversity Outbred (DO) mice; 392 DO mice (156 males, 236 females) were phenotyped using the same reversal learning test utilized previously. Our primary indicator of impulsive responding, a measure that isolates the relative difficulty mice have with reaching performance criteria under reversal conditions, revealed a genome-wide significant QTL on chromosome 7 (max LOD score = 8.73, genome-wide corrected p

Background: Alcohol use disorder is characterized by perseverative alcohol use despite negative consequences. This hallmark feature of addiction potentially relates to impairments in behavioral flexibility, which can be measured by probabilistic reversal learning (PRL) paradigms. We here aimed to examine the cognitivemechanisms underlying impaired PRL task performance in patients with alcohol use disorder (AUDP) using computational models of reinforcement learning. Methods: Twenty-eight early abstinent AUDP and 27 healthy controls (HC) performed an extensive PRL paradigm. We compared conventional behavioral variables of choices (perseveration; correct responses) between groups. Moreover, we fitted Bayesian computational models to the task data to compare differences in latent cognitive variables including reward and punishment learning and choice consistency between groups. Results: AUDP and HC did not significantly differ with regard to direct perseveration rates after reversals. However, AUDP made overall less correct responses and specifically showed decreased win-stay behavior compared to HC. Interestingly, AUDP showed premature switching after no or little negative feedback but elevated proneness to stay when accumulation of negative feedback would make switching a more optimal option. Computational modeling revealed that AUDP compared to HC showed enhanced learning from punishment, a tendency to learn less from positive feedback and lower choice consistency. Conclusion: Our data do not support the assumption that AUDP are characterized by increased perseveration behavior. Instead our findings provide evidence that enhanced negative reinforcement and decreased non-drug-related reward learning as well as diminished choice consistency underlie dysfunctional choice behavior in AUDP. [ABSTRACT FROM AUTHOR]

Precisely timed behavior and accurate time perception plays a critical role in our everyday lives, as our wellbeing and even survival can depend on well-timed decisions. Although the temporal structure of the world around us is essential for human decision making, we know surprisingly little about how representation of temporal structure of our everyday environment impacts decision making. How does the representation of temporal structure affect our ability to generate well-timed decisions? Here we address this question by using a well-established dynamic probabilistic learning task. Using computational modeling, we found that human subjects’ beliefs about temporal structure are reflected in their choices to either exploit their current knowledge or to explore novel options. The model-based analysis illustrates a large within-group and within-subject heterogeneity. To explain these results, we propose a normative model for how temporal structure is used in decision making, based on the semi-Markov formalism in the active inference framework. We discuss potential key applications of the presented approach to the fields of cognitive phenotyping and computational psychiatry. [ABSTRACT FROM AUTHOR]

Simple Summary: Horse training exposes horses to many difficult learning challenges, including tasks that run counter to their natural behaviour and research from neuroscience can be used to understand how horses respond to these learning challenges. Horses can also quickly develop habits, however if the habit is undesirable, the horse may be subjected to retraining where it must learn to suppress the unwanted behaviour and learn a new response. This is called cognitive flexibility and is underpinned by complex neural processes and can be impaired by exposure to repeated or chronic stress. We trained horses to acquire habit-like responses in one of two industry-style aversive instrumental learning scenarios (moving away from the stimulus-instinctual-IS or moving towards the stimulus-non-instinctual-NIS) and evaluated the effect of repeated stress exposures on their cognitive flexibility in a reversal task. We measured heart rate, salivary cortisol and serum brain derived neurotrophic factor to infer possible neural correlates of the learning outcomes. Horses trained in the NIS task took longer to learn task than the horses trained in the IS task, however they were quicker to learn the IS task during the reversal. There was no significant effect of the stress exposures on cognitive flexibility, however the stress did make horses more sensitive to the aversive training stimuli. These results provide guidance for trainers to adapt their practices when training tasks that are difficult for horses to learn and during retraining. In particular, even when horses have been trained to approach aversive stimuli they can quickly learn to avoid them. This has implications for retraining unwanted responses during aversive situations such as trailer loading. Horse training exposes horses to an array of cognitive and ethological challenges. Horses are routinely required to perform behaviours that are not aligned to aspects of their ethology, which may delay learning. While horses readily form habits during training, not all of these responses are considered desirable, resulting in the horse being subject to retraining. This is a form of cognitive flexibility and is critical to the extinction of habits and the learning of new responses. It is underpinned by complex neural processes which can be impaired by chronic or repeated stress. Domestic horses may be repeatedly exposed to multiples stressors. The potential contribution of stress impairments of cognitive flexibility to apparent training failures is not well understood, however research from neuroscience can be used to understand horses' responses to training. We trained horses to acquire habit-like responses in one of two industry-style aversive instrumental learning scenarios (moving away from the stimulus-instinctual or moving towards the stimulus-non-instinctual) and evaluated the effect of repeated stress exposures on their cognitive flexibility in a reversal task. We measured heart rate as a proxy for noradrenaline release, salivary cortisol and serum Brain Derived Neurotrophic Factor (BDNF) to infer possible neural correlates of the learning outcomes. The instinctual task which aligned with innate equine escape responses to aversive stimuli was acquired significantly faster than the non-instinctual task during both learning phases, however contrary to expectations, the repeated stress exposure did not impair the reversal learning. We report a preliminary finding that serum BDNF and salivary cortisol concentrations in horses are positively correlated. The ethological salience of training tasks and cognitive flexibility learning can significantly affect learning in horses and trainers should adapt their practices where such tasks challenge innate equine behaviour. [ABSTRACT FROM AUTHOR]

Cognitive flexibility, the ability to adapt to unexpected changes, is critical for healthy environmental and social interactions, and thus to everyday functioning. In neuropsychiatric diseases, cognitive flexibility is often impaired and treatment options are lacking. Probabilistic reversal learning (PRL) is commonly used to measure cognitive flexibility in rodents and humans. In PRL tasks, subjects must sample choice options and, from probabilistic feedback, find the current best choice which then changes without warning. However, in rodents, pharmacological models of human cognitive impairment tend to disrupt only the first (or few) of several contingency reversals, making quantitative assessment of behavioral effects difficult. To address this limitation, we developed a novel rat PRL where reversals occur at relatively long intervals in time that demonstrates increased sensitivity to the non-competitive NMDA receptor antagonist MK-801. Here, we quantitively compare behavior in timebased PRL with a widely used task where reversals occur based on choice behavior. In time-based PRL, MK-801 induced sustained reversal learning deficits both in time and across reversal blocks but, at the same dose, only transient weak effects in performance-based PRL. Moreover, time-based PRL yielded better estimates of behavior and reinforcement learning model parameters, which opens meaningful pharmacological windows to efficiently test and develop novel drugs preclinically with the goal of improving cognitive impairment in human patients. [ABSTRACT FROM AUTHOR]

Background: A core symptom of autism spectrum disorder (ASD) is repetitive and restrictive patterns of behavior. Cognitive inflexibility has been proposed as a potential basis for these symptoms of ASD. More generally, behavioral inflexibility has been proposed to underlie repetitive and restrictive behavior in ASD. Here, we investigated whether and how behavioral flexibility is compromised in a widely used animal model of ASD. Methods: We compared the behavioral performance of Shank2-knockout mice and wild-type littermates in reversal learning employing a probabilistic classical trace conditioning paradigm. A conditioned stimulus (odor) was paired with an unconditioned appetitive (water, 6 µl) or aversive (air puff) stimulus in a probabilistic manner. We also compared air puff-induced eye closure responses of Shank2-knockout and wild-type mice. Results: Male, but not female, Shank2-knockout mice showed impaired reversal learning when the expected outcomes consisted of a water reward and a strong air puff. Moreover, male, but not female, Shank2-knockout mice showed stronger anticipatory eye closure responses to the air puff compared to wild-type littermates, raising the possibility that the impairment might reflect enhanced fear. In support of this contention, male Shank2-knockout mice showed intact reversal learning when the strong air puff was replaced with a mild air puff and when the expected outcomes consisted of only rewards. Limitations: We examined behavioral flexibility in one behavioral task (reversal learning in a probabilistic classical trace conditioning paradigm) using one ASD mouse model (Shank2-knockout mice). Thus, future work is needed to clarify the extent to which our findings (that enhanced fear limits behavioral flexibility in ASD) can explain the behavioral inflexibility associated with ASD. Also, we examined only the relationship between fear and behavioral flexibility, leaving open the question of whether abnormalities in processes other than fear contribute to behavioral inflexibility in ASD. Finally, the neurobiological mechanisms linking Shank2-knockout and enhanced fear remain to be elucidated. Conclusions: Our results indicate that enhanced fear suppresses reversal learning in the presence of an intact capability to learn cue-outcome contingency changes in Shank2-knockout mice. Our findings suggest that behavioral flexibility might be seriously limited by abnormal emotional responses in ASD. [ABSTRACT FROM AUTHOR]

The serotonin transporter (5-HTT) plays an important role in regulating serotonergic transmission via removal of serotonin (5-HT) from synaptic clefts. Alterations in 5-HTT expression and subsequent 5-HT transmission have been found to be associated with changes in behaviour, such as fearfulness or activity, in humans and other vertebrates. In humans, alterations in 5-HTT expression have been suggested to be able to lead to better learning performance, with more fearful persons being better at learning. Similar effects of the variation in the 5-HTT on fearfulness have been found in chickens, and in this study, we investigated effects on learning. Therefore, we tested 52 adult laying hens, differing in their functional 5-HTT genotype (W/W, W/D and D/D) in an operant learning paradigm in three different phases (initial learning, reversal learning and extinction) and in a tonic immobility test for fearfulness. We found that the 5-HTT polymorphism affects the initial learning performance of laying hens, with homogeneous wild-type (W/W) hens being the slowest learners, and the most fearful birds. W/W hens, showed significantly more choices to solve the initial learning task (LME, p = 0.031) and had the highest latencies in a tonic immobility test (p = 0.039), indicating the highest fearfulness. Our results provide interesting first insights into the role of 5-HTT in chickens and its sensitive interaction with the environment. We further suggest that the 5-HTT gene can be an interesting target gene for future breeding strategies as well as for further experimental studies. [ABSTRACT FROM AUTHOR]

Our world is full of uncertainty. Animals, including humans, need to behave flexibly to adjust to ever-changing environments. Reversal learning tasks have been used to assess behavioral flexibility in many species. However, there are some limitations in the traditional free-moving methodology, including (1) sessions to train the animals, (2) within-session number of trials associated with reversals, (3) factors of physical movement unrelated to the task in the maze or operant box, and (4) incompatibility with techniques, such as two-photon imaging. Therefore, to address these limitations, we established a novel spatiotemporal Pavlovian head-fixed reversal learning task for mice. Six experimentally naive adult C57BL/6J mice were used in this study. First, we trained head-fixed mice on a fixed-time schedule task. Sucrose solution was delivered every 10 s with a single drinking spout placed within the licking distance of the mice. After the mice showed anticipatory licking toward the timing of sucrose solution delivery, we began training the mice on the fixed-time schedule reversal learning task with two licking spouts. In this task, sucrose solution was delivered through one of the two drinking spouts. The rewarding spout was switched every 10 trials. Mice quickly learned to switch anticipatory licking to the rewarding side of the spouts, suggesting that they learned this head-fixed reversal learning task. Using the head-fixed experimental design, behavioral measures can be simplified by eliminating the complex behavioral sequences observed in free-moving animals. This novel head-fixed reversal learning task is a useful assay for studying the neurobiological mechanism of behavioral flexibility that is impaired in various psychopathological conditions. [ABSTRACT FROM AUTHOR]

Cognitive flexibility deficits are a hallmark feature of autism spectrum disorder (ASD), but few evidence-based behavioral interventions have successfully addressed this treatment target. Outcome measurement selection may help account for previous findings. The probabilistic reversal learning task (PRL) is a measure of cognitive flexibility previously validated for use in ASD, but its use as an outcome measure has not yet been assessed. The current study examined the feasibility, reproducibility, and sensitivity of PRL in a within-subjects trial of Regulating Together, a group-based intervention targeting emotion regulation. We demonstrated the PRL is highly feasible, showed test–retest reproducibility, and is sensitive to detect change following the intervention. Our findings demonstrate the PRL task may be a useful outcome measure of cognitive flexibility in future intervention trials in ASD. [ABSTRACT FROM AUTHOR]

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Childhood neglect is associated with cortical thinning, hyperactivity, and deficits in cognitive flexibility that are difficult to reverse later in life. Despite being the most prevalent form of early adversity, little is currently understood about the mechanisms responsible for these neurodevelopmental abnormalities, and no animal models have yet replicated key structural and behavioral features of childhood neglect/deprivation. To address these gaps, we have recently demonstrated that mice exposed to impoverished conditions, specifically limited bedding (LB), exhibit behavioral and structural changes that resemble those observed in adolescents who have experienced severe neglect. Here, we show that LB leads to long-term deficits in reversal learning, which can be fully reversed by briefly exposing LB pups to enrichment (toys) in their home cage from postnatal days 14 to 25. Reversal learning failed to induce normal c-fos activation in the orbitofrontal cortex (OFC) of LB mice, a deficit that was normalized by early enrichment. Additionally, LB decreased the density of parvalbumin-positive cells surrounded by perineuronal nets (PV+PNN+) and increased the ratio of glutamatergic to inhibitory synapse densities in the OFC, deficits that were also reversed by enrichment. Degradation of PNN in the OFC of adult mice impaired reversal learning, reduced c-fos activation, and increased the ratio of glutamatergic to inhibitory synapse densities in the OFC to levels comparable to those observed in LB mice. Collectively, our findings suggest that postnatal deprivation and enrichment impact the formation of PV+PNN+ cells in the OFC, a developmental process that is essential for cognitive flexibility in adulthood., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

The midsession reversal task involves a simultaneous discrimination between stimuli S1 and S2. Choice of S1 but not S2 is reinforced during the first 40 trials, and choice of S2 but not S1 is reinforced during the last 40 trials. Trials are separated by a constant intertrial interval (ITI). Pigeons learn the task seemingly by timing the moment of the reversal trial. Hence, most of their errors occur around trial 40 (S2 choices before trial 41 and S1 choices after trial 40). It has been found that when the ITI is doubled on a test session, the reversal trial is halved, a result consistent with timing. However, inconsistent with timing, halving the ITI on a test session did not double the reversal trial. The asymmetry of ITI effects could be due to the intrusion of novel cues during testing, cues that preempt the timing cue. To test this hypothesis, we ran two types of tests after the regular training in the midsession reversal task, one with S1 and S2 choices always reinforced, and another with S1 always reinforced but S2 reinforced only after 20 trials when the ITI doubled or 40 trials when the ITI halved. For most pigeons, performance was consistent with timing both when the ITI doubled and when it was halved, but some pigeons appeared to follow strategies based on counting or on reinforcement contingencies., (© 2023. The Author(s).)

Recent data suggest that interactions between systems involved in higher order knowledge and associative learning drive responses during value-based learning. However, it is unknown how these systems impact subjective responses, such as pain. We tested how instructions and reversal learning influence pain and pain-evoked brain activation. Healthy volunteers (n=40) were either instructed about contingencies between cues and aversive outcomes or learned through experience in a paradigm where contingencies reversed three times. We measured predictive cue effects on pain and heat-evoked brain responses using functional magnetic resonance imaging. Predictive cues dynamically modulated pain perception as contingencies changed, regardless of whether participants received contingency instructions. Heat-evoked responses in the insula, anterior cingulate, and other regions updated as contingencies changed, and responses in the prefrontal cortex mediated dynamic cue effects on pain, whereas responses in the brainstem’s rostroventral medulla (RVM) were shaped by initial contingencies throughout the task. Quantitative modeling revealed that expected value was shaped purely by instructions in the Instructed Group, whereas expected value updated dynamically in the Uninstructed Group as a function of error-based learning. These differences were accompanied by dissociations in the neural correlates of value-based learning in the rostral anterior cingulate, thalamus, and posterior insula, among other regions. These results show how predictions dynamically impact subjective pain. Moreover, imaging data delineate three types of networks involved in pain generation and value-based learning: those that respond to initial contingencies, those that update dynamically during feedback-driven learning as contingencies change, and those that are sensitive to instruction. Together, these findings provide multiple points of entry for therapies designs to impact pain.

Precisely timed behavior and accurate time perception plays a critical role in our everyday lives, as our wellbeing and even survival can depend on well-timed decisions. Although the temporal structure of the world around us is essential for human decision making, we know surprisingly little about how representation of temporal structure of our everyday environment impacts decision making. How does the representation of temporal structure affect our ability to generate well-timed decisions? Here we address this question by using a well-established dynamic probabilistic learning task. Using computational modeling, we found that human subjects' beliefs about temporal structure are reflected in their choices to either exploit their current knowledge or to explore novel options. The model-based analysis illustrates a large within-group and within-subject heterogeneity. To explain these results, we propose a normative model for how temporal structure is used in decision making, based on the semi-Markov formalism in the active inference framework. We discuss potential key applications of the presented approach to the fields of cognitive phenotyping and computational psychiatry.

Cognitive flexibility, the ability to adapt to unexpected changes, is critical for healthy environmental and social interactions, and thus to everyday functioning. In neuropsychiatric diseases, cognitive flexibility is often impaired and treatment options are lacking. Probabilistic reversal learning (PRL) is commonly used to measure cognitive flexibility in rodents and humans. In PRL tasks, subjects must sample choice options and, from probabilistic feedback, find the current best choice which then changes without warning. However, in rodents, pharmacological models of human cognitive impairment tend to disrupt only the first (or few) of several contingency reversals, making quantitative assessment of behavioral effects difficult. To address this limitation, we developed a novel rat PRL where reversals occur at relatively long intervals in time that demonstrates increased sensitivity to the non-competitive NMDA receptor antagonist MK-801. Here, we quantitively compare behavior in time-based PRL with a widely used task where reversals occur based on choice behavior. In time-based PRL, MK-801 induced sustained reversal learning deficits both in time and across reversal blocks but, at the same dose, only transient weak effects in performance-based PRL. Moreover, time-based PRL yielded better estimates of behavior and reinforcement learning model parameters, which opens meaningful pharmacological windows to efficiently test and develop novel drugs preclinically with the goal of improving cognitive impairment in human patients.

BackgroundAlcohol use disorder is characterized by perseverative alcohol use despite negative consequences. This hallmark feature of addiction potentially relates to impairments in behavioral flexibility, which can be measured by probabilistic reversal learning (PRL) paradigms. We here aimed to examine the cognitive mechanisms underlying impaired PRL task performance in patients with alcohol use disorder (AUDP) using computational models of reinforcement learning.MethodsTwenty-eight early abstinent AUDP and 27 healthy controls (HC) performed an extensive PRL paradigm. We compared conventional behavioral variables of choices (perseveration; correct responses) between groups. Moreover, we fitted Bayesian computational models to the task data to compare differences in latent cognitive variables including reward and punishment learning and choice consistency between groups.ResultsAUDP and HC did not significantly differ with regard to direct perseveration rates after reversals. However, AUDP made overall less correct responses and specifically showed decreased win–stay behavior compared to HC. Interestingly, AUDP showed premature switching after no or little negative feedback but elevated proneness to stay when accumulation of negative feedback would make switching a more optimal option. Computational modeling revealed that AUDP compared to HC showed enhanced learning from punishment, a tendency to learn less from positive feedback and lower choice consistency.ConclusionOur data do not support the assumption that AUDP are characterized by increased perseveration behavior. Instead our findings provide evidence that enhanced negative reinforcement and decreased non-drug-related reward learning as well as diminished choice consistency underlie dysfunctional choice behavior in AUDP.

The serotonin transporter (5-HTT) plays an important role in regulating serotonergic transmission via removal of serotonin (5-HT) from synaptic clefts. Alterations in 5-HTT expression and subsequent 5-HT transmission have been found to be associated with changes in behaviour, such as fearfulness or activity, in humans and other vertebrates. In humans, alterations in 5-HTT expression have been suggested to be able to lead to better learning performance, with more fearful persons being better at learning. Similar effects of the variation in the 5-HTT on fearfulness have been found in chickens, and in this study, we investigated effects on learning. Therefore, we tested 52 adult laying hens, differing in their functional 5-HTT genotype (W/W, W/D and D/D) in an operant learning paradigm in three different phases (initial learning, reversal learning and extinction) and in a tonic immobility test for fearfulness. We found that the 5-HTT polymorphism affects the initial learning performance of laying hens, with homogeneous wild-type (W/W) hens being the slowest learners, and the most fearful birds. W/W hens, showed significantly more choices to solve the initial learning task (LME, p = 0.031) and had the highest latencies in a tonic immobility test (p = 0.039), indicating the highest fearfulness. Our results provide interesting first insights into the role of 5-HTT in chickens and its sensitive interaction with the environment. We further suggest that the 5-HTT gene can be an interesting target gene for future breeding strategies as well as for further experimental studies.

• Local mPFC and global Aβ infusion induces a prominent reduction in WM and reversal learning. • Local mPFC Aβ infusion increases neuronal firing, blocked LTP and leads to LTD. • Aβ induces cognitive executive dysfunctions and changes in PFC excitability/plasticity. Prefrontal cortex (PFC)-related functions, such as working memory (WM) and cognitive flexibility (CF), are among the first to be altered at early stages of Alzheimer's disease (AD). Likewise, transgenic AD models carrying different AD-related mutations, mostly linked to the overproduction of amyloid beta (Aβ) and other peptides, show premature behavioral and functional symptoms associated with PFC alterations. However, little is known about the effects of intracerebral or intra-PFC Aβ infusion on WM and CF, as well as on pyramidal cell excitability and plasticity. Thus, here we evaluated the effects of a single Aβ injection, directly into the PFC, or its intracerebroventricular (icv) application, on PFC-dependent behaviors and on the intrinsic and synaptic properties of layer V pyramidal neurons in PFC slices. We found that a single icv Aβ infusion reduced learning and performance of a delayed non-matching-to-sample WM task and prevented reversal learning in a matching-to-sample version of the task, several weeks after its infusion. The inhibition of WM performance was reproduced more potently by a single PFC Aβ infusion and was associated with Aβ accumulation. This behavioral disruption was related to increased layer V pyramidal cell firing, larger sag membrane potential, increased fast after-hyperpolarization and a failure to sustain synaptic long-term potentiation, even leading to long-term depression, at both the hippocampal-PFC pathway and intracortical synapses. These findings show that Aβ can affect PFC excitability and synaptic plasticity balance, damaging PFC-dependent functions, which could constitute the foundations of the early alterations in executive functions in AD patients. [ABSTRACT FROM AUTHOR]

Based on the clinical observations of severe cognitive deficits in schizophrenia patients and the relationship between environmental parameters and the severity of schizophrenia symptoms, the present study investigated these parameters in an dizocilpine (MK‐801)‐induced schizophrenia model in rats. In addition to, it evaluated whether a post‐weaning enriched environment (EE) would affect the nicotine‐induced conditioned place preference (CPP) and the motor and cognitive deficits caused by MK‐801 treatment. Male Wistar rat pups were injected peritoneally with MK‐801 (1 mg/kg) on a daily basis between the 6th and the 10th postnatal days (P) and were exposed to either an enriched or a standard cage from P21 until the end of the experiments. The rats were evaluated in open‐field and three‐chamber social interaction tests. Moreover, spatial and reversal learning was assessed by the Morris water maze (MWM). The animals were conditioned with 0.6 mg/kg nicotine and tested for CPP. Increased self‐grooming, exploratory behaviour, potentiated nicotine‐CPP and decreased social behaviours, delayed spatial learning and memory and impaired reversal learning in the water maze were observed in the MK‐801 treatment group. Housing in an EE improved cognitive and behavioural deficits associated with postnatal MK‐801 treatment. The results suggested that neonatal N‐methyl‐d‐aspartate (NMDA) receptor hypofunction may cause susceptibility to these behaviours and indicated the importance of environmental conditions in the development of schizophrenia and probably other neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social and communication impairments and restricted and repetitive behavior. Although there is currently no established cure for ASD, early interventions for deficits of attention to other individuals are expected to reduce the progression of ASD symptoms in later life. To confirm this hypothesis and improve early therapeutic interventions, it is desirable to develop an animal model of ASD in which social attention is impaired in childhood and ASD-like social behavior is observed in adulthood. However, rodent models of ASD have difficulty in recapitulating the deficit of gaze-based social attention. In this study, we examined the direction of gaze toward other conspecifics during childhood and puberty in a three-chamber test setting using an ASD marmoset model produced by maternal exposure to valproic acid (VPA). We also conducted a reversal learning test in adult VPA-exposed marmosets as an indicator of perseveration, a core symptom of ASD that has not previously been investigated in this model. The results showed that time spent gazing at other conspecifics was reduced in VPA-exposed marmosets in childhood, and that mature animals persisted with previous strategies that required long days for acquisition to pass the test. In a longitudinal study using the same animals, deficits in social attention in childhood correlated well with ASD-like social disturbance (inequity aversion and third-party reciprocity) and inflexible behavior in adulthood. Since VPA-exposed marmosets exhibit these diverse ASD-like behaviors that are consistent from childhood to adulthood, VPA-exposed marmosets will provide a valuable means of elucidating mechanisms for early intervention and contribute to the development of early therapies. [ABSTRACT FROM AUTHOR]

Night work leads to sleepiness and reduced vigilant attention during work hours, and bright light interventions may reduce such effects. It is also known that total sleep deprivation impairs cognitive flexibility as measured by reversal learning tasks. Whether night work impairs reversal learning task performance or if bright light can mitigate reversal learning deficits during night work is unclear. In this counterbalanced crossover study (ClinicaTrials.gov Identifier NCT03203538), young healthy individuals completed a reversal learning task twice during each of three consecutive simulated night shifts (23:00–07:00 h). The night shifts were performed in a laboratory under a full-spectrum (4000 K) bright light (~900 lx) and a standard light (~90 lx) condition. Reversal learning task performance was reduced towards the end of the night shifts (04:50 h), compared to the first part of the night shifts (00:20 h) in both light conditions. However, with bright light, the reversal learning task performance improved towards the end of the night shifts, compared to standard light. The study shows that bright light may mitigate performance deficits on a reversal learning task during night work and implies that bright light interventions during night work may be beneficial not only for vigilant attention but also for cognitive flexibility. [ABSTRACT FROM AUTHOR]