Effects of transcutaneous auricular vagus nerve stimulation on reversal learning, tonic pupil size, salivary alpha-amylase, and cortisol.

This study investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) enhances reversal learning and augments noradrenergic biomarkers (i.e., pupil size, cortisol, and salivary alpha-amylase [sAA]). We also explored the effect of taVNS on respiratory rate and cardiac vagal activity (CVA). Seventy-one participants received stimulation of either the cymba concha (taVNS) or the earlobe (sham) of the left ear. After learning a series of cue-outcome associations, the stimulation was applied before and throughout a reversal phase in which cue-outcome associations were changed for some (reversal), but not for other (distractor) cues. Tonic pupil size, salivary cortisol, sAA, respiratory rate, and CVA were assessed at different time points. Contrary to our hypothesis, taVNS was not associated with an overall improvement in performance on the reversal task. Compared to sham, the taVNS group performed worse for distractor than reversal cues. taVNS did not increase tonic pupil size and sAA. Only post hoc analyses indicated that the cortisol decline was steeper in the sham compared to the taVNS group. Exploratory analyses showed that taVNS decreased respiratory rate but did not affect CVA. The weak and unexpected effects found in this study might relate to the lack of parameters optimization for taVNS and invite to further investigate the effect of taVNS on cortisol and respiratory rate.

A specific olfactory cortico-thalamic pathway contributing to sampling performance during odor reversal learning.

A growing body of evidence shows that olfactory information is processed within a thalamic nucleus in both rodents and humans. The mediodorsal thalamic nucleus (MDT) receives projections from olfactory cortical areas including the piriform cortex (PCX) and is interconnected with the orbitofrontal cortex (OFC). Using electrophysiology in freely moving rats, we recently demonstrated the representation of olfactory information in the MDT and the dynamics of functional connectivity between the PCX, MDT and OFC. Notably, PCX-MDT coupling is specifically increased during odor sampling of an odor discrimination task. However, whether this increase of coupling is functionally relevant is unknown. To decipher the importance of PCX-MDT coupling during the sampling period, we used optogenetics to specifically inactivate the PCX inputs to MDT during an odor discrimination task and its reversal in rats. We demonstrate that inactivating the PCX inputs to MDT does not affect the performance accuracy of an odor discrimination task and its reversal, however, it does impact the rats' sampling duration. Indeed, rats in which PCX inputs to MDT were inactivated during the sampling period display longer sampling duration during the odor reversal learning compared to controls-an effect not observed when inactivating OFC inputs to MDT. We demonstrate a causal link between the PCX inputs to MDT and the odor sampling performance, highlighting the importance of this specific cortico-thalamic pathway in olfaction.

Dopamine, Salience, and Response Set Shifting in Prefrontal Cortex.

Dopamine is implicated in multiple functions, including motor execution, action learning for hedonically salient outcomes, maintenance, and switching of behavioral response set. Here, we used a novel within-subject psychopharmacological and combined functional neuroimaging paradigm, investigating the interaction between hedonic salience, dopamine, and response set shifting, distinct from effects on action learning or motor execution. We asked whether behavioral performance in response set shifting depends on the hedonic salience of reversal cues, by presenting these as null (neutral) or salient (monetary loss) outcomes. We observed marked effects of reversal cue salience on set-switching, with more efficient reversals following salient loss outcomes. L-Dopa degraded this discrimination, leading to inappropriate perseveration. Generic activation in thalamus, insula, and striatum preceded response set switches, with an opposite pattern in ventromedial prefrontal cortex (vmPFC). However, the behavioral effect of hedonic salience was reflected in differential vmPFC deactivation following salient relative to null reversal cues. l-Dopa reversed this pattern in vmPFC, suggesting that its behavioral effects are due to disruption of the stability and switching of firing patterns in prefrontal cortex. Our findings provide a potential neurobiological explanation for paradoxical phenomena, including maintenance of behavioral set despite negative outcomes, seen in impulse control disorders in Parkinson's disease.

Mediodorsal thalamus hypofunction impairs flexible goal-directed behavior.

BACKGROUND: Cognitive inflexibility is a core symptom of several mental disorders including schizophrenia. Brain imaging studies in schizophrenia patients performing cognitive tasks have reported decreased activation of the mediodorsal thalamus (MD). Using a pharmacogenetic approach to model MD hypofunction, we recently showed that decreasing MD activity impairs reversal learning in mice. While this demonstrates causality between MD hypofunction and cognitive inflexibility, questions remain about the elementary cognitive processes that account for the deficit. METHODS: Using the Designer Receptors Exclusively Activated by Designer Drugs system, we reversibly decreased MD activity during behavioral tasks assessing elementary cognitive processes inherent to flexible goal-directed behaviors, including extinction, contingency degradation, outcome devaluation, and Pavlovian-to-instrumental transfer (n = 134 mice). RESULTS: While MD hypofunction impaired reversal learning, it did not affect the ability to learn about nonrewarded cues or the ability to modulate action selection based on the outcome value. In contrast, decreasing MD activity delayed the ability to adapt to changes in the contingency between actions and their outcomes. In addition, while Pavlovian learning was not affected by MD hypofunction, decreasing MD activity during Pavlovian learning impaired the ability of conditioned stimuli to modulate instrumental behavior. CONCLUSIONS: Mediodorsal thalamus hypofunction causes cognitive inflexibility reflected by an impaired ability to adapt actions when their consequences change. Furthermore, it alters the encoding of environmental stimuli so that they cannot be properly utilized to guide behavior. Modulating MD activity could be a potential therapeutic strategy for promoting adaptive behavior in human subjects with cognitive inflexibility.

Dissociable effects of dorsal and ventral hippocampal DHA content on spatial learning and anxiety-like behavior.

Chronic deficiency of dietary docosahexaenoic acid (DHA) during critical developmental windows results in severe deficits in spatial learning, anxiety and hippocampal neuroplasticity that parallel a variety of neuropsychiatric disorders. However, little is known regarding the influence of long-term, multigenerational exposure to dietary DHA enrichment on these same traits. To characterize the potential benefits of multigenerational DHA enrichment, mice were fed a purified 10:1 omega-6/omega-3 diet supplemented with either 0.1% preformed DHA/kg feed weight or 1.0% preformed DHA/kg feed weight through three generations. General locomotor activity, spatial learning, and anxiety-like behavior were assessed in adult male offspring of the third generation. Following behavioral assessments, ventral and dorsal hippocampus was collected for DHA and arachidonic acid (AA) analysis. Animals consuming the 0.1% and 1.0% DHA diet did not differ from control animals for locomotor activity or on performance during acquisition learning, but made fewer errors and showed more stable across-day performance during reversal learning on the spatial task and showed less anxiety-like behavior. Consumption of the DHA-enriched diets increased DHA content in the ventral and dorsal hippocampus in a region-specific manner. DHA content in the dorsal hippocampus predicted performance on the reversal training task. DHA content in the ventral hippocampus was correlated with anxiety-like behavior, but AA content in the dorsal hippocampus was a stronger predictor of this behavior. These results suggest that long-term, multigenerational DHA administration improves performance on some aspects of complex spatial learning, decreases anxiety-like behavior, and that modulation of DHA content in sub-regions of the hippocampus predicts which behaviors are likely to be affected.

Enhanced cognitive flexibility in reversal learning induced by removal of the extracellular matrix in auditory cortex.

During brain maturation, the occurrence of the extracellular matrix (ECM) terminates juvenile plasticity by mediating structural stability. Interestingly, enzymatic removal of the ECM restores juvenile forms of plasticity, as for instance demonstrated by topographical reconnectivity in sensory pathways. However, to which degree the mature ECM is a compromise between stability and flexibility in the adult brain impacting synaptic plasticity as a fundamental basis for learning, lifelong memory formation, and higher cognitive functions is largely unknown. In this study, we removed the ECM in the auditory cortex of adult Mongolian gerbils during specific phases of cortex-dependent auditory relearning, which was induced by the contingency reversal of a frequency-modulated tone discrimination, a task requiring high behavioral flexibility. We found that ECM removal promoted a significant increase in relearning performance, without erasing already established-that is, learned-capacities when continuing discrimination training. The cognitive flexibility required for reversal learning of previously acquired behavioral habits, commonly understood to mainly rely on frontostriatal circuits, was enhanced by promoting synaptic plasticity via ECM removal within the sensory cortex. Our findings further suggest experimental modulation of the cortical ECM as a tool to open short-term windows of enhanced activity-dependent reorganization allowing for guided neuroplasticity.

Maternal obesity caused by overnutrition exposure leads to reversal learning deficits and striatal disturbance in rats.

Maternal obesity caused by overnutrition during pregnancy increases susceptibility to metabolic risks in adulthood, such as obesity, insulin resistance, and type 2 diabetes; however, whether and how it affects the cognitive system associated with the brain remains elusive. Here, we report that pregnant obesity induced by exposure to excessive high fatty or highly palatable food specifically impaired reversal learning, a kind of adaptive behavior, while leaving serum metabolic metrics intact in the offspring of rats, suggesting a much earlier functional and structural defects possibly occurred in the central nervous system than in the metabolic system in the offspring born in unfavorable intrauterine nutritional environment. Mechanically, we found that above mentioned cognitive inflexibility might be associated with significant striatal disturbance including impaired dopamine homeostasis and disrupted leptin signaling in the adult offspring. These collective data add a novel perspective of understanding the adverse postnatal sequelae in central nervous system induced by developmental programming and the related molecular mechanism through which priming of risk for developmental disorders may occur during early life.

The thalamostriatal pathway and cholinergic control of goal-directed action: interlacing new with existing learning in the striatum.

The capacity for goal-directed action depends on encoding specific action-outcome associations, a learning process mediated by the posterior dorsomedial striatum (pDMS). In a changing environment, plasticity has to remain flexible, requiring interference between new and existing learning to be minimized, yet it is not known how new and existing learning are interlaced in this way. Here we investigated the role of the thalamostriatal pathway linking the parafascicular thalamus (Pf) with cholinergic interneurons (CINs) in the pDMS in this process. Removing the excitatory input from Pf to the CINs was found to reduce the firing rate and intrinsic activity of these neurons and produced an enduring deficit in goal-directed learning after changes in the action-outcome contingency. Disconnection of the Pf-pDMS pathway produced similar behavioral effects. These data suggest that CINs reduce interference between new and existing learning, consistent with claims that the thalamostriatal pathway exerts state control over learning-related plasticity.

Ameliorative effect of traditional Japanese medicine yokukansan on age-related impairments of working memory and reversal learning in rats.

Aging is thought to impair prefrontal cortical (PFC) structure-sensitive cognitive functions and flexibility, such as working memory and reversal learning. A traditional Japanese medicine, yokukansan (YKS), is frequently used to treat age-related neurodegenerative disorders such as Alzheimer's disease in Japan, but its pharmacological properties have not been elucidated. The present study was designed to examine whether YKS improves age-related cognitive deficits using aged rats. YKS was administered to 21-month-old rats for 3 months. The ability to learn initially a reward rule for a T-maze discrimination task (initial learning) was examined in young control (4-month-old), aged control (24-month-old) and YKS-treated aged (24-month-old) rats. Subsequently, working memory and reversal learning were examined in delayed alternation and reversal discrimination T-maze tasks, respectively. Locomotor activity was also measured in new environments. Although performance accuracy in the initial learning procedure did not differ among any experimental groups, accuracy in the delayed alternation task was significantly decreased in aged rats compared to young rats. Aged rats also showed significant decreases in accuracy in the reversal discrimination task. YKS treatment significantly ameliorated the age-related decreases in accuracy in the delayed alternation and reversal discrimination tasks. The ameliorative effects of YKS on impaired delayed alternation performance were reduced by intracranial infusions of a dopamine D1 receptor antagonist, SCH 23390, into the prelimbic cortical region of the PFC, and the YKS effects on impaired reversal learning were done by the infusions into the orbitofrontal cortex (OFC). Locomotor activity did not change in any experimental group. Thus, YKS ameliorated age-related impairments of working memory and reversal learning, which might be mediated by a dopaminergic mechanism in the PFC structure. These investigations provide information important for the treatment of brain dysfunctions in the elderly people.

Human medial orbitofrontal cortex is recruited during experience of imagined and real rewards.

Human decision-making frequently relies on mental simulation of future rewards to guide action choice. In this study, we sought to uncover brain regions engaged during reward imagery and to address whether these regions functionally overlap with regions activated by tangible rewards. We found that medial orbitofrontal cortex (mOFC) is engaged both for real and imagined rewards and is preferentially engaged for imagery with rewarding content compared with other nonrewarding imagery. These findings support a critical role for mOFC in the representation of rewarding goal states, even if hypothetical.

Pre-surgical training ameliorates orbitofrontal-mediated impairments in spatial reversal learning.

We recently reported that orbitofrontal cortical (OFC) lesions impaired reversal learning of an instrumental two-lever spatial discrimination task, a deficit manifested as increased perseveration on the pre-potent response. Here we examine whether exposure to reversal learning test pre-operatively may have a beneficial effect for future reversal learning of OFC-lesioned animals. Rats were trained on a novel instrumental two-lever spatial discrimination and reversal learning task, measuring both 'cognitive flexibility' and constituent processes including response inhibition. Both levers were presented, only one of which was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, two reversals were introduced. Rats were then matched according to their reversal performance and subjected to bilateral excitotoxic OFC lesions. Following recovery, a series of four reversals was presented. OFC lesions impaired neither retention nor reversal phases. These data, together with the previously reported reversal deficit following OFC lesions, suggest that OFC is not needed when task experience has been gained but it is necessary when task demands are relatively high.

Neurotoxic lesions of the medial prefrontal cortex or medial striatum impair multiple-location place learning in the water task: evidence for neural structures with complementary roles in behavioural flexibility.

This series of experiments assessed the effects of neurotoxic damage to either the medial prefrontal cortex or the medial striatum on the acquisition of multiple-location place learning in the water task. During training, normal subjects learn to search for a new hidden platform location at the beginning of each training session and to continue to swim to that location until the end of training during that session. By the end of training, normal subjects show one-trail place learning in which they find the new location on the first trial and swim directly to that location on the second swim. Rats with damage to either the medial prefrontal cortex or dorso-medial striatum showed deficits in learning to swim to the new location each day. These deficits were interpreted as impairments in behavioural flexibility. The lesion-induced impairment was not caused by perseverative errors but was manifested in an inability to rapidly acquire a new spatial position in conflict with the previous position. Interestingly, the subjects from both lesion groups were able to show normal place learning and memory after repeated training within a session. The results were interpreted as suggestive of a complementary role of these neural structures in behavioural flexibility.

Thalamic and hippocampal mechanisms in spatial navigation: a dissociation between brain mechanisms for learning how versus learning where to navigate.

Various studies of hippocampus and medial thalamus (MT) suggest that these brain areas play a crucial, marginal, or no essential role in spatial navigation. These divergent views were examined in experiments using electrolytic Lesions of fimbria-fornix (FF) or radiofrequency or neurotoxic Lesions of MT of rats subsequently trained to find a stable visible (experiment 1) or hidden platform (experiments 2 and 3) in a water maze (WM) pool. Rats with electrolytic Lesions of FF or radiofrequency Lesions of MT were impaired in swimming to a stable visible platform, particularly the MT Lesion Group, suggesting impairment of WM strategies acquisition. Additional Lesioned rats were then tested in a hidden platform version of the WM task. Some rats were given Morris's nonspatial pretraining prior to Lesioning to provide them with training in the required WM behavioral strategies. Nonspatially Pretrained rats with FF Lesions eventually were able to navigate to the hidden platform, but the accuracy of place responding was impaired. This impairment occurred without problems in the motoric control of swimming or the use of WM behavioral strategies, suggesting that these rats had a spatial mapping impairment. Radiofrequency MT Lesions blocked acquisition of WM behavioral strategies by Naive rats throughout 3 days of training, severely impairing performance on all aspects of the hidden platform task. Nonspatially Pretrained rats given the same MT Lesions readily learned the hidden platform location and were indistinguishable from controls throughout spatial training. Rats given neurotoxic Lesions of MT for removal of cells were only mildly impaired and improved considerably during training, suggesting an important role for fibers of passage in WM strategies learning. The results provide a clear dissociation between a role for MT in learning WM behavioral strategies and the hippocampal formation in spatial mapping and memory. This is the first identification of a brain area, MT, that is essential for learning behavioral strategies that by themselves do not constitute the solution to the task but are necessary for the successful use of an innate learning ability: place response learning using spatial mapping.

Event-related potentials elicited by distractors in an auditory oddball paradigm in schizophrenia.

Patients with schizophrenia are affected more adversely than healthy controls by distracting conditions, due to their inability to adequately apportion attentional resources to targets or distractors. We attempted to re-evaluate the effects of distractors in 25 patients with chronic schizophrenia and in 12 controls. They performed an auditory target-detection task with 1500 Hz tone distractors and an additional control condition where a 1500-Hz tone was used as the target. The rate of target misses for patients with schizophrenia was 3.79% in non-distractor conditions and 14.79% in distractor conditions. Significantly reduced N100 responses to distractors and distractor condition targets were found. P300 responses to all target stimulus categories were reduced, but P300 responses to distractors were equal to those in the control group. There was a reduction of P300 amplitudes to distractors in both groups; however, only the control group showed significant enlargement of P300 amplitude when the distractors became the target stimuli. There is evidence that patients with schizophrenia tend to be less able to allocate their attentional resources adequately to target vs. distractor stimuli. When the distractors became the target stimuli, their responses remained unchanged, which suggests their inability to appropriately integrate stimulus information with contextual information.

Serotonergic modulation of prefrontal cortex during negative feedback in probabilistic reversal learning.

This study used functional magnetic resonance imaging to examine the effects of acute tryptophan (TRP) depletion (ATD), a well-recognized method for inducing transient cerebral serotonin depletion, on brain activity during probabilistic reversal learning. Twelve healthy male volunteers received a TRP-depleting drink or a balanced amino-acid drink (placebo) in a double-blind crossover design. At 5 h after drink ingestion, subjects were scanned while performing a probabilistic reversal learning task and while viewing a flashing checkerboard. The probabilistic reversal learning task enabled the separate examination of the effects of ATD on behavioral reversal following negative feedback and negative feedback per se that was not followed by behavioral adaptation. Consistent with previous findings, behavioral reversal was accompanied by significant signal change in the right ventrolateral prefrontal cortex (PFC) and the dorsomedial prefrontal cortex. ATD enhanced reversal-related signal change in the dorsomedial PFC, but did not modulate the ventrolateral PFC response. The ATD-induced signal change in the dorsomedial PFC during behavioral reversal learning extended to trials where subjects received negative feedback but did not change their behavior. These data suggest that ATD affects reversal learning and the processing of aversive signals by modulation of the dorsomedial PFC.

Long-term treatment with antioxidants and a program of behavioral enrichment reduces age-dependent impairment in discrimination and reversal learning in beagle dogs.

The effects of long-term treatment with both antioxidants and a program of behavioral enrichment were studied as part of a longitudinal investigation of cognitive aging in beagle dogs. Baseline performance on a battery of cognitive tests was used to assign 48 aged dogs (9-12 years) into four cognitively equivalent groups, of 12 animals per group: Group CC (control food-control environment), group CE (control food-enriched environment); Group AC (antioxidant fortified food-control environment); Group AE (fortified food-enriched environment). We also tested a group of young dogs fed the control food and a second group fed the fortified food. Both groups of young dogs received a program of behavioral enrichment. To evaluate the effects of the interventions on cognition after 1 year, the dogs were tested on a size discrimination learning task and subsequently on a size discrimination reversal learning task. Both tasks showed age-sensitivity, with old dogs performing more poorly than young dogs. Both tasks were also improved by both the fortified food and the behavioral enrichment. However, in both instances the treatment effects largely reflected improved performance in the combined treatment group. These results suggest that the effectiveness of antioxidants in attenuating age-dependent cognitive decline is dependent on behavioral and environmental experience.

Effects of selective thalamic and prelimbic cortex lesions on two types of visual discrimination and reversal learning.

The effects of excitotoxic lesions of the mediodorsal nucleus of the thalamus, the anterior thalamic nuclei and of the prelimbic cortex were examined on two tests of discrimination and reversal learning. In experiment 1A (visual discrimination and reversal), rats were required to discriminate two stimuli, and respond to the stimulus associated with reward (the S+ stimulus). There was no effect of lesion on acquisition of this task. However, when stimulus-reward contingencies were reversed, animals with lesions of the mediodorsal nucleus of the thalamus made significantly more errors than control animals or animals of other lesion groups. In experiment 1B (conditional discrimination), animals were required to learn a rule of the type 'If stimulus A then go left, if stimulus B then go right'. No main effect of lesion on acquisition was observed in this experiment. To test the generality of the reversal effect obtained in experiment 1A, a second cohort of animals with the same lesions was tested on acquisition of the visuospatial conditional task immediately postsurgery, followed by the reversal of the conditional rule (experiment 2). As in experiment 1B, no main effect of lesion group was observed during acquisition of the task. However, lesions of the mediodorsal nucleus of the thalamus resulted in a mild impairment according to number of sessions required to attain criterion performance of the task when the response rule was reversed. The results of the present study provide evidence for a role for the mediodorsal nucleus of the thalamus in new learning, particularly when stimulus-reward contingencies are reversed. Furthermore, they show that the functions of this thalamic nucleus can be dissociated from those of the anterior thalamus and the prelimbic cortex.

Tactile learning and the individual evaluation of the reward in honey bees (Apis mellifera L.).

Using the proboscis extension response we conditioned pollen and nectar foragers of the honey bee (Apis mellifera L.) to tactile patterns under laboratory conditions. Pollen foragers demonstrated better acquisition, extinction, and reversal learning than nectar foragers. We tested whether the known differences in response thresholds to sucrose between pollen and nectar foragers could explain the observed differences in learning and found that nectar foragers with low response thresholds performed better during acquisition and extinction than ones with higher thresholds. Conditioning pollen and nectar foragers with similar response thresholds did not yield differences in their learning performance. These results suggest that differences in the learning performance of pollen and nectar foragers are a consequence of differences in their perception of sucrose. Furthermore, we analysed the effect which the perception of sucrose reward has on associative learning. Nectar foragers with uniform low response thresholds were conditioned using varying concentrations of sucrose. We found significant positive correlations between the concentrations of the sucrose rewards and the performance during acquisition and extinction. The results are summarised in a model which describes the relationships between learning performance, response threshold to sucrose, concentration of sucrose and the number of rewards.

The recognition memory deficit caused by mediodorsal thalamic lesion in non-human primates: a comparison with rhinal cortex lesion.

Two earlier studies found that rhinal cortex ablations in the monkey (Macaca fascicularis) impaired delayed matching-to-sample (DMS) when the stimuli in the experiment came from a large population of possible stimuli, but not when the stimulus population was small, while uncinate fascicle section had no effect on DMS whatever the stimulus population size. The mediodorsal thalamus receives a large projection from the rhinal cortex, and has been implicated in recognition memory performance. We trained monkeys preoperatively in delayed matching-to-sample with large and small stimulus populations, exactly as in the earlier studies, then examined the effect of bilaterally ablating the medial portion of the mediodorsal thalamic nucleus. Mediodorsal lesion impaired postoperative delayed matching-to-sample performance with a large stimulus set, but had no effect on performance of DMS with a small stimulus population. In comparison with the earlier data from rhinal cortex lesions with the same methods, wherever a deficit was seen in the rhinal-lesioned animals the mediodorsal thalamic nucleus-lesioned animals showed a smaller deficit. We conclude that other efferents from the rhinal cortex, possibly those to the adjacent inferior temporal cortex, enable better performance in the mediodorsal thalamic nucleus-lesioned animals than in the animals with rhinal cortex ablation.

Lack of effect of lesions in the anterior cingulate cortex and retrosplenial cortex on certain tests of spatial memory in the rat.

The effects of cytotoxic lesions in either the anterior cingulate cortex or the retrosplenial cortex were compared with those of fornix lesions on three tests of spatial memory. Two of the tasks, delayed nonmatching-to-position and spatial reversal learning, were tested in an automated apparatus. The third task, forced alternation, was tested in a T-maze. Neither anterior cingulate nor retrosplenial cortex damage produced any significant impairment on the three tasks. In contrast, rats with fornix lesions (hippocampal system damage) were markedly impaired on all three tasks. The results, which were considered in the light of proposals for a hippocampal--anterior thalamic--cingulate system that is important for spatial memory, suggest that neither of the cingulate regions involved in this study form a critical subcomponent of this proposed system. It is therefore assumed that the cingulate cortices are only critical for certain classes of spatial problem. It is also suggested that in some previous studies the effects of inadvertent damage to the cingulum bundle may have contributed to the apparent effects of cingulate lesions.