Impact of Metacognitive and Psychological Factors in Learning-Induced Plasticity of Resting State Networks.

While resting-state networks are able to rapidly adapt to experiences and stimuli, it is currently unknown whether metacognitive processes such as confidence in learning and psychological temperament may influence this process. We explore the neural traces of confidence in learning and their variability by: (1) targeting rs-networks in which functional connectivity (FC) modifications induced by a learning task were associated either with the participant's performance or confidence in learning; and (2) investigating the links between FC changes and psychological temperament. Thirty healthy individuals underwent neuropsychological and psychometric evaluations as well as rs-fMRI scans before and after a visuomotor associative learning task. Confidence in learning was positively associated with the degree of FC changes in 11 connections including the cerebellar, frontal, parietal, and subcortical areas. Variability in FC changes was linked to the individual's level of anxiety sensitivity. The present findings indicate that reconfigurations of resting state networks linked to confidence in learning differ from those linked to learning accuracy. In addition, certain temperament characteristics appear to influence these reconfigurations.

Learning-driven cerebellar intrinsic functional connectivity changes in men.

Learning involves distributed but coordinated activity among the widespread connected brain areas. Increase in areas connections' strength may be established offline, that is, aside from the task itself, in a resting-state. The resulting functional connectivity may hence constitute a neural trace of the learning episode. The present study examined whether a conditional visuomotor learning task previously shown to activate the cerebellum would modify cerebellar intrinsic connectivity in groups of young and older male subjects. In the group of young subjects, resting-state connectivity within several cerebellar networks (fronto-cerebellar, temporo-cerebellar, cerebello-cerebellar) was modified following the task. In most cases, modulation resulted in increased anticorrelations between cerebellar and cortical areas and the amplitude of changes was correlated with learning efficacy. The group of older subjects drastically differed, with sparser modifications of resting-state functional connectivity and no cerebellar networks involved. The findings of this exploratory study indicate that associative learning modifies the strength of intrinsic connectivity in young subjects but to a lesser degree in older subjects. They further suggest that functional connectivity within cerebellar networks may play an operative role in this kind of learning.

Psychological and neuropsychological correlates of dependence-related behaviour in medication overuse headaches: a one year follow-up study.

BACKGROUND: Medication Overuse Headache (MOH) can be related in some patients to dependence-related behaviour characterised by craving, a deficit in controlling substance intake, which is associated to orbitofrontal cortex (OFC) dysfunction. The aim of this study was to explore the psychological correlates in MOH patients and the functioning of the OFC through neuropsychological assessment (Iowa Gambling Task: IGT) and to relate it to prognosis at a one year follow-up point. FINDINGS: Seventeen subjects suffering from probable MOH were included and compared to 19 migraineurs and to 17 controls. The results show significant between group differences for behavioural dependence, depression, anxiety, catastrophizing. There were no between group differences for impulsivity. Mean IGT score did not allow differentiation of MOH patients from the other groups, whereas the score was significantly different between opiate abusers and other medication abusers (45 +/-5.7 versus 57.1 +/-8.2, p = 0.019). Among the clinical variables rated at inclusion, the amount of acute headache medication taken per month was the only one predicting the prognosis (RR = 1.05, 95% CI = 1-1.06, p = 0.04). A slight increase in risk of relapse at 1 year was observed in patients with poorer IGT scores (RR = 0.92, 95% CI = 0.85-1, p = 0.05) and higher behavioural-dependence scores (RR = 1.07, 95% CI = 1-1.14, p = 0.05). None of the other psychological variables predicted relapse risk. CONCLUSIONS: These results must be interpreted with caution due to the low number of subjects. They showed a deficit in decision making processes in MOH patients who overuse medications containing psychoactive substances like opiates. Moreover dependence-related variables are related to the prognosis.

Parallel maturation of goal-directed behavior and dopaminergic systems during adolescence.

Adolescence is a crucial developmental period characterized by specific behaviors reflecting the immaturity of decision-making abilities. However, the maturation of precise cognitive processes and their neurobiological correlates at this period remain poorly understood. Here, we investigate whether a differential developmental time course of dopamine (DA) pathways during late adolescence could explain the emergence of particular executive and motivational components of goal-directed behavior. First, using a contingency degradation protocol, we demonstrate that adolescent rats display a specific deficit when the causal relationship between their actions and their consequences is changed. When the rats become adults, this deficit disappears. In contrast, actions of adolescents remain sensitive to outcome devaluation or to the influence of a pavlovian-conditioned stimulus. This aspect of cognitive maturation parallels a delayed development of the DA system, especially the mesocortical pathway involved in action adaptation to rule changes. Unlike in striatal and nucleus accumbens regions, DA fibers and DA tissue content continue to increase in the medial prefrontal cortex from juvenile to adult age. Moreover, a sustained overexpression of DA receptors is observed in the prefrontal region until the end of adolescence. These findings highlight the relationship between the emergence of specific cognitive processes, in particular the adaptation to changes in action consequences, and the delayed maturation of the mesocortical DA pathway. Similar developmental processes in humans could contribute to the adolescent vulnerability to the emergence of several psychiatric disorders characterized by decision-making deficits.

The role of the rat medial prefrontal cortex in adapting to changes in instrumental contingency.

In order to select actions appropriate to current needs, a subject must identify relationships between actions and events. Control over the environment is determined by the degree to which action consequences can be predicted, as described by action-outcome contingencies--i.e. performing an action should affect the probability of the outcome. We evaluated in a first experiment adaptation to contingency changes in rats with neurotoxic lesions of the medial prefrontal cortex. Results indicate that this brain region is not critical to adjust instrumental responding to a negative contingency where the rats must refrain from pressing a lever, as this action prevents reward delivery. By contrast, this brain region is required to reduce responding in a non-contingent situation where the same number of rewards is freely delivered and actions do not affect the outcome any more. In a second experiment, we determined that this effect does not result from a different perception of temporal relationships between actions and outcomes since lesioned rats adapted normally to gradually increasing delays in reward delivery. These data indicate that the medial prefrontal cortex is not directly involved in evaluating the correlation between action--and reward--rates or in the perception of reward delays. The deficit in lesioned rats appears to consist of an abnormal response to the balance between contingent and non-contingent rewards. By highlighting the role of prefrontal regions in adapting to the causal status of actions, these data contribute to our understanding of the neural basis of choice tasks.

Retrospective revaluation and its neural circuit in rats.

Contingency learning is essential for establishing predictive or causal judgements. Retrospective revaluation captures essential aspects of the updating of this knowledge, according to new experience. In the present study, retrospective revaluation and its neural substrate was investigated in a rat conditioned magazine approach. One element of a previously food-reinforced Tone-Light compound stimulus was either further reinforced (inflation) or extinguished (extinction). These treatments affected the predictive value of the alternate stimulus (target), but only when the target was a weakly salient stimulus such as a Light, and the inflation/extinction procedure concerned the more salient element, that is the Tone. As the predictive value of the Light was decreased in comparison with a relevant control group, this revaluation was interpreted as backward blocking, and not unovershadowing. This observation challenges retrospective revaluation models focused on acquisition and prediction error detection, and is better accounted for by retrieval-based associative theories such as the comparator model (Miller and Matzel) [5]. Immunohistochemical detection of the Fos protein after the test phase revealed activation of the orbitofrontal and infralimbic cortices as well as nucleus accumbens core and shell, in rats that exhibited retrospective revaluation. Our results suggest that rats integrate successive experiences at the retrieval stage of retrospective revaluation, and that prefronto-accumbal interactions are involved in this function.

Transient role of the rat prelimbic cortex in goal-directed behaviour.

Lesion studies show that goal-directed actions mediated by action-outcome (A-O) associations and habits mediated by stimulus-response (S-R) associations can be dissociated during instrumental training, with the prelimbic region of the medial prefrontal cortex being involved in the former and the infralimbic region in the latter. The present work further investigates the role of the prelimbic region in acquisition vs. expression of goal-directed instrumental behaviour, using reversible neuronal inactivation and outcome devaluation procedures. In a first experiment, inactivating the prelimbic cortex at the time of testing did not alter the sensitivity to devaluation, indicating that this region was not essential for the expression of A-O associations. In a second experiment, the prelimbic cortex was inactivated throughout the training phase. At the time of testing the performance was insensitive to devaluation, indicating that the acquired response was not goal-directed but mediated by an S-R association. These data challenge the view that the habit system replaces the goal-directed system as training progresses. They show that the prelimbic cortex plays a transient but crucial role in the acquisition of goal-directed responding and that the A-O and S-R systems can operate in a competitive fashion early in training.

A cholinergic-dependent role for the entorhinal cortex in trace fear conditioning.

Trace conditioning is considered a model of higher cognitive involvement in simple associative tasks. Studies of trace conditioning have shown that cortical areas and the hippocampal formation are required to associate events that occur at different times. However, the mechanisms that bridge the trace interval during the acquisition of trace conditioning remain unknown. In four experiments with fear conditioning in rats, we explored the involvement of the entorhinal cortex (EC) in the acquisition of fear under a trace-30 s protocol. We first determined that pretraining neurotoxic lesions of the EC selectively impaired trace-, but not delay-conditioned fear as evaluated by freezing behavior. A local cholinergic deafferentation of the EC using 192-IgG-saporin did not replicate this deficit, presumably because cholinergic interneurons were spared by the toxin. However, pretraining local blockade of EC muscarinic receptors with the M1 antagonist pirenzepine yielded a specific and dose-dependent deficit in trace-conditioned responses. The same microinjections performed after conditioning were without effect on trace fear responses. These effects of blocking M1 receptors are consistent with the notion that conditioned stimulus (CS)-elicited, acetylcholine-dependent persistent activities in the EC are needed to maintain a representation of a tone CS across the trace interval during the acquisition of trace conditioning. This function of the EC is consistent with recent views of this region as a short-term stimulus buffer.

A role for medial prefrontal dopaminergic innervation in instrumental conditioning.

To investigate the involvement of dopaminergic projections to the prelimbic and infralimbic cortex in the control of goal-directed responses, a first experiment examined the effect of pretraining 6-OHDA lesions of these cortices. We used outcome devaluation and contingency degradation procedures to separately assess the representation of the outcome as a goal or the encoding of the contingency between the action and its outcome. All groups acquired the instrumental response at a normal rate, indicating that dopaminergic activity in the medial prefrontal cortex is not necessary for the acquisition of instrumental learning. Sham-operated animals showed sensitivity to both outcome devaluation and contingency degradation. Animals with dopaminergic lesions of the prelimbic cortex, but not the infralimbic cortex, failed to adapt their instrumental response to changes in contingency, whereas their response remained sensitive to outcome devaluation. In a second experiment, aimed at determining whether dopamine was specifically needed during contingency changes, we performed microinfusions of the dopamine D(1)/D(2) receptor antagonist flupenthixol in the prelimbic cortex only before contingency degradation sessions. Animals with infusions of flupenthixol failed to adapt their response to changes in contingency, thus replicating the deficit of animals with dopaminergic lesions in Experiment 1. These results demonstrate that dissociable neurobiological mechanisms support action-outcome relationships and goal representation, dopamine signaling in the prelimbic cortex being necessary for the former but not the latter.

Goal-directed responding is sensitive to lesions to the prelimbic cortex or basolateral nucleus of the amygdala but not to their disconnection.

The current view of instrumental conditioning indicates that performance in the early stage of training is maintained by a representation of the outcome, as indexed by its sensitivity to changes in the value of the reward. In the present study, the authors tested the effects of a disconnection of the prelimbic cortex (PL) and the basolateral nucleus of the amygdale (BLA), using an asymmetric lesion procedure, to determine whether these structures interact sequentially as part of a corticolimbic system. In marked contrast to the effects of bilateral lesions of the PL or the BLA, which both altered rats' sensitivity to outcome devaluation, the disconnection of these 2 brain areas was without an effect on outcome devaluation. These results demonstrate that the PL and the BLA mediate different aspects of outcome representation in goal-directed responding.

Entorhinal cortex and cognition.

Understanding the function of the entorhinal cortex (EC) has been an important subject over the years, not least because of its cortical intermediary to and from the hippocampus proper, and because of electrophysiological advances which have started to reveal the physiology in behaving animals. Clearly, a lot more needs to be done but is clear to date that EC is not merely a throughput station providing all hippocampal subfields with sensory information, but that processing within EC contributes significantly to attention, conditioning, event and spatial cognition possibly by compressing representations that overlap in time. These are transmitted to the hippocampus, where they are differentiated again and returned to EC. Preliminary evidence for such a role, but also their possible pitfalls are summarised.

Differential contribution of dorsal and ventral hippocampus to trace and delay fear conditioning.

Trace conditioning relies on the maintained representation of a stimulus across a trace interval, and may involve a persistent trace of the conditioned stimulus (CS) and/or a contribution of contextual conditioning. The role of hippocampal structures in these two types of conditioning was studied by means of pretraining lesions and reversible inactivation of the hippocampus in rats. Similar levels of conditioning to a tone CS and to the context were obtained with a trace interval of 30 s. Neurotoxic lesions of the whole hippocampus or reversible muscimol inactivation of the ventral hippocampus impaired both contextual and tone freezing in both trace- and delay-conditioned rats. Dorsal hippocampal injections impaired contextual freezing and trace conditioning, but not delay conditioning. No dissociation between trace and contextual conditioning was observed under any of these conditions. Altogether, these data indicate that the ventral and dorsal parts of the hippocampus compute different aspects of trace conditioning, with the ventral hippocampus being involved in fear and anxiety processes, and the dorsal hippocampus in the temporal and contextual aspects of event representation.

Lesion of the lateral entorhinal cortex amplifies odor-induced expression of c-fos, junB, and zif 268 mRNA in rat brain.

Paradoxical facilitation of olfactory learning following entorhinal cortex (EC) lesion has been described, which may result from widespread functional alterations taking place within the olfactory system. To test this hypothesis, expression of the immediate early genes c-fos, junB, and zif 268 was studied in response to an olfactory stimulation in several brain areas in control and in EC-lesioned rats. Olfactory stimulation in control rats induced the expression of the three genes in the granular/mitral and glomerular layers of the olfactory bulb, as well as c-fos and junB expression in the piriform cortex. However EC lesion was devoid of effects in nonstimulated animals; it significantly amplified the odor-induced expression of the three genes in these areas, as well as in the amygdala, hippocampus, and parietal-temporal cortices. The data suggest that EC lesion modifies the neural processing of odor by suppressing an inhibitory influence on brain areas connected to this cortex.

Aversive effects elicited by electrical stimulation of the inferior colliculus in normal and audiogenic seizure susceptible rats.

Trains of electrical stimulations were applied to the dorsal or ventral part of the inferior colliculus (IC) of audiogenic seizure susceptible rats from the AGSR strain. Threshold and duration of wild running (WR), were evaluated in the first experiment. All stimulation sites elicited WR, even in normal control rats. Stimulation of the IC of AGSR rats required a lower quantity of current, i.e., such brain sites were more sensitive to the current, than normal controls. The duration of post-stimulus WR was shorter in AGSR rats. Lower quantities of current applied to the ventral IC were needed to elicit WR than to the dorsal IC in AGSR rats. In a second experiment, using the same stimulations sites in the same rats, the emotional effect of the stimulation was tested through an instrumental learning procedure (switch-off paradigm) in which the rat was trained to press a bar to put an end to the stimulation. Both dorsal and ventral IC stimulation sites sustained switch-off behavior in AGSR rats, but only ventral IC stimulation sites sustained switch-off learning in control rats.

The entorhinal cortex-nucleus accumbens pathway and latent inhibition: a behavioral and neurochemical study in rats.

Latent inhibition (LI) refers to the decrease in conditioned response produced by the repeated nonrein-forced preexposure to the to-be-conditioned stimulus. Experiment I investigated the effects of electrolytic lesions of the entorhinal cortex on LI in a conditioned emotional response procedure. Entorhinal cortex lesions attenuated LI. Experiments 2 and 3 investigated whether this attenuation of LI could result from a modification in nucleus accumbens (NAcc) dopamine (DA) release. Rats with entorhinal cortex lesions displayed normal spontaneous and amphetamine-induced locomotor activity, as well as normal basal and amphetamine-induced release of DA within the NAcc (assessed by microdialysis). Taken together, these results show that entorhinal cortex lesions disrupt LI in a way that is unlikely to be due to an alteration of DA release within the NAcc.