Changes of ongoing activity in Cebus monkey perirhinal cortex correlate with behavioral performance

A Cebus apella monkey weighing 4 kg was trained in a saccadic eye movement task and while the animal performed the task we recorded the extracellular activity of perirhinal cortical neurons. Although the task was very simple and maintained at a constant level of difficulty, we observed considerable changes in the performance of the monkey within each experimental session. The behavioral states responsible for such variation may be related to arousal, motivation or attention of the animal while engaged in the task. In approximately 20% (16/82) of the units recorded, long-term direct or inverse correlations could be demonstrated between the monkey's behavioral state and the cells' ongoing activity (independent of the visual stimulation or of the specific behavior along a trial). The perirhinal cortex and other medial temporal structures have long been associated with normal memory function. The data presented here were interpreted in terms of recent reports focusing on the subcortical afferents to temporal lobe structures and their possible role in controlling arousal, motivation, or attention.

Changes in the biogenic amine content of the prefrontal cortex, amygdala, dorsal hippocampus, and nucleus accumbens of rats submitted to single and repeated sessions of the elevated plus-maze test

It has been demonstrated that exposure to a variety of stressful experiences enhances fearful reactions when behavior is tested in current animal models of anxiety. Until now, no study has examined the neurochemical changes during the test and retest sessions of rats submitted to the elevated plus maze (EPM). The present study uses a new approach (HPLC) by looking at the changes in dopamine and serotonin levels in the prefrontal cortex, amygdala, dorsal hippocampus, and nucleus accumbens in animals upon single or double exposure to the EPM (one-trial tolerance). The study involved two experiments: i) saline or midazolam (0.5 mg/kg) before the first trial, and ii) saline or midazolam before the second trial. For the biochemical analysis a control group injected with saline and not tested in the EPM was included. Stressful stimuli in the EPM were able to elicit one-trial tolerance to midazolam on re-exposure (61.01%). Significant decreases in serotonin contents occurred in the prefrontal cortex (38.74%), amygdala (78.96%), dorsal hippocampus (70.33%), and nucleus accumbens (73.58%) of the animals tested in the EPM (P < 0.05 in all cases in relation to controls not exposed to the EPM). A significant decrease in dopamine content was also observed in the amygdala (54.74%, P < 0.05). These changes were maintained across trials. There was no change in the turnover rates of these monoamines. We suggest that exposure to the EPM causes reduced monoaminergic neurotransmission activity in limbic structures, which appears to underlie the "one-trial tolerance" phenomenon.

Influence of progesterone on GAD65 and GAD67 mRNA expression in the dorsolateral striatum and prefrontal cortex of female rats repeatedly treated with cocaine

Female rats are intensely affected by cocaine, with estrogen probably playing an important role in this effect. Progesterone modulates the GABA system and attenuates the effects of cocaine; however, there is no information about its relevance in changing GABA synthesis pathways after cocaine administration to female rats. Our objective was to investigate the influence of progesterone on the effects of repeated cocaine administration on the isoenzymes of glutamic acid decarboxylase (GAD65 and GAD67) mRNA in brain areas involved in the addiction circuitry. Ovariectomized, intact and progesterone replacement-treated female rats received saline or cocaine (30 mg/kg, ip) acutely or repeatedly. GAD isoenzyme mRNA levels were determined in the dorsolateral striatum (dSTR) and prefrontal cortex (PFC) by RT-PCR, showing that repeated, but not acute, cocaine decreased GADs/β-actin mRNA ratio in the dSTR irrespective of the hormonal condition (GAD65: P < 0.001; and GAD67: P = 0.004). In the PFC, repeated cocaine decreased GAD65 and increased GAD67 mRNA ratio (P < 0.05). Progesterone replacement decreased both GAD isoenzymes mRNA ratio after acute cocaine in the PFC (P < 0.001) and repeated cocaine treatment reversed this decrease (P < 0.001). These results suggest that cocaine does not immediately affect GAD mRNA expression, while repeated cocaine decreases both GAD65 and GAD67 mRNA in the dSTR of female rats, independently of their hormonal conditions. In the PFC, repeated cocaine increases the expression of GAD isoenzymes, which were decreased due to progesterone replacement.

In vivo photorelease of GABA in the mouse cortex

Electrical stimulation has been used for more than 100 years in neuroscientific and biomedical research as a powerful tool for controlled perturbations of neural activity. Despite quickly driving neuronal activity, this technique presents some important limitations, such as the impossibility to activate or deactivate specific neuronal populations within a single stimulation site. This problem can be avoided by pharmacological methods based on the administration of receptor ligands able to cause specific changes in neuronal activity. However, intracerebral injections of neuroactive molecules inherently confound the dynamics of drug diffusion with receptor activation. Caged compounds have been proposed to circumvent this problem, for spatially and temporally controlled release of molecules. Caged compounds consist of a protecting group and a ligand made inactive by the bond between the two parts. By breaking this bond with light of an appropriate wavelength, the ligand recovers its activity within milliseconds. To test these compounds in vivo, we recorded local field potentials (LFPs) from the cerebral cortex of anesthetized female mice (CF1, 60-70 days, 20-30 g) before and after infusion with caged γ-amino-butyric-acid (GABA). After 30 min, we irradiated the cortical surface with pulses of blue light in order to photorelease the caged GABA and measure its effect on global brain activity. Laser pulses significantly and consistently decreased LFP power in four different frequency bands with a precision of few milliseconds (P < 0.000001); however, the inhibitory effects lasted several minutes (P < 0.0043). The technical difficulties and limitations of neurotransmitter photorelease are presented, and perspectives for future in vivo applications of the method are discussed.

Decreased levels of pNR1 S897 protein in the cortex of neonatal Sprague Dawley rats with hypoxic-ischemic or NMDA-induced brain damage

Our objective was to investigate the protein level of phosphorylated N-methyl-D-aspartate (NMDA) receptor-1 at serine 897 (pNR1 S897) in both NMDA-induced brain damage and hypoxic-ischemic brain damage (HIBD), and to obtain further evidence that HIBD in the cortex is related to NMDA toxicity due to a change of the pNR1 S897 protein level. At postnatal day 7, male and female Sprague Dawley rats (13.12 ± 0.34 g) were randomly divided into normal control, phosphate-buffered saline (PBS) cerebral microinjection, HIBD, and NMDA cerebral microinjection groups. Immunofluorescence and Western blot (N = 10 rats per group) were used to examine the protein level of pNR1 S897. Immunofluorescence showed that control and PBS groups exhibited significant neuronal cytoplasmic staining for pNR1 S897 in the cortex. Both HIBD and NMDA-induced brain damage markedly decreased pNR1 S897 staining in the ipsilateral cortex, but not in the contralateral cortex. Western blot analysis showed that at 2 and 24 h after HIBD, the protein level of pNR1 S897 was not affected in the contralateral cortex (P > 0.05), whereas it was reduced in the ipsilateral cortex (P < 0.05). At 2 h after NMDA injection, the protein level of pNR1 S897 in the contralateral cortex was also not affected (P > 0.05). The levels in the ipsilateral cortex were decreased, but the change was not significant (P > 0.05). The similar reduction in the protein level of pNR1 S897 following both HIBD and NMDA-induced brain damage suggests that HIBD is to some extent related to NMDA toxicity possibly through NR1 phosphorylation of serine 897.

Changes in tau phosphorylation levels in the hippocampus and frontal cortex following chronic stress

Studies have indicated that early-life or early-onset depression is associated with a 2- to 4-fold increased risk of developing Alzheimers disease (AD). In AD, aggregation of an abnormally phosphorylated form of the tau protein may be a key pathological event. Tau is known to play a major role in promoting microtubule assembly and stabilization, and in maintaining the normal morphology of neurons. Several studies have reported that stress may induce tau phosphorylation. The main aim of the present study was to investigate possible alterations in the tau protein in the hippocampus and frontal cortex of 32 male Sprague-Dawley rats exposed to chronic unpredictable mild stress (CUMS) and then re-exposed to CUMS to mimic depression and the recurrence of depression, respectively, in humans. We evaluated the effects of CUMS, fluoxetine, and CUMS re-exposure on tau and phospho-tau. Our results showed that a single exposure to CUMS caused a significant reduction in sucrose preference, indicating a state of anhedonia. The change in behavior was accompanied by specific alterations in phospho-tau protein levels, but fluoxetine treatment reversed the CUMS-induced impairments. Moreover, changes in sucrose preference and phospho-tau were more pronounced in rats re-exposed to CUMS than in those subjected to a single exposure. Our results suggest that changes in tau phosphorylation may contribute to the link between depression and AD.

Voluntary exercise prior to traumatic brain injury alters miRNA expression in the injured mouse cerebral cortex

MicroRNAs (miRNAs) may be important mediators of the profound molecular and cellular changes that occur after traumatic brain injury (TBI). However, the changes and possible roles of miRNAs induced by voluntary exercise prior to TBI are still not known. In this report, the microarray method was used to demonstrate alterations in miRNA expression levels in the cerebral cortex of TBI mice that were pretrained on a running wheel (RW). Voluntary RW exercise prior to TBI: i) significantly decreased the mortality rate and improved the recovery of the righting reflex in TBI mice, and ii) differentially changed the levels of several miRNAs, upregulating some and downregulating others. Furthermore, we revealed global upregulation of miR-21, miR-92a, and miR-874 and downregulation of miR-138, let-7c, and miR-124 expression among the sham-non-runner, TBI-non-runner, and TBI-runner groups. Quantitative reverse transcription polymerase chain reaction data (RT-qPCR) indicated good consistency with the microarray results. Our microarray-based analysis of miRNA expression in mice cerebral cortex after TBI revealed that some miRNAs such as miR-21, miR-92a, miR-874, miR-138, let-7c, and miR-124 could be involved in the prevention and protection afforded by voluntary exercise in a TBI model.

Effect of hyperbaric oxygenation on mitochondrial function of neuronal cells in the cortex of neonatal rats after hypoxic-ischemic brain damage

The timing and mechanisms of protection by hyperbaric oxygenation (HBO) in hypoxic-ischemic brain damage (HIBD) have only been partially elucidated. We monitored the effect of HBO on the mitochondrial function of neuronal cells in the cerebral cortex of neonatal rats after HIBD. Neonatal Sprague-Dawley rats (total of 360 of both genders) were randomly divided into normal control, HIBD, and HIBD+HBO groups. The HBO treatment began immediately after hypoxia-ischemia (HI) and continued once a day for 7 consecutive days. Animals were euthanized 0, 2, 4, 6, and 12 h post-HI to monitor the changes in mitochondrial membrane potential (ΔΨm) occurring soon after a single dose of HBO treatment, as well as 2, 3, 4, 5, 6, and 7 days post-HI to study ΔΨm changes after a series of HBO treatments. Fluctuations in ΔΨm were observed in the ipsilateral cortex in both HIBD and HIBD+HBO groups. Within 2 to 12 h after HI insult, the ΔΨm of the HIBD and HIBD+HBO groups recovered to some extent. A secondary drop in ΔΨm was observed in both groups during the 1-4 days post-HI period, but was more severe in the HIBD+HBO group. There was a secondary recovery of ΔΨm observed in the HIBD+HBO group, but not in the HIBD group, during the 5-7 days period after HI insult. HBO therapy may not lead to improvement of neural cell mitochondrial function in the cerebral cortex in the early stage post-HI, but may improve it in the sub-acute stage post-HI.

Individual differences in risk-taking and associated characteristics : a test of specificity in executive functions /

Multiple measures have been devised by clinicians and theorists from many different backgrounds for the purpose of assessing the influence of the frontal lobes on behaviour. Some utilize self-report measures to investigate behavioural characteristics such as risktaking, sensation seeking, impulsivity, and sensitivity to reward and punishment in an attempt to understand complex human decision making. Others rely more on neuroimaging and electrophysiological investigation involving experimental tasks thought to demonstrate executive functions in action, while other researchers prefer to study clinical populations with selective damage. Neuropsychological models of frontal lobe functioning have led to a greater appreciation of the dissociations among various aspects of prefrontal cortex function. This thesis involves (1) an examination of various psychometric and experimental indices of executive functions for coherence as one would predict on the basis of highly developed neurophysiological models of prefrontal function, particularly those aspects of executive function that involve predominantly cognitive abilities versus processes characterized by affect regulation; and (2) investigation of the relations between risk-taking, attentional abilties and their associated characteristics using a neurophysiological model of prefrontal functions addressed in (1). Late adolescence is a stage in which the prefrontal cortices undergo intensive structural and functional maturational changes; this period also involves increases in levels of risky and sensation driven behaviours, as well as a hypersensitivity to reward and a reduction in inhibition. Consequently, late adolescence spears to represent an ideal developmental period in which to examine these decision-making behaviours due to the maximum variability of behavioural characteristics of interest. Participants were 45 male undergraduate 18- to 19-year olds, who completed a battery of measures that included self-report, experimental and behavioural measures designed to assess particular aspects of prefrontal and executive functioning. As predicted, factor analysis supported the grouping of executive process by type (either primarily cognitive or affective), conforming to the orbitofrontal versus dorsolateral typology; risk-taking and associated characteristics were associated more with the orbitofrontal than the dorsolateral factor, whereas attentional and planning abilities tended to correlate more strongly with the dorsolateral factor. Results are discussed in light of future assessment, investigation and understanding of complex human decision-making and executive functions. Implications, applications and suggestions for future research are also proposed.

Hot cognition and activation of the medial prefrontal cortex: Self-regulating in contexts involving motivational pressures

The medial prefrontal cortex (mPFC) is involved in performance-monitoring and has been implicated in the generation of several electrocortical responses associated with self-regulation. The error-related negativity (ERN), the inhibitory Nogo N2 (N2), and the feedback-related negativity (FRN) are event-related potential (ERP) components which reflect mPFC activity associated with feedback to behavioural (ERN, N2) and environmental (FRN) consequences. Our main goal was to determine whether or not rnPFC activation varies as a function of motivational context (e.g., those involving performance-related incentives) or the use of internally versus externally generated feedback signals (i.e., errors). Additionally, we assessed medial prefrontal activity in relation to individual differences in personality and temperament. Participants completed a combination of tasks in which performance-related incentives were associated with task performance and feedback generated from internal versus external responses. MPFC activity was indexed using both ERP scalp voltage peaks and intracerebral current source density (CSD) of dorsal and ventral regions. Additionally, participants completed several questionnaires assessing personality and temperament styles. Given previous studies have shown that enhanced mPFC activity to loss (or negative) feedback, we expected that activity in the mPFC would generally be greater during the Loss condition relative to the Win condition for both the ERN and N2. Also, due to the evidence that the (vmPFC) is engaged in arousing contexts, we hypothesized that activity in the ventromedial prefrontal cortex (vmPFC) would be greater than activity in the dorsomedial prefrontal cortex (dmPFC), especially in the Loss condition of the GoNogo task (ERN). Similarly, loss feedback in the BART (FRN) was expected to engage the vmPFC more than the dmPFC. Finally, we predicted that persons rating themselves as more willing to engage in approach-related behaviours or to exhibit rigid cognitive styles would show reduced activity of the mPFC. Overall, our results emphasize the role of affective evaluations of behavioural and environmental consequences when self-regulating. Although there were no effects of context on brain activity, our data indicate that, during the time of the ERN and N2 on the MW Go-Nogo task and the FRN on the BART, the vrnPFC was more active compared to the dmPFC. Moreover, regional recruitment in the mPFC was similar across internally (ERN) and externally (FRN) generated errors signals associated with loss feedback, as reflected by relatively greater activity in the vmPFC than the dmPFC. Our data also suggest that greater activity in the mPFC is associated with better inhibitory control, as reflected by both scalp and CSD measures. Additionally, deactivation of the subgenual anterior cingulate cortex (sgACC) and lower levels of self-reported positive affect were both related to increased voluntary risk-taking on the BART. Finally, persons reporting higher levels of approach-related behaviour or cognitive rigidity showed reduced activity of the mPFC. These results are in line with previous research emphasizing that affect/motivation is central to the processes reflected by mediofrontal negativities (MFNs), that the vmPFC is involved in regulating demands on motivational/affective systems, and that the underlying mechanisms driving these functions vary across both individuals and contexts.

Disambiguating the Effects of Social Instability Stress in Adolescence on Learning and Memory Tasks that Involve the Medial Prefrontal Cortex and Hippocampus

Exposure to chronic stress can alter the structure and function of brain regions involved in learning and memory, and these effects are typically long-lasting if the stress occurs during sensitive periods of development. Until recently, adolescence has received relatively little attention as a sensitive period of development, despite marked changes in behaviour, heightened reactivity to stressors, and cognitive and neural maturation. Therefore, the purpose of the present study was to investigate the long-term effects of chronic stress in adolescence on two spatial learning and memory tasks (Morris water maze and Spatial Object Location test) and on a working memory task (Delayed Alternation task). Male rats were randomly assigned to chronic social instability stress (SS; daily 1 hour isolation and subsequent change of cage partner between postnatal days 30 and 45) or to a no-stress control group (CTL). During acquisition learning in the Morris water maze task, SS rats demonstrated impaired long-term memory for the location of the hidden escape platform compared to CTL rats, although the impairment was only seen after the first day of training. Similarly, SS rats had impaired long-term memory in the Spatial Object Location test after a long delay (240 minutes), but not after shorter delays (15 or 60 minutes) compared to CTL rats. On the Delayed Alternation task, which assessed working memory across delays ranging from 5 to 90 seconds, no group differences were observed. These results are partially in line with previous research that revealed adult impairment on spatial learning and memory tasks after exposure to chronic social instability stress in adolescence. The observed deficits, however, appear to be limited to long-term memory as no group differences were observed during brief periods of retention.

Intrahemispheric dysfunction in primary motor cortex without corpus callosum: a transcranial magnetic stimulation study

Affiliation: Département de Psychologie, Université de Montréal

Plasticité intermodale chez le hamster énucléé à la naissance : Études de la distribution des interneurones CaBPir dans les cortex visuel et auditif primaires.

La période postnatale et l’expérience sensorielle sont critiques pour le développement du système visuel. Les interneurones inhibiteurs exprimant l’acide γ-aminobutyrique (GABA) jouent un rôle important dans le contrôle de l’activité neuronale, le raffinement et le traitement de l’information sensorielle qui parvient au cortex cérébral. Durant le développement, lorsque le cortex cérébral est très susceptible aux influences extrinsèques, le GABA agit dans la formation des périodes critiques de sensibilité ainsi que dans la plasticité dépendante de l’expérience. Ainsi, ce système inhibiteur servirait à ajuster le fonctionnement des aires sensorielles primaires selon les conditions spécifiques d’activité en provenance du milieu, des afférences corticales (thalamiques et autres) et de l’expérience sensorielle. Certaines études montrent que des différences dans la densité et la distribution de ces neurones inhibiteurs corticaux reflètent les caractéristiques fonctionnelles distinctes entre les différentes aires corticales. La Parvalbumine (PV), la Calretinine (CR) et la Calbindine (CB) sont des protéines chélatrices du calcium (calcium binding proteins ou CaBPs) localisées dans différentes sous-populations d’interneurones GABAergiques corticaux. Ces protéines tamponnent le calcium intracellulaire de sorte qu’elles peuvent moduler différemment plusieurs fonctions neuronales, notamment l’aspect temporel des potentiels d’action, la transmission synaptique et la potentialisation à long terme. Plusieurs études récentes montrent que les interneurones immunoréactifs (ir) aux CaBPs sont également très sensibles à l’expérience et à l’activité sensorielle durant le développement et chez l’adulte. Ainsi, ces neurones pourraient avoir un rôle crucial à jouer dans le phénomène de compensation ou de plasticité intermodale entre les cortex sensoriels primaires. Chez le hamster (Mesocricetus auratus), l’énucléation à la naissance fait en sorte que le cortex visuel primaire peut être recruté par les autres modalités sensorielles, telles que le toucher et l’audition. Suite à cette privation oculaire, il y a établissement de projections ectopiques permanentes entre les collicules inférieurs (CI) et le corps genouillé latéral (CGL). Ceci a pour effet d’acheminer l’information auditive vers le cortex visuel primaire (V1) durant le développement postnatal. À l’aide de ce modèle, l’objectif général de ce projet de thèse est d’étudier l’influence et le rôle de l’activité sensorielle sur la distribution et l’organisation des interneurones corticaux immunoréactifs aux CaBPs dans les aires sensorielles visuelle et auditive primaires du hamster adulte. Les changements dans l’expression des CaBPs ont été déterminés d’une manière quantitative en évaluant les profils de distribution laminaire de ces neurones révélés par immunohistochimie. Dans une première expérience, nous avons étudié la distribution laminaire des CaBPs dans les aires visuelle (V1) et auditive (A1) primaires chez le hamster normal adulte. Les neurones immunoréactifs à la PV et la CB, mais non à la CR, sont distribués différemment dans ces deux cortex primaires dédiés à une modalité sensorielle différente. Dans une deuxième étude, une comparaison a été effectuée entre des animaux contrôles et des hamsters énucléés à la naissance. Cette étude montre que le cortex visuel primaire de ces animaux adopte une chimioarchitecture en PV similaire à celle du cortex auditif. Nos recherches montrent donc qu’une suppression de l’activité visuelle à la naissance peut influencer l’expression des CaBPs dans l’aire V1 du hamster adulte. Ceci suggère également que le type d’activité des afférences en provenance d’autres modalités sensorielles peut moduler, en partie, une circuiterie corticale en CaBPs qui lui est propre dans le cortex hôte ou recruté. Ainsi, nos travaux appuient l’hypothèse selon laquelle il serait possible que certaines de ces sous-populations d’interneurones GABAergiques jouent un rôle crucial dans le phénomène de la plasticité intermodale.

Les mécanismes endogènes de modulation de la douleur et leur dysfonction dans le syndrome de l'intestin irritable

La douleur est une expérience subjective multidimensionnelle accompagnée de réponses physiologiques. Ces dernières sont régulées par des processus cérébraux qui jouent un rôle important dans la modulation spinale et cérébrale de la douleur. Cependant, les mécanismes de cette régulation sont encore mal définis et il est essentiel de bien les comprendre pour mieux traiter la douleur. Les quatre études de cette thèse avaient donc comme objectif de préciser les mécanismes endogènes de modulation de la douleur par la contreirritation (inhibition de la douleur par une autre douleur) et d’investiguer la dysfonction de ces mécanismes chez des femmes souffrant du syndrome de l’intestin irritable (Sii). Dans un premier temps, un modèle expérimental a été développé pour mesurer l’activité cérébrale en imagerie par résonance magnétique fonctionnelle concurremment à l’enregistrement du réflexe nociceptif de flexion (RIII : index de nociception spinale) et des réponses de conductance électrodermale (SCR : index d’activation sympathique) évoqués par des stimulations électriques douloureuses. La première étude indique que les différences individuelles d’activité cérébrale évoquée par les stimulations électriques dans les cortex orbitofrontal (OFC) et cingulaire sont associées aux différences individuelles de sensibilité à la douleur, de réactivité motrice (RIII) et de réactivité autonomique (SCR) chez des sujets sains. La deuxième étude montre que l’analgésie par contreirritation produite chez des sujets sains est accompagnée de l’inhibition de l’amygdale par OFC et d’une modulation du réflexe RIII par la substance grise périaqueducale (PAG) et le cortex somesthésique primaire (SI). Dans les troisième et quatrième études, il est montré que la contreirritation ne produit pas d’inhibition significative de la douleur et du réflexe RIII chez les patientes Sii en comparaison aux contrôles. De plus, les résultats indiquent que la sévérité des symptômes psychologiques est associée au déficit de modulation de la douleur et à une hypersensibilité diffuse chez les patientes Sii. Dans l’ensemble, cette thèse précise le rôle de certaines structures cérébrales dans les multiples composantes de la douleur et dans l’analgésie par contreirritation et montre que les patientes Sii présentent une dysfonction des mécanismes spinaux et cérébraux impliqués dans la perception et la modulation de la douleur.

Modèle informatique du coapprentissage des ganglions de la base et du cortex : l'apprentissage par renforcement et le développement de représentations

Tout au long de la vie, le cerveau développe des représentations de son environnement permettant à l’individu d’en tirer meilleur profit. Comment ces représentations se développent-elles pendant la quête de récompenses demeure un mystère. Il est raisonnable de penser que le cortex est le siège de ces représentations et que les ganglions de la base jouent un rôle important dans la maximisation des récompenses. En particulier, les neurones dopaminergiques semblent coder un signal d’erreur de prédiction de récompense. Cette thèse étudie le problème en construisant, à l’aide de l’apprentissage machine, un modèle informatique intégrant de nombreuses évidences neurologiques. Après une introduction au cadre mathématique et à quelques algorithmes de l’apprentissage machine, un survol de l’apprentissage en psychologie et en neuroscience et une revue des modèles de l’apprentissage dans les ganglions de la base, la thèse comporte trois articles. Le premier montre qu’il est possible d’apprendre à maximiser ses récompenses tout en développant de meilleures représentations des entrées. Le second article porte sur l'important problème toujours non résolu de la représentation du temps. Il démontre qu’une représentation du temps peut être acquise automatiquement dans un réseau de neurones artificiels faisant office de mémoire de travail. La représentation développée par le modèle ressemble beaucoup à l’activité de neurones corticaux dans des tâches similaires. De plus, le modèle montre que l’utilisation du signal d’erreur de récompense peut accélérer la construction de ces représentations temporelles. Finalement, il montre qu’une telle représentation acquise automatiquement dans le cortex peut fournir l’information nécessaire aux ganglions de la base pour expliquer le signal dopaminergique. Enfin, le troisième article évalue le pouvoir explicatif et prédictif du modèle sur différentes situations comme la présence ou l’absence d’un stimulus (conditionnement classique ou de trace) pendant l’attente de la récompense. En plus de faire des prédictions très intéressantes en lien avec la littérature sur les intervalles de temps, l’article révèle certaines lacunes du modèle qui devront être améliorées. Bref, cette thèse étend les modèles actuels de l’apprentissage des ganglions de la base et du système dopaminergique au développement concurrent de représentations temporelles dans le cortex et aux interactions de ces deux structures.