A computerized virtual version of the Morris water maze (vMWM) was used to assess human gender differences in spatial working memory. In Experiment 1, the release point and platform location was changed on every other trial for 20 trials. Men had significantly reduced acquisition latencies and more accurate heading errors on the first daily trial compared to women. In Experiment 2, the release point and platform location was changed every fourth trial for 20 trials. Men had significantly shorter acquisition latencies and path lengths than women. Experiment 3 was identical to Experiment 2, except that environmental cues were changed throughout testing. Men had significantly shorter acquisition latencies and path lengths than did the women. These studies are the first to demonstrate significant gender differences in a spatial working memory version of the vMWM.

Posttraumatic stress disorder (PTSD) is classified as an anxiety disorder and the characteristic symptoms (re-experiencing, avoidance as well as numbing of general responsiveness and hyperarousal) of this disorder develop in response to a traumatic event. The disorder is characterised by hypothalamic-pituitary-adrenal (HPA) axis abnormalities linked with changes in cortisol moreover, the hippocampus and cortex also play a role in the neurobiology. With regard to the neurochemistry of this disorder it is known that gamma amino butyric acid (GABA) is involved however, the precise role of GABA in PTSD and how stress changes GABA concentrations in the brain are still not fully understood. Another aspect regarding PTSD that has not been clearly defined is the treatment of PTSD. Classic anxiolytics such as diazepam is expected to relieve the anxiety linked with PTSD. Studies with this group of drugs have however not produced the concrete evidence needed to establish it as a treatment of choice for PTSD and subsequently other classes of drugs have been investigated as possible treatment options for PTSD. Among these is lamotrigine, which in a clinical study was found to be effective in alleviating symptoms of PTSD. Moreover, a possible pharmacokinetic-pharmacodynamic relationship for each of these drugs has also not been elucidated. In order to elude on some of these uncertainties, an animal model of PTSD, time dependent sensitisation (TDS), was used. GABA levels in the rat hippocampus and frontal cortex were determined at two different time intervals following the TDS procedure (1 day and 7 days post re-stress). High performance liquid chromatography (HPLC) with electrochemical (EC) detection was used to determine gamma amino butyric acid (GABA) concentrations. To investigate the possible anxiolytic effects of diazepam and lamotrigine in this model, as well as a possible pharmacokinetic-pharmacodynamic relationship for each drug, pharmacokinetic profiles for both drugs were established in order to find the times of peak and trough levels of each drug. Blood samples were collected at different time intervals after drug administration either from the tail vein of rats (lamotrigine) or directly from the heart (diazepam). Subsequently, drug concentrations at each time interval were determined by means of HPLC with ultraviolet (UV) detection. The behaviour of rats was analysed using the elevated plus-maze (EPM) at peak or trough concentrations of the drugs and this was performed after either acute administration of the drug, or after a 14 day chronic treatment regime. GABA levels in the hippocampus were not found to change statistically significantly in response to stress at either 1 day or 7 days post re-stress. In the frontal cortex, however, GABA levels increased in response to stress at 1 day post re-stress, with a statistically insignificant, but strong trend towards an increase, at 7 days post re-stress. With regard to the pharmacokinetic profiles, the peak concentration of diazepam was found to occur at 60 minutes, with lamotrigine's peak at 120 minutes. The behavioural studies indicated that acute treatment with diazepam 3 mg/kg resulted in a statistically significant increase in both ratio open arm entries and ratio time spent in the open arms at peak level of the drug. After acute treatment with diazepam 3 mg/kg a statistically significant decrease in ratio time spent in open arms was also found when the ratio time spent in open arms at peak level of the drug and the ratio time spent in open arms at trough level of the drug was compared. In response to chronic treatment with diazepam 3 mg/kg for 14 days, test animals exhibited an increase in the ratio open arm entries at trough level of the drug, with a statistically insignificant yet definite trend towards an increase at peak level. Acute treatment with lamotrigine 10 mg/kg resulted in no statistically significant change in EPM parameters. In response to chronic treatment, however, a statistically significant increase was found in ratio time spent in open arms at peak level of the drug, with a statistically insignificant trend towards an increase at trough level. From the results of this study, we may therefore conclude that GABA-levels in the brain are definitely affected, but in different ways, following TDS-stress. A pharmacokinetic-pharmacodynamic relationship between the drugs' levels and aversive behaviour could also be established. Furthermore it appears that more sustained anxiolytic effects are evident following chronic treatment with both drugs than with acute administration of these drugs. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2006

Posttraumatic stress disorder (PTSD) is an anxiety disorder that may follow exposure to severe emotional trauma and presents with various symptoms of anxiety, hyperarousal and cognitive anomalies. Interestingly, only 10-30% of an exposed population will go on to develop full-blown PTSD. Cholinergic neurotransmission is implicated in anxiety as well as other typical manifestations of PTSD, particularly cognitive changes. The frontal cortex and hippocampus regulate and in turn are affected by stress, and have also been implicated in the underlying neuropathology of PTSD. These areas are densely innervated by cholinergic neurons originating from the basal forebrain. In this study, the time dependent sensitization (TDS) model was used to induce symptoms of PTSD in animals. The study was designed to determine the long-term effects of an intense, prolonged aversive procedure on central muscarinic acetylcholine receptor (mAChR) characteristics and the correlation if any of those findings to cognitive aspects and general arousal as characteristics associated with PTSD. In order to achieve this goal, male Sprague-Dawley rats were exposed to the TDS stress paradigm with behavioral/neuro-receptor assessments performed on day 7 post re-stress (duration of each experiment in whole is 14 days). Acoustic startle reflex (ASR) was used to determine emotional state (hyperarousal), while the conditioned taste aversion (CTA) paradigm was implemented in order to assess aversive memory. Muscarinic receptor binding studies were performed in the frontal cortex and hippocampus. Moreover, both the stress-exposed and control animals were pre-tested in the acoustic startle chamber in order to attempt to separate stress sensitive from stress-resilient animals based on predetermined ASR criteria. The ASR niodel was previously validated in our laboratory, while the CTA model was validated in this project before application. In the CTA model, an i.p. injection with lithium chloride (LiCl) (associated with digestive malaise), was used as unconditioned stimulus (US) and was paired with a saccharinlcyclamate drinking solution as conditioned stimulus (CS) to induce aversion to the novel taste (CS) when presented in the absence of the US. Population data of animals tested in the ASR experiment indicated no statistical significant difference between stressed and control animals. However, when each animal was assessed individually, 22.5 % of the exposed population displayed all increase above the predetermined criteria of 35 % in startle response, indicating a state of heightened arousal. In contrast, only 4.2 O h of control animals (no stress) displayed an increase in arousal based on the above mentioned criteria. Muscarinic receptor densities (Bm,) in the total population of animals exposed to stress showed a statistical significant increase in both the hippocampus and frontal cortex when compared to controls, with no changes in & values observed in either one of the areas. In the CTA experiment, TDS stress was implemented as US paired with a saccharinlcyclamate drinking solution as CS. An acute session of prolonged stress (as used in the TDS model) effectively induced aversion to a novel taste and a subsequent reminder of the stress (restress) paired with the CS sustained the acquire adversive memory. Furthermore, LiCl was reintroduced as US in order to assess the effect of prior exposure to two types of stress (acute and TDS) on subsequently acquired CTA memory. Prior exposure to acute stress had no significant effect on subsequently acquired aversive memory when measured either 3- or 7 days post-conditioning (CS-US). Stress-restress (TDS) exposure, however, indicated a significant decrease in aversive memory from 3- to 7 days post-conditioning (CS-US) as well as a significant decrease in aversive memory between the control- and the TDS group 7 days post-conditioning. The mAChR density (B,,) in the frontal cortex; but not in the hippocampus, was elevated at the same point in time (7 days post CS-US pairing) that CTA memory was impaired following TDS stress (stress-restress). Ultimately, these data support an association between altered cholinergic receptors and hyperarousallanxiety in an animal model of PTSD. The data also support the phenomenon of individual susceptibility to stress in animals that parallels that observed in humans exposed to severe trauma. Impaired aversive memory (CTA) is a consequence of prior exposure to TDS stress, but not acute stress, and is likewise mediated by an altered central cholinergic transmission displayed as an increase in mAChRs in the frontal cortex. The lack of studies regarding the influence of the cholinergic system in PTSD related behavior earns ,this project value as inimitable PTSD research. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2007.

[pt] Este estudo investiga o envolvimento do córtex pré-frontal medial ventral nos comportamentos de defesa inatos e aprendidos em paradigmas de condicionamento de medo e estimulação elétrica intracraniana em ratos. A lesão cortical aumentou significativamente o comportamento defensivo condicionado. No comportamento defensivo incondicionado, a lesão cortical diminuiu significativamente o congelamento pós-fuga dos animais. Os resultados replicam os dados da literatura científica a respeito do papel do córtex infralímbico como uma estrutura inibitória do estímulo condicionado em um circuito amidaloide de medo condicionado, e indicam uma participação do córtex pré-frontal na modulação dos comportamentos de defesa originários da estimulação da MCPd, em especial a sustentação do congelamento motor pós fuga. / [en] This study investigates the role of the prefrontal cortex in the innate and conditioned defensive behaviors in rats during classical conditioning and intracranial electrical stimulation procedurals. It was found that the cortical lesion augmented the conditioned freezing behavior to contextual fear cues. On the other hand, the lesions impaired the motor freezing presented after the escaping provoked by dPAG stimulation. These results replicate the findings from the literature about a prefrontal cortex role as an inhibitory structure in the aversive classic conditioning circuitry, as well as presenting a role for it in modulating freezing behavior in a panic circuitry involving the dPAG, especially regarding its function as a possible short term memory device for innate fear expression.

O córtex pré-frontal medial (PFCm) é caracterizado por entradas glutamatérgicas e dopaminérgicas que convergem sobre os mesmos neurônios alvos. Devido à escassa informação sobre as bases anatômicas das interações entre a dopamina (DA) e o glutamato (Glu), mapeamos a distribuição de subunidades (Su) de receptores (Rs) de Glu do tipo AMPA, NMDA e kainato no PFCm e investigamos a sua expressão em neurônios contendo a fosfoproteína DARPP-32 e em interneurônios. Os resultados mostram que as Su GluR2/3 dos Rs do tipo AMPA são as mais amplamente distribuídas no PFCm e expressas em todos os neurônios DARPP-32+. GluR2/3 é também amplamente co-localizado com as Su NMDAR1 dos Rs de Glu do tipo NMDA e GluR5/6/7 dos Rs do tipo kainato. Em contraste, as Su GluR1 e GluR4 são somente fracamente expressos no PFCm e não são co-localizados com DARPP-32, porém com GABA ou parvalbumina. Os resultados indicam que as Su GluR2/3, NMDAR1 e GluR5/6/7 são amplamente expressos em neurônios piramidais DARPP-32+ enquanto GluR1 e GluR4 são predominantemente expressos em interneurônios do PFCm. / The medial prefrontal cortex (PFCm) is characterized by glutamatergic and dopaminergic afferents that converge on the same target neurons. Since there is only limited information about the anatomical bases for interactions between dopamine (DA) and glutamate (Glu), we mapped the distribution of AMPA, NMDA and kainate Glu receptor (Rs) subunits (Su) in the PFcm and investigated their expression in neurons containing the phosphprotein DARPP-32 and in interneurons. Results show that the Su GluR2/3 of AMPA type Rs are the most prominently distributed in the PFCm and expressed in all neurons DARPP-32+. GluR2/3 is also widely co-localized with the NMDA type Su NMDAR1 and the Kainate Su GluR5/6/7. In contrast, the Su GluR1 and GluR4 are only weakly expressed in the PFCm and are not colocalized with DARPP-32 but with GABA or parvalbumin. Results indicate that the Su GluR2/3, NMDAR1, and GluR5/6/7 are prominently expressed in DARPP-32+ pyramidal neurons, whereas GluR1 and GluR4 are predominantly expressed by interneurons in the PFC.

In der vorliegenden Habilitationsschrift wurde eine Serie von Studien zusammengefasst, die menschliches räumliches Arbeitsgedächtnis, den "Visuospatialen Skizzenblock", untersucht haben. Dieses Kurzzeitgedächtnissystem ist häufig im Rahmen von Erkrankungen des frontalen Kortex und seiner mit ihm verbundenen Hirnareale, z.B. dem Morbus Parkinson, dem Morbus Alzheimer oder der Schizophrenie, beeinträchtigt und für einen relevanten Teil der kognitiven Defizite dieser Patienten verantwortlich. Wir untersuchten sowohl Gesunde als auch Patienten mit fokalen Läsionen des Gehirns mit Varianten des "Gedächtnissakkaden"-Paradigmas, einem etablierten okulomotorischen Verfahren zur Untersuchung von Raumgedächtnis. Es wurden sowohl behaviorale Aspekte von Arbeitsgedächtnis als auch mögliche anatomische Substrate dieses Gedächtnissystems sowie zeitstabilerer "Langzeit"-Gedächtnissysteme untersucht. Ziel war es, klarere Korrelationen zwischen messbarem Verhalten einerseits und Anatomie/Physiologie von Raumgedächtnis andererseits zu etablieren. Wir konnten erstmals zeigen, dass menschliches räumliches Arbeitsgedächtnis selektiv für aktuelles Verhalten relevante Wahrnehmungsinhalte repräsentiert. Der Zugang verhaltensirrelevanter Rauminformationen zu räumlichem Arbeitsgedächtnis wird offenbar durch effiziente (Aufmerksamkeits-) Filtermechanismen verhindert. Für die Existenz solcher Filtermechanismen gab es bislang nur elektrophysiologische Belege im Tiermodell. Da die Speicherkapazität von Arbeitsgedächtnis gering ist, erlauben diese Filtermechanismen möglicherweise einen effizienteren Umgang mit der Fülle und Komplexität unserer Umwelt. Umgekehrt lässt die in unserem Experiment sichtbar gewordene enge Verzahnung von Arbeitsgedächtnis und Aufmerksamkeit die Hypothese zu, dass eine gestörte Arbeitsgedächtniskapazität sowohl durch eine primäre Beeinträchtigung der Speichermechanismen selbst als auch durch Störungen der attentionalen Kontrolle derselben zustande kommen kann. Des weiteren konnten wir erstmals zeigen, dass menschliches räumliches Arbeitsgedächtnis eine klare Zeitgrenze hat, die für einzelne räumliche items bei ungefähr 20 Sekunden liegt. Jenseits dieser Zeitgrenze scheint eine vom Arbeitsgedächtnis unabhängige Raumrepräsentation für menschliches Verhalten bedeutsam zu werden. Der Begriff "Arbeitsgedächtnis" sollte also für Gedächtnisaufgaben reserviert bleiben, deren Gedächtnisphase 20 Sekunden nicht überschreitet. Unsere Befunde zeigen weiterhin, dass bei ansonsten konstantem Design einer Gedächtnisaufgabe, die Dauer der Gedächtnisphase bereits wesentlich darüber entscheidet, welches Gedächtnissystem untersucht wird. Die von uns durchgeführten Läsionsstudien an Patienten und neurophysiologischen Studien an Gesunden bestätigen, dass räumliches Arbeitsgedächtnis durch ein Netzwerk kortikaler Areale kontrolliert wird, das unter anderem den Dorsolateralen Präfrontalen Kortex, den Posterioren Parietalen Kortex und das Frontale Augenfeld umfasst. Innerhalb dieses Netzwerks nehmen diese Areale jedoch klar verschiedene kognitive Partialfunktionen wahr. Der Dorsolaterale Präfrontale Kortex und der Posteriore Parietale Kortex scheinen in erster Linie der Repräsentation von Raum in perzeptuellen Koordinaten, d.h. einem räumlichen "Wahrnehmungsbild" zu dienen, mit einer nur kurzfristigen Rolle des Posterioren Parietalen Kortex und einer dominierenden Rolle des Dorsolateralen Präfrontalen Kortex während der Gedächtnisphase einer Arbeitsgedächtnisaufgabe. Das Frontale Augenfeld scheint der Repräsentation von Raum in okulomotorischen Koordinaten zu dienen, d.h. der kurzzeitigen Speicherung einer geplanten okulomotorischen Antwort auf einen räumlichen Wahrnehmungsinhalt. Schließlich sprechen unsere Ergebnisse dafür, dass es mit dem Wechsel von Arbeitsgedächtnis zu einer zeitstabileren Raumrepräsentation bei Gedächtnisphasen von mehr als 20 Sekunden Länge auch zu einem Wechsel der anatomischen Substrate von Raumgedächtnis kommt. Die von uns durchgeführten Läsionsstudien zeigen, dass jenseits der Zeitgrenzen von räumlichem Arbeitsgedächtnis neokortikale Areale des Medialen Temporallappens eine aktive Rolle für Raumgedächtnis spielen. Hier konnten wir erstmals zeigen, dass der menschliche Parahippokampale Kortex eigenständige und vom Hippokampus unabhängige Raumgedächtnisfunktionen wahrnimmt. Möglicherweise ist diese Region das Substrat eines intermediären Gedächtnissystems zwischen räumlichem Arbeitsgedächtnis und Hippokampus-abhängigem Langzeitgedächtnis. Es wird ferner deutlich, dass in einer Gedächtnisaufgabe allein durch die Wahl verschiedener Dauern der Gedächtnisphase verschiedene anatomische Substrate von Gedächtnis untersucht werden können. Die in dieser Habilitationsschrift zusammengefassten Studien zeigen am Beispiel des räumlichen Arbeitsgedächtnisses, dass es möglich ist, mit einfachen physiologischen Paradigmen Gedächtnissysteme am Menschen zu untersuchen. Bestimmte mnestische Subfunktionen lassen sich mit den hier verwandten Paradigmen präzise quantifizieren und bestimmten Hirnregionen zuordnen. Wir glauben, dass dieser methodische Ansatz sowohl eine präzisere Diagnostik von kognitiven Defiziten bei Hirnerkrankungen erlaubt, als auch die Möglichkeit eröffnet, die Therapie von Gedächtnisstörungen effektiv zu kontrollieren. / This publication summarizes a series of experimental studies examining spatial working memory, the "visuospatial scratch pad", in humans. This short-term memory system is frequently affected in disorders involving the frontal cortex and connected subcortical structures, e.g. in Parkinson's disease, Alzheimer's disease or schizophrenia. Healthy human subjects and patients with focal cerebral lesions were tested with a series of "memory-guided saccade" paradigms, i.e. oculomotor spatial memory tasks. We examined both behavioural aspects and possible anatomical substrates of spatial working memory and more stable "long-term" memory systems. Our aim was to clarify the relationship between behavioural measures of spatial memory and its neuronal substrates. In a first experiment, we were able to show that visuospatial working memory selectively represents behaviourally relevant information. Access of irrelevant visuospatial information to working memory appears to be prevented by efficient attentional filters. Facing the limited storage capacity of spatial working memory, these filters may allow for successful behaviour in perceptually complex environments. Furthermore, the tight coupling of spatial attention and spatial working memory allows for the conclusion, that spatial working memory deficits in patients may likewise result from deficient storage systems and deficient attentional control. In a second experiment, we were able to demonstrate a clear temporal limit of about 20 seconds for spatial working memory. Beyond this temporal limit, an independent and more stable spatial memory system, less susceptible to the passage of time, becomes behaviourally relevant. Thus, the term "working memory" should be confined to spatial memory tasks where the memory delay does not exceed 20 seconds. In addition, these results show that selection of a certain memory delay in a given spatial memory task is a decisive factor when examining spatial memory systems. A third series of lesion studies in patients and neurophysiological experiments in healthy subjects confirmed that cortical control of spatial working memory involves dorsolateral prefrontal cortex, posterior parietal cortex and frontal eye field. Within this network, the dorsolateral prefrontal cortex and posterior parietal cortex appear to store spatial information in perceptual coordinates, with a transient role of the posterior parietal cortex at the very beginning of the memory delay and a dominating role of the dorsolateral prefrontal cortex for most of the delay. By contrast, the frontal eye field appears to store spatial information in oculomotor coordinates, i.e. to maintain a prepared eye movement to a remembered target location across a delay. A fourth series of lesion studies in patients showed that spatial memory for delays longer than 20 seconds is controlled by anatomical substrates distinct from those controlling spatial working memory. Beyond the temporal limits of spatial working memory, neocortical regions of the medial temporal lobe appear to contribute significantly to spatial memory. Within these neocortical regions, the parahippocampal cortex may carry spatial memory functions independent of the hippocampal formation and distinct from spatial working memory. We propose that this region is the neuronal substrate of an intermediate memory system, linking spatial working memory and spatial long-term memory both functionally and anatomically. Moreover, these results show that selection of a certain memory delay in a given spatial memory task is a decisive factor when examining neuronal substrates of spatial memory. Taken together, our experiments show that human memory can effectively be investigated with simple physiological paradigms. Spatial memory functions can precisely be quantified with oculomotor paradigms and related to defined anatomical substrates. This approach may allow for precise diagnosis of cognitive deficits and efficient monitoring of treatment of memory disorders.

Les inhibiteurs sélectifs de recapture de la sérotonine (5-HT) (ISRS) bloquent directement le transporteur de la 5-HT (SERT) et stimulent indirectement de multiples auto- et hétérorécepteurs5-HT par l’augmentation de la concentration extracellulaire de 5-HT dans la fente synaptique. Cependant, le rôle des différents récepteurs ainsi que leur interaction dans les effets thérapeutiques des ISRS restent mal connus. Nous avons tenté de les identifier à l'aide de tests neurochimiques (microdialyse intracérébrale in vivo) et électrophysiologiques en utilisant une approche pharmacologique (utilisation de escitalopram, de ligands des récepteurs 5-HT1A/2A) et génétique (utilisation de souris knock-out [KO] SERT, 5-HT1A ou 5-HT2A). Les études neurochimiques et électrophysiologiques révèlent que les auto-(1A) et hétéro-(2A) récepteursagissent de concert pour maintenir une influence inhibitrice sur le système sérotoninergique, en particulier, en réponse au escitalopram : l'absence d'un récepteur est compensée par une régulation de l'autre. Enfin, les souris KO SERT constituent un nouveau modèle pour tester le mécanisme du escitalopram dans l’augmentation des concentrations de noradrénaline (NA). / Selective serotonin (5-HT) reuptake inhibitors (SSRIs) directly block the 5-HT transporter(SERT) and indirectly stimulate multiple 5-HT (auto- and hetero-) receptors by enhancing itsextracellular levels in the synaptic cleft, although the role of particular receptors as well asinteraction(s) among different receptors in the therapeutic effects of SSRIs is not fullyunderstood. We tried to highlight it using neurochemical (in vivo intracerebral microdialysis) andelectrophysiological tests with a pharmacological (using escitalopram, 5-HT1A/2A receptorsagonists and antagonists) and genetic (using SERT, 5-HT1A ou 5-HT2A receptor knock-out [KO]mice) approaches. Neurochemical and electrophysiological experiments indicated that 5-HT1Aauto- and 5-HT2A hetero-receptors act in concert to maintain an inhibitory influence on theserotonergic system, particularly in response of escitalopram to increased levels of endogenous 5-HT: the absence of one receptor being compensated by an up-regulation of the other. Finally,SERT knockout mice might be a new model to test the mechanism of escitalopram for anincrease of norephedrine (NE) level.

Notre environnement est complexe et changeant, ce qui apporte de l'incertitude dans les décisions de tous les jours. La capacité de détecter et résoudre l'incertitude est cruciale pour un comportement flexible et adapté. Notre hypothèse est que l'efficacité et la flexibilité comportementale en situation d'incertitude dépendent de la façon dont l'individu a appris à apprendre. Dans une 1ère étude, trois singes ont acquis un learning set pour une tâche aux règles stochastiques et changeantes. Leur réactivité aux évènements inattendus a augmenté lors de l'apprentissage, suivant l'évolution du degré d'incertitude environnementale. Cela a permis un transfert sans coût à une tâche plus complexe partageant la même structure, suggérant que les singes ont appris à apprendre la structure statistique de l'environnement. Nous avons ensuite étudié les mécanismes cérébraux sous-jacents à ce comportement flexible. Deux animaux ont reçu un implant d'électrocorticographie, sur les aires frontales et pariétales. Nous montrons d'abord, avec les données d'un animal, que des potentiels évoqués au feedback sont sensibles à la valence et au degré de surprise du feedback, et prédisent la stratégie à venir. Ensuite, nous présentons des résultats préliminaires montrant que des oscillations dans les bandes beta et thêta sont présentes au moment du feedback et de la décision, et que leur puissance est modulée de manière différente par les facteurs de la tâche. Ces résultats contribuent à révéler la complexité du réseau frontal pour la flexibilité comportementale, et ouvrent la voie à de nouvelles expériences pour comprendre comment ces mécanismes sont façonnés au cours du processus d'apprendre à apprendre / Our environment is both complex and changing, which triggers uncertainty in every decision we make. The ability to detect and solve the resulting uncertainty is crucial for adapted and flexible behavior. Our hypothesis is that behavioral efficiency and flexibility in an uncertain environment depend on the way the agent has learnt to learn. In a first study, 3 macaque monkeys developed a learning-set for a task with stochastic and changing rules. Monkey’s reactivity to unexpected feedback increased across learning and paralleled the evolution of the degree of environmental uncertainty. This enabled them to transfer, without cost, to a more complex task with the same structure, suggesting that they learned to learn the statistical structure of the environment. We then studied the cerebral mechanisms underpinning this flexible behavior. Two animals were implanted with an electrocorticography implant over the frontal and parietal areas. We first showed, using data from one animal, that feedback related potentials were sensitive to feedback valence and unexpectedness, and predictive of the upcoming behavioral strategy. Then, we present preliminary results showing that oscillations in the beta and theta bands can be recorded at the time of feedback and at the time of decision, and that their power is modulated differently depending on the various task factors. These results contribute to reveal the complexity of the frontal cortical network enabling behavioral flexibility and open new horizons for future research to understand how these mechanisms are shaped throughout the learning to learn process

La stimulation transcrânienne par courant continu (tDCS) sert à moduler l’activité neuronale. Elle consiste à appliquer un faible courant constant entre deux électrodes placées sur le cuir chevelu. Deux montages semblent efficaces pour moduler les capacités cognitives et/ou soulager des symptômes cliniques. Cependant, les effets neurobiologiques de la tDCS sont encore mal connues. Ce travail de thèse a tenté de clarifier les mécanismes cérébraux de la tDCS chez les sujets sains, en particulier en lien avec le système dopaminergique. En utilisant un design randomisée en double aveugle, nous avons combiné une session de tDCS online avec plusieurs modalités d'imagerie (PET ou PET-IRM simultanée) chez le sujet au repos. Une première étude (n=32, 2mA, 20min) a montré que la tDCS bifrontale induit une augmentation de la dopamine extracellulaire dans le striatum ventral, impliqué dans le réseau de récompense-motivation, après la stimulation. Une seconde étude (n=30, 1mA, 30min) a montré que la tDCS fronto-temporale induit une augmentation de la dopamine extracellulaire dans la partie exécutive du striatum et une diminution de la perfusion dans une région du réseau du default mode (DMN), après la stimulation. L'analyse des données de cette étude est toujours en cours. Dans l’ensemble, ce travail fournit la preuve qu'une seule session de tDCS frontale peut impacter le système dopaminergique dans des régions connectées aux zones corticales stimulées. Par conséquent, les niveaux d'activité et réactivité dopaminergique doivent être de nouveaux éléments à considérer dans l’hypothèse globale de modulation de l’activité cérébrale par la tDCS frontale / Transcranial direct current stimulation (tDCS) is used to modulate neuronal activity in the brain. It consists in applying a small constant current between two electrodes placed over the scalp. Two frontal tDCS montages have shown promises in modulating cognitive abilities and/or helping to alleviate clinical symptoms. However, the effects of tDCS on brain physiology are still poorly understood. The aim of this thesis work was to clarify brain mechanisms underlying frontal tDCS in healthy subjects, specifically in relation to the dopaminergic system. Using a double blind sham-controlled design, we combined a single session of tDCS online with several imaging techniques (PET or simultaneous PET-MRI) with the subject at rest. A first study (n=32, 2mA, 20min) showed that bifrontal tDCS induced an increase in extracellular dopamine in the ventral striatum, involved in the reward-motivation network, after the stimulation period. A second study (n=30, 1mA, 30min) showed that fronto-temporal tDCS induced an increase in extracellular dopamine in the executive part of striatum as well as a decrease in perfusion in a region part of the default mode network (DMN), after the stimulation period. The data analysis of this study is still ongoing. Overall, the present work provides evidence that a single session of frontal tDCS impacts the dopaminergic system in regions connected to the stimulated cortical areas. Therefore, levels of dopamine activity and reactivity should be new elements to consider for a general hypothesis of brain modulation by frontal tDCS

Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2006.