Des études récentes ont montré que le noyau caudé interagissait avec le cortex préfrontal et qu’il pourrait être impliqué dans les fonctions exécutives. Le but de cette thèse était d’étudier la contribution du noyau caudé dans les fonctions exécutives, plus précisément dans des tâches de monitoring et de changement de règle, et d’observer comment ces régions fronto-striatales interagissent avec le réseau par défaut (RPD). Dans un premier temps, nous avons étudié le rôle du noyau caudé dans les deux types de monitoring : le monitoring d’origine interne, consistant à effectuer un suivi sur l’état de l’information en mémoire de travail afin de pouvoir faire un choix subséquent, et dans le monitoring d’origine externe où le suivi sur l’état des items est effectué par l’individu, mais la sélection est exécutée par une source externe. Il a été montré que le cortex préfrontal dorsolatéral (CPFDL) est impliqué dans les deux types de monitoring. À l’aide de l’imagerie par résonance magnétique fonctionnelle (IRMf), nos résultats ont montré une augmentation significative du signal BOLD au niveau du CPFDL dans les contrastes des conditions de monitoring d’origine interne et monitoring d’origine externe par rapport à la condition contrôle. De manière plus importante, une augmentation significative de l’activité a été observée dans le noyau caudé seulement dans les soustractions impliquant le monitoring d’origine interne par rapport à la condition contrôle, et par rapport à la condition de monitoring d’origine externe. En deuxième lieu, des études ont montré une contribution spécifique des régions fronto-striatales dans l’exécution d’un changement de règle. Toutefois, l’effet d’un changement de règle sur l’activité cérébrale n’a jamais été étudié sur les essais subséquents. À l’aide de l’IRMf, le cortex préfrontal ventrolatéral (CPFVL) et le noyau caudé ont montré une augmentation significative de leur activité lors des changements de règle continus et lors des changements de règles sporadiques par rapport à la condition contrôle, et aussi lors des essais où le maintien d’une même règle devait être effectué pour une courte durée par opposition au contrôle. Cependant, aucune activité fronto-striatale n’a été observée lorsqu’une même règle devait être appliquée pour une plus longue période. De plus, une diminution significative de l’activité du noyau caudé a été observée lors de la répétition de l’exécution d’une même règle suggérant une meilleure intégration de cette dernière. Finalement, plusieurs études ont montré une déactivation du RPD lors de l’exécution de tâches. À l’aide de l’IRMf, nous avons posé l’hypothèse que le RPD serait corrélé négativement avec les régions fronto-striatales lors de l’exécution d’une tâche de changement de règle. Nos résultats montrent une augmentation significative de l’activité des régions fronto-striatales lors d’une augmentation du nombre d’essais de changement de règle consécutif, pendant que le RPD montre une déactivation continue. De façon intéressante, pendant que les régions fronto-striatales montrent une diminution de leur activité lors de l’exécution d’une même règle pour une longue période, le RPD augmente son activité de façon significative. On conclut donc que le noyau caudé joue un rôle important dans la planification d’une nouvelle action lorsque plusieurs possibilités doivent être considérées en mémoire de travail, et ce en même temps. Finalement, le RPD montre une corrélation négative avec les régions fronto-striatales suggérant sa participation dans l’intégration d’une tâche devenant de plus en plus familière. / Recent studies have shown that the caudate nucleus interacts with the prefrontal cortex, and that it is involved in executive processes. The goal of the thesis was to investigate the role of the caudate nucleus in executive processes, and to observe how the frontostriatal regions are interacting with the default mode network (DMN). Firstly, we studied the role of the caudate nucleus in self-ordered monitoring, which consist of keeping track of which stimuli have been selected and which remains to be selected, and externally-triggered monitoring, which refers to keeping track of one’s selection when an external source is performing the selection. It has been shown that de dorsolateral prefrontal cortex (DLPFC) was particularly involved in both types of monitoring. Using functional magnetic resonance imaging (fMRI), a significant increase of activity has been observed in the DLPFC during both monitoring conditions vs control condition. Importantly, significant increased activity in the caudate nucleus was observed only in subtractions involving self-ordered monitoring (the self-ordered vs control and self-ordered vs externally-triggered conditions). Secondly, previous studies have shown a specific contribution of frontostriatal regions during set-shifting. However, the effect of set-shifting on subsequent trials had yet to be determined. Using fMRI, significant increase of activity was observed in the ventrolateral prefrontal cortex (VLPFC) and the caudate nucleus during shifting trials versus control and in trials where the same rule was applied for a few trials before a set-shift occurred. However, no frontostriatal activity was observed when the same rule was applied for a longer period. Decreased activity in the caudate nucleus correlated with increasing trial position in trials where no set-shift occurred, suggesting that the more a rule is executed, the better it is established. Finally, several studies have shown a deactivation of the DMN during the execution of a goal-directed task. Using fMRI, we hypothesized that the DMN was negatively correlated with the frontostriatal regions during the execution of a set-shifting task. Our results showed a significant increase of activity in the frontostriatal regions as more set-shifts are being performed while the DMN gets more deactivated. Interestingly, as decreased activity was observed in the frontostriatal regions during the execution of the same rule for a long period, the DMN showed increasing activity. We concluded that the caudate nucleus is specifically involved during the planning of a novel action when several possibilities are available at the same time. Finally, the DMN shows a negative correlation with the frontostriatal regions suggesting its contribution to the execution of a more familiar task.

No description available.

This thesis extends the understanding of the neural and neurochemical contributions to two forms of behavioural adaptation, reversal learning and contingency degradation, in which stimulus/action-reward contingencies are altered. The results are interpreted within the psychological framework of the compulsivity construct, and their implications for the pathological behaviour of obsessive-compulsive-disorder (OCD) are considered. The orbitofrontal cortex (OFC) and striatum are key brain structures involved in reversal learning, as are the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA) within those respective regions. However, there has been little empirical evidence of how these two structures and neurochemical systems interact, especially in the functional context of reversal learning. In Chapter Three, the impact of experimentally-induced reductions of 5-HT in the anterior OFC on monoamine levels in subcortical structures such as the striatum and amygdala was determined, DA being found to be significantly up-regulated in the amygdala. Functionally, 5-HT depletion of the OFC has previously been shown to induce deficits in reversal learning. To determine the possible causal significance of amygdala dopamine up-regulation for said reversal learning deficit, the effects of blocking the upregulation with the infusion of intra amygdala DA receptor antagonists following bilateral OFC 5-HT depletion were investigated in a reversal learning paradigm. In Chapter Four, the differential roles of regions of striatum were examined in visual reversal learning. Two recent investigations in non-human primates highlighted the role of the striatum in reversal learning,but pinpointed the critical region to be either the ventromedial caudate or the putamen. Marmosets were trained on a serial reversal task that allowed multiple acute neural manipulations, and the ventromedial caudate and putamen were then reversibly inactivated using the GABAA agonist muscimol. Results indicated dose-related impairments specifically in reversal learning within the putamen, with sparing of discrimination retention. By contrast, similar reversible inactivation of the caudate nucleus produced marked deficits in visual discrimination performance (retention). In Chapter Five, the neural basis of action-outcome contingency knowledge was investigated by inactivating distinct regions of the PFC, the perigenual ACC (pgACC; area 32) and the anterior OFC, and determining response sensitivity to the degradation of action-outcome contingencies. In previous work, excitotoxic lesions of either the pgACC or the OFC had been found to induce insensitivity to contingency degradation in marmosets. However, the design of that experiment did not allow specification of whether stimulus- or action-outcome associations were disrupted, and a precise neural locus could not be determined for the behavioural effects as the OFC lesions included parts of the lateral and medial OFC. I therefore developed a novel contingency degradation paradigm that distinguished between stimulus- and action-outcome associations to enable the study of acute pharmacological manipulations in both brain regions. The pgACC and OFC were reversibly inactivated using GABAA-GABAB agonists (muscimol-baclofen). Whereas the pgACC inactivation produced selective deficits in sensitivity to action-outcome contingency degradation, OFC inactivation reduced the suppressive effect of noncontingent reward on responding more generally but left intact sensitivity to degradation of the contingencies. These results are discussed in terms of different theories of the functions of the pgACC and OFC. In the final discussion the findings on the neural substrates of reversal learning and contingency degradation are drawn together in terms of their significance for theories of PFC involvement in cognitive control, and for the understanding of OCD and other neuropsychiatric disorders.

<p>Premenstrual dysphoria, so severe that it affects the lives of the women afflicted, is the condition studied in this thesis. Physiological and pharmacological mechanisms of pathogenetic relevance were investigated. </p><p>Women with premenstrual dysphoria showed a stronger and less dampened response of LH to an estradiol challenge than asymptomatic women, indicating an altered neuroendocrine regulation. In women with premenstrual dysphoria, the LH response was correlated to the severity of irritability and bloating, and the early FSH response was correlated to the severity of depressed mood. </p><p>The positron-emission study showed strong, consistent correlations between worsening of mood symptoms and a decrease in brain trapping of the immediate serotonin precursor, from the mid-follicular to the late luteal phase in women with premenstrual dysphoria. The strongest correlations were seen for the cardinal mood symptoms of premenstrual dysphoria, and for their opposites. Physical symptoms showed weaker or no correlations with the exception of nociceptive symptoms from erogenous body regions which showed positive correlations to serotonin precursor trapping in the right caudate nucleus. The findings are consistent with the serotonin hypothesis of premenstrual dysphoria, and might possibly explain the observed effects of serotonin-augmenting drugs in this condition.</p><p>The partial 5-HT_1A receptor agonist buspirone was superior to placebo in the treatment of premenstrual dysphoria. The weak SRI and 5-HT₂ receptor antagonist nefazodone was not superior to placebo. For women with premenstrual dysphoria in need of medication and who do not tolerate SRIs because of the sexual sideeffects, buspirone may be an alternative drug, since it had no adverse effects on sexual function. </p><p>The prevalence of polycystic ovaries and serum levels of androgens were not higher in women with premenstrual dysphoria than in their asymptomatic counterparts. The findings are not consistent with the hypothesis that irritability in women with premenstrual dysphoria is induced by elevated testosterone levels. </p><p>Thesis results, which are in line with the serotonin hypothesis of premenstrual dysphoria, may imply that increased brain sensitivity is one of the factors underlying severe premenstrual mood symptoms, thereby further supporting a common serotonergic dysregulation in this condition.</p>

Premenstrual dysphoria, so severe that it affects the lives of the women afflicted, is the condition studied in this thesis. Physiological and pharmacological mechanisms of pathogenetic relevance were investigated. Women with premenstrual dysphoria showed a stronger and less dampened response of LH to an estradiol challenge than asymptomatic women, indicating an altered neuroendocrine regulation. In women with premenstrual dysphoria, the LH response was correlated to the severity of irritability and bloating, and the early FSH response was correlated to the severity of depressed mood. The positron-emission study showed strong, consistent correlations between worsening of mood symptoms and a decrease in brain trapping of the immediate serotonin precursor, from the mid-follicular to the late luteal phase in women with premenstrual dysphoria. The strongest correlations were seen for the cardinal mood symptoms of premenstrual dysphoria, and for their opposites. Physical symptoms showed weaker or no correlations with the exception of nociceptive symptoms from erogenous body regions which showed positive correlations to serotonin precursor trapping in the right caudate nucleus. The findings are consistent with the serotonin hypothesis of premenstrual dysphoria, and might possibly explain the observed effects of serotonin-augmenting drugs in this condition. The partial 5-HT1A receptor agonist buspirone was superior to placebo in the treatment of premenstrual dysphoria. The weak SRI and 5-HT2 receptor antagonist nefazodone was not superior to placebo. For women with premenstrual dysphoria in need of medication and who do not tolerate SRIs because of the sexual sideeffects, buspirone may be an alternative drug, since it had no adverse effects on sexual function. The prevalence of polycystic ovaries and serum levels of androgens were not higher in women with premenstrual dysphoria than in their asymptomatic counterparts. The findings are not consistent with the hypothesis that irritability in women with premenstrual dysphoria is induced by elevated testosterone levels. Thesis results, which are in line with the serotonin hypothesis of premenstrual dysphoria, may imply that increased brain sensitivity is one of the factors underlying severe premenstrual mood symptoms, thereby further supporting a common serotonergic dysregulation in this condition.

本研究以神經毒素ibotenic acid破壞不同尾核區域以及鋰鹽去價值程序為操弄變項，觀測此兩種實驗操弄對於大鼠之迷津行為之影響，進而探討標誌系統之行為內涵及神經機制。實驗所採用的作業為線索學習作業以及自我中心作業，分別代表標誌系統下的線索導引策略及體位導向策略。實驗一及實驗二在於檢驗尾核功能缺損對於大鼠迷津行為之影響，從探測嘗試發現大鼠在線索學習的行為表現需依賴砂紙線索的導引，而在自我中心作業之行為則不以環境刺激為依據（實驗一A、二A），顯示大鼠在各迷津作業的行為符合標誌系統的運作原則。神經機制之操弄結果顯示在記憶習得階段，尾核破壞之受試在線索學習作業上的表現並沒有顯著變差，尾核功能缺損並未導致學習的延宕或阻斷，其進步的速度仍與控制組相同（實驗一B）。相較於線索學習作業，尾核破壞之受試在自我中心作業上的表現則明顯變差，幾乎沒有進步的趨勢（實驗二B）。而在記憶保持階段，不管是線索學習作業或自我中心作業之表現皆會因尾核破壞而顯著變差（實驗一C、二C）。實驗三及實驗四則利用鋰鹽去價值程序降低食餌之誘因價值，觀測大鼠行為有無相對應改變。結果發現去價值程序的操弄只會影響到大鼠在自我中心作業的行為表現（實驗四），而不影響其在線索學習作業之行為（實驗三）。由此可知，兩種迷津作業所形成的記憶表徵是不同的，自我中心學習歷程會將增強物表徵在聯結單位中，而線索學習之習得歷程則不會。綜合上述實驗結果，標誌系統下確實有兩個不同空間行為機制，一個為線索導引策略，另一個為體位導向策略，雖皆受到尾核的調節，但調節的程度是不同的。不管是記憶習得或保持階段，尾核在體位導向策略的運作中皆扮演重要的角色，而在線索導引策略只參與了記憶保持歷程的運作。另外，兩個空間行為機制在學習內涵上也不盡相同，以線索導引策略為依據之空間行為會形成刺激反應(S-R)的聯結型態，而以體位導向策略為依據之空間行為則會形成反應及增強物(R-S*)聯結。 / This study investigated the neurobehavioral mechanisms of taxon system of spatial memory through manipulating lesions of subareas in the caudate nucleus by ibotenic acid and lithium chloride (LiCl)-induced reward devaluation. With respect to behavioral measurement in an eight-arm radial maze, a cue learning task and an egocentric task were used for testing the guidance and orientation hypotheses of taxon system, respectively. Data from probing procedures showed that the performance of rats in the cue learning task was impaired when the cue was removed, but the performance in the egocentric task was not affected by changing the context (Experiments 1A and 2A). These results indicate that behavior reactions in two tasks are corresponding to those two operational principles of taxon system. In terms of the acquisition, deficits were significantly produced by the lesion of the dorsomedial caudate on egocentric task, while the ibotenate lesions did not affect cue learning task (Experiments 1B and 2B). For retention test, the performances in both cue learning and egocentric tasks were impaired by dorsomedial caudate lesion, no such impairment was observed from dorsolateral and posterolateral caudate lesions (Experiments 1C and 2C). In the third and fourth experiments, LiCl devaluation procedure was employed to lower the reward value of the bait in the maze. This manipulation significantly impaired the performance of egocentric task but not that of the cue learning task. These results indicate that the memory representations in the two tasks used in the present study are different. The memory representation in the egocentric task contains the reinforcer, whereas that in the cue learning task is not necessarily relevant to the reinforcer. In conclusion, the guidance and orientation hypotheses can be differentiated as behavioral mechanisms existing in the taxon system of spatial memory. Although the caudate nucleus is critically important for the operation of both hypotheses, the degrees of this brain site to get involved are different. The caudate nucleus participates in the acquisition and retention of orientation hypothesis, but only in the retention of guidance hypothesis. In addition, behavioral performance of the spatial memory using guidance hypothesis is based on forming the association of stimulus and response (S-R), while that using orientation hypothesis is based on forming the association of response and reinforcer (R-S*).