Há décadas os campos magnéticos (CMs) são alvo de investigação científica. Entretanto, o grande corpo de evidências, está relacionado a campos eletromagnéticos e não a campos magnéticos contínuos. Nosso interesse é direcionado para a modulação das respostas comportamentais e motoras, na preservação de neurônios pós-lesão isquêmica e na possibilidade de uma interferência funcional com drogas que modifiquem a neurotransmissão encefálica. Utilizamos 130 Gerbilos, alocados em 13 grupos experimentais. Grupos específicos foram submetidos a isquemia encefálica global bilateral e a implantação de um capacete magnético com potencia de 3200G. Quatro dias após os procedimentos cirúrgicos os animais foram avaliados no monitor de atividades e no Rotarod, após receberem uma injeção de Apomorfina (APO) (2,5mg /kg) ou Racloprida (RAC) (0,9ml/kg). Valor de p significativo <0,05. No monitor de atividades, os animais do grupo isquemia atravessaram o maior número de sensores horizontais (F12,117: 9,39) e verticais (F12,117: 10,60) do que todos os outros grupos. Animais isquêmicos injetados com APO e tratados com campo magnético atravessam um número menor de sensores do que os grupos isquêmicos. Os isquêmicos injetados com APO e estimulados com o polo norte dispararam menos sensores do que os isquêmicos injetados com APO. Animais injetados com RAC com ou sem estimulação magnética disparam menos sensores do que os animais isquêmicos e isquêmicos tratados com polo norte e sul. No teste do Rotarod, o grupo isquêmico apresentou o menor tempo de permanência no teste do que os demais grupos. Ainda, animais isquêmicos tratados com APO e RAC e estimulação magnética pelo polo norte apresentam maior tempo de permanência em relação aos grupos isquemia e isquemia injetado com Apo e RAC (F12,117: 11,29). Nossos dados confirmam a possibilidade de interação dos polos magnéticos e os mecanismos de ação das drogas utilizadas no experimento. / For decades, magnetic fields (CMs) have been the subject of scientific research. However, the great body of evidence is related to electromagnetic fields and not to continuous magnetic fields. Our interest is directed to the modulation of behavioral and motor responses, the preservation of neurons after brain ischemic injury and the possibility of functional interference with drugs that modify brain neurotransmission. We used 130 gerbils, allocated in 13 experimental groups. Specific groups were submitted to bilateral global brain ischemia and the implantation of a magnetic helmet with power of 3200G. Four days after the surgical procedures, the animals were evaluated on the activity monitor and Rotarod after receiving an injection of Apomorphine (APO) (2.5 mg / kg) or Raclopride (RAC) (0.9 ml / kg). Significant p value was set as <0.05. In the activity monitor, the animals in the ischemia group crossed fired the largest number of horizontal sensors (F12,117: 9,39) and vertical sensors (F12,117: 10,60) than all the other groups. Ischemic animals injected with APO and magnetic field fired a smaller number of sensors than the ischemic groups and injected with APO. Animals stimulated with the north pole fired fewer sensors than ischemic animals injected with APO. RAC injected animals, with or without magnetic stimulation fired fewer sensors than ischemic animals or ischemic with north and south magnetic stimulation. In the Rotarod test, the ischemic group had the shortest permanence time in the test than the other groups. Still, ischemic animals treated with APO and RAC and North Pole magnetic stimulation present a longer permanence time in comparison to the ischemia group and ischemia with APO and RAC. Ischemic animals injected with APO and magnetic field pass through a smaller number of sensors than the ischemic groups and injected with APO. In the Rotarod test, the ischemic group had the shortest residence time in the test than the other groups. Still, ischemic animals treated with APO and north pole present a longer residence time in relation to the ischemia groups with APO and RAC (F12,117: 11,29). Our data confirm the possibility of interaction of the magnetic poles and the action mechanisms of action of the drugs used in the experiment.

Há décadas os campos magnéticos (CMs) são alvo de investigação científica. Entretanto, o grande corpo de evidências, está relacionado a campos eletromagnéticos e não a campos magnéticos contínuos. Nosso interesse é direcionado para a modulação das respostas comportamentais e motoras, na preservação de neurônios pós-lesão isquêmica e na possibilidade de uma interferência funcional com drogas que modifiquem a neurotransmissão encefálica. Utilizamos 130 Gerbilos, alocados em 13 grupos experimentais. Grupos específicos foram submetidos a isquemia encefálica global bilateral e a implantação de um capacete magnético com potencia de 3200G. Quatro dias após os procedimentos cirúrgicos os animais foram avaliados no monitor de atividades e no Rotarod, após receberem uma injeção de Apomorfina (APO) (2,5mg /kg) ou Racloprida (RAC) (0,9ml/kg). Valor de p significativo <0,05. No monitor de atividades, os animais do grupo isquemia atravessaram o maior número de sensores horizontais (F12,117: 9,39) e verticais (F12,117: 10,60) do que todos os outros grupos. Animais isquêmicos injetados com APO e tratados com campo magnético atravessam um número menor de sensores do que os grupos isquêmicos. Os isquêmicos injetados com APO e estimulados com o polo norte dispararam menos sensores do que os isquêmicos injetados com APO. Animais injetados com RAC com ou sem estimulação magnética disparam menos sensores do que os animais isquêmicos e isquêmicos tratados com polo norte e sul. No teste do Rotarod, o grupo isquêmico apresentou o menor tempo de permanência no teste do que os demais grupos. Ainda, animais isquêmicos tratados com APO e RAC e estimulação magnética pelo polo norte apresentam maior tempo de permanência em relação aos grupos isquemia e isquemia injetado com Apo e RAC (F12,117: 11,29). Nossos dados confirmam a possibilidade de interação dos polos magnéticos e os mecanismos de ação das drogas utilizadas no experimento. / For decades, magnetic fields (CMs) have been the subject of scientific research. However, the great body of evidence is related to electromagnetic fields and not to continuous magnetic fields. Our interest is directed to the modulation of behavioral and motor responses, the preservation of neurons after brain ischemic injury and the possibility of functional interference with drugs that modify brain neurotransmission. We used 130 gerbils, allocated in 13 experimental groups. Specific groups were submitted to bilateral global brain ischemia and the implantation of a magnetic helmet with power of 3200G. Four days after the surgical procedures, the animals were evaluated on the activity monitor and Rotarod after receiving an injection of Apomorphine (APO) (2.5 mg / kg) or Raclopride (RAC) (0.9 ml / kg). Significant p value was set as <0.05. In the activity monitor, the animals in the ischemia group crossed fired the largest number of horizontal sensors (F12,117: 9,39) and vertical sensors (F12,117: 10,60) than all the other groups. Ischemic animals injected with APO and magnetic field fired a smaller number of sensors than the ischemic groups and injected with APO. Animals stimulated with the north pole fired fewer sensors than ischemic animals injected with APO. RAC injected animals, with or without magnetic stimulation fired fewer sensors than ischemic animals or ischemic with north and south magnetic stimulation. In the Rotarod test, the ischemic group had the shortest permanence time in the test than the other groups. Still, ischemic animals treated with APO and RAC and North Pole magnetic stimulation present a longer permanence time in comparison to the ischemia group and ischemia with APO and RAC. Ischemic animals injected with APO and magnetic field pass through a smaller number of sensors than the ischemic groups and injected with APO. In the Rotarod test, the ischemic group had the shortest residence time in the test than the other groups. Still, ischemic animals treated with APO and north pole present a longer residence time in relation to the ischemia groups with APO and RAC (F12,117: 11,29). Our data confirm the possibility of interaction of the magnetic poles and the action mechanisms of action of the drugs used in the experiment.

Les modèles du contrôle exécutif et du cortex préfrontal accordent une place grandissante au signal de récompense dans la prise de décision. La dopamine pourrait jouer un rôle clé en signalant l'écart entre la récompense reçue et celle qui était prédite (erreur de prédiction de la récompense).<br />Nous avons combiné les méthodes de psychophysique, d'imagerie par résonance magnétique fonctionnelle (IRMf), et de tomographie par émission de positons (TEP) avec un antagoniste des récepteurs dopaminergiques D2/D3 (11C-raclopride) afin d'étudier chez l'homme les mécanismes de l'apprentissage d'une séquence motrice guidé par la récompense. L'IRMf nous a permis d'analyser en détail la dynamique de cet effort mental, impliquant un réseau préfrontal, pariétal et striatal distribué qui s'activait rapidement durant les périodes de recherche de séquences par essais et erreurs et s'effondrait durant les périodes suivantes de répétition routinière. Cet effondrement pouvait être conduit par un processus de déduction élémentaire préalable à la réception de la récompense (autoévaluation).<br />De plus, certaines sous-régions de ce réseau étaient particulièrement engagées dans le traitement de paramètres statistiques de la récompense (l'erreur de prédiction et la quantité d'information).<br />Parallèlement, nous avons développé une méthode récente d'évaluation dynamique de la libération de dopamine in vivo en TEP, et avons montré que la libération de dopamine augmentait bilatéralement au sein du striatum ventral et du noyau caudé durant la tâche de recherche. Afin de valider ces observations et d'évaluer la sensibilité de cette méthode, nous avons mis en oeuvre un paradigme TEP standard (mesure du « binding potential » du raclopride). Celui-ci nous a en outre permis de mesurer une corrélation entre la libération de dopamine dans le striatum ventral droit et les valeurs comportementales des sujets. Ces résultats sont en accord avec l'hypothèse d'un rôle de la dopamine striatale dans l'apprentissage guidé par la récompense chez l'homme.<br />Pour la première fois à notre connaissance, l'emploi combiné de l'IRMf et du marquage des récepteurs dopaminergiques en TEP nous a ainsi permis de considérer à la fois la dynamique de l'activation cérébrale et la « neurochimie cognitive » dans une situation d'effort mental et d'apprentissage guidés par la récompense.

Background: Performing aerobic exercise and maintaining high levels of aerobic fitness may have positive effects on both brain structure and function in older adults. Despite decades of research however, there is still a rather poor understanding of the neurocognitive mechanisms explaining the positive effects of aerobic exercise on cognition. Changes in prefrontal gray matter as well as dopaminergic neurotransmission in striatum are both candidate neurocognitive mechanisms. The main aims of this thesis are: 1. To investigate the effects of aerobic exercise and fitness on cognition and magnetic resonance imaging (MRI) derived gray matter volumes using data from a 6 month physical exercise intervention in older adults (Study I). 2. To simulate the effect of atrophy in longitudinal positron emission tomography (PET) which could pose a challenge to interpreting changes in longitudinal PET imaging (Study II). 3. To study the influence of aerobic exercise and fitness on the dopamine D2-receptor (D2R) system in striatum using [11C]raclopride PET as a potential mechanism for improved cognition (Study III). Results: In Study I, aerobic exercise was found to improve cognitive performance in a broad, rather than domain-specific sense. Moreover, aerobic fitness was related to prefrontal cortical thickness, and improved aerobic fitness over 6 months was related to increased hippocampal volume. In Study II, we identified areas in the striatum vulnerable to the effect of shrinkage, which should be considered in longitudinal PET imaging. Finally, in Study III, the effect of being aerobically fit, and improving fitness levels was found to impact dopaminergic neurotransmission in the striatum, which in turn mediated fitness-induced improvements in working memory updating performance. Conclusion: The findings in this thesis provide novel evidence regarding the neurocognitive mechanisms of aerobic exercise-induced improvements in cognition, and impacts the interpretation of longitudinal PET imaging. Performing aerobic exercise and staying aerobically fit at an older age have positive effects on cognition and brain systems important for memory and cognition. Specifically, fitness-induced changes to the dopaminergic system stands out as one novel neurocognitive mechanism explaining the positive effects of aerobic fitness on working-memory performance in healthy older adults.

本研究為能瞭解多巴胺在壓力源引發個體古典制約行為學習中的參與角色，採用一個與多巴胺相關的場地制約偏好行為作為研究工具，並利用一較溫和的禁錮壓力源作為非制約刺激與場地環境制約刺激進行配對制約。本研究假設內側前額葉皮質處的多巴胺參與在此壓力源引發場地制約行為學習中。實驗一針對單次禁錮壓力源的非制約刺激效果進行檢驗，分別檢測壓力源對個體的生理、情緒或是行為活動量的影響。實驗二利用「同時制約」或是「倒序制約」等兩種制約方式來進行單次禁錮壓力源引發場地制約偏好行為作業，並分別於制約程序的不同時間點施予多巴胺專屬受器拮抗劑，檢驗多巴胺在制約行為學習作業中的參與。實驗三在「同時制約」或是「倒序制約」兩種制約程序中的不同時間點，施予局部麻醉藥物二丁卡因暫時抑制內側前額葉皮質活動，以檢驗該區塊在單次禁錮壓力源引發場地制約偏好行為下的參與角色。實驗四為了解內側前額葉皮質處多巴胺在單次禁錮壓力源引發場地制約偏好行為中的角色，在「同時制約」程序的不同時間點施打多巴胺專屬受器拮抗劑至內側前額葉皮質區。 實驗結果發現：本研究所使用的單次30分鐘禁錮壓力源，確實可以引發實驗動物體內的壓力賀爾蒙糖皮質素大量增加、提高焦慮情緒或是降低自發性行為活動量。單次禁錮壓力源在「同時制約」或是「倒序制約」等兩種制約程序下，都能建立場地制約偏好行為。在禁錮壓力源操弄「之前」或「之後」，周邊施打多巴胺D1或是D2專屬受器拮抗劑，在「同時制約」或是「倒序制約」兩種制約程序中都會減抑禁錮壓力源建立場地制約偏好行為的效果。在「倒序制約」方式中，在「實驗動物接受完30分鐘壓力源操弄後被置入制約箱之前」才給予多巴胺拮抗劑，也會破壞後續的配對制約形成。在中樞內側前額葉皮質部分，在「同時制約」或是「倒序制約」兩種制約程序中，二丁卡因在壓力源與環境刺激配對「之前」給予才會抑制禁錮壓力源建立場地制約偏好行為的效果。在壓力源與環境刺激配對「之後」才抑制該處神經活動則不影響壓力源建立制約行為的效果。中樞內側前額葉皮質施予多巴胺D1或是D2專屬受器拮抗劑，也得到前述相同實驗結果。 本研究的實驗結果證明單次禁錮壓力源確實可以建立場地制約，為另類的古典制約行為。壓力源的操弄可引發多巴胺釋放量增加，及內側前額葉皮質處的多巴胺確實參與了此禁錮壓力源引發場地制約偏好行為。總結本研究結果顯示內側前額葉皮質處多巴胺在壓力下會對制約行為學習造成影響，並冀望此結果可以擴展對於內側前額葉皮質功能失能與心智疾患間關係的瞭解。在演化上，壓力對於人類或是其他族群的生存有其必要性。動物對於其環境中的危險或是威脅事件必須進行行為學習或因應，才能避免生命的損失。 / To investigate the role of dopamine in stressor involved in classical conditioning, the present study used a dopamine-related task, conditioned place preference (CPP), as behavioral measurement. The mild restraint stressor was used and presumed to serve as the unconditioned stimulus to be paired with the contextual conditioned stimulus. The medial prefrontal cortex (mPFC) was hypothesized to be involved in this type of stressor induced place conditioning. Experiment 1 examined the effects of restraint stressor on physiological, emotional or locomotor tests. Experiment 2 investigated the involvement of dopamine in the stressor induced CPP, which conditioning procedures were manipulated by either simultaneous or backward form. The selective dopamine receptor antagonists were systemically administered in different time points during the conditioning procedures. Experiment 3 took lidocaine, a local anesthetic, to induce temporal deactivation of the mPFC. Lidocaine was infused in the mPFC at various time points, in either simultaneous or backward conditioning, to evaluate the involvement of the mPFC in stressor induced place conditioning. To further investigate the effects of dopamine receptors in the mPFC in the present type of CPP, the selective dopamine receptor antagonists were locally infused into the mPFC in simulutaneous conditioning procedure in Experiment 4. The results showed that the manipulation of acute 30 min. restraint stressor increased the corticosterone, anxiety, but reduced the locomotor activities in rats. Consitent with previous work, this acute restraint stressor treatment given in either simultaneous or backward conditioning form significantly induced CPP. Systemic injection of dopamine D1 or D2 receptor antagonist given “before” or “after” the manipulation of restraint stressor, in either simultaneous or backward conditioning, attenuated the formation of stressor induced CPP. When these drugs were infused “right after the stressor manipulation and before the commencement of place conditioning” in the backward conditioning, the induction of CPP was also impaired. The attenuation of stressor formed place conditioning was showed when lidocaine was infused in the mPFC “before”, but not “after” the manipulation of restraint stressor. Such an attenuation effect was also seen when the selective D1 or D2 dopamine antagonist was infused in the mPFC. The present study showed restraint stressor induced place conditioning as a novel type of classical conditioning. Consistent with the evidence showing that the manipulation of this stressor increases the release of dopamine, this study further verifed that the dopamine in the mPFC is involved in this restraint stressor induced CPP.