La mémoire de reconnaissance visuelle (MRV) est atteinte précocement dans la maladie d'Alzheimer (MA). Or, elle reposerait sur deux processus : la familiarité (simple sentiment d'avoir déjà rencontré un item) et la recollection (récupération de détails associés à l'item lors de son encodage). Si la recollection est clairement atteinte au début de la MA, les résultats concernant la familiarité sont à ce jour contradictoires. Supposée plus rapide que la recollection, la familiarité devrait pouvoir être évaluée directement par une approche temporelle. Son atteinte dans la MA pourrait alors être mieux comprise.Pour tester ces hypthèses, la procédure comportementale SAB (Speed and Accuracy Boosting) a été créée. Permettant d'étudier les propriétés de la MRV (sa vitesse-limite, Articles 1 et 2, ou sa nature « bottom-up », Article 3), ainsi que l'hypothèse que la familiarité est plus rapide que la recollection, cette méthode s'est montrée évaluer majoritairement la familiarité (Article 1). Chez des patients à risque de MA, une dissociation inattendue au sein de la familiarité a alors pu être révélée, avec une atteinte des signaux tardifs de familiarité (utilisés lors d'un jugement classique), mais une préservation des premiers signaux (supportant la détection rapide évaluée en SAB) (Article 4).En outre, la segmentation manuelle d'images IRM du lobe temporal interne (premières régions cérébrales touchées dans la MA, et clées pour la MRV) a été appliquée à la problématique connexe de l'effet de l'âge au début de la MA (Article 5).Indépendamment, ces méthodes ont permis de mieux comprendre la MRV et son atteinte au début de la MA ; leur combinaison s'annonce très prometteuse. / Visual recognition memory (VRM) is impaired early in Alzheimer's Disease (AD), but would rely on two processes : familiarity (mere feeling that an item has been seen previously) and recollection (retrieval of details associated to the item at encoding). If recollection is clearly impaired in early AD, results concerning familiarity remain contradictory. Supposed to be faster than recollection, familiarity should be better understood using a temporal approach. Its possible impairment in AD could then be better understood.In order to test this, a behavioural procedure was designed: the SAB (Speed and Accuracy Boosting). Revealing different properties of VRM (its speed-limit, Articles 1 and 2; its « bottom-up » nature, Article 3) and some of its processes (familiarity appeares indeed faster than recollection, Article 1), results showed that the SAB procedure was mainly assessing familiarity (Article 1). In patients at risk of AD, an unexpected dissociation within familiarity processes was evidenced, with an impairment of late signals of familiarity (as used for classical judgements), but a preservation of the first signals (supporting fast detection assessed with the SAB) (Article 4).Last, manual segmentation of MRI images of the medial temporal lobe (first cerebral regions affected in AD, known for their key role in VRM) was also used to assess age effect at the early stage of AD (Article 5).Independently, both methods allowed understanding better the VRM and its impairment in early AD; their combination appears very promising.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / By definition Traumatic brain injury (TBI) is a common involvement in all societies and covers the entire set of processes that alone or in combination can damage the brain. In children and adolescents TBI is an interruption in their normal development, with estimates ranging from 200 to 500 cases per 100,000 per year. Most cases are characterized as mild, with few long-term consequences, however, a significant portion of young people suffer more serious injuries. Furthermore, Juvenile TBI is the major cause of death and disability in children and adolescents. An important factor is that the sports and youth have always been closely related. In this sense, it called attention traumas, especially for young people during practice of contact sports such as martial arts, football, ice hockey, baseball. Because of the wide variety of conditions associated with TBI, there is considerable interest in the development and subsequent application of biochemical markers that relate the severity of brain damage with the development of neurological problems such as memory and learning deficits. In this context, this study aimed, at first, to see if the young animals subjected to TBI had cognitive impairment fifteen days after the injury and whether creatine supplementation has protective effect by changing the activity of CK enzyme, modulating the expression of AMPK protein, CREB, p-CREB and BDNF involved in cognitive impairment and histological damage generated by TBI To this end the present study used young male Wistar rats at 35 days of life subjected to TBI or subjected to all processes except TBI were divided into four groups which were randomized to receive the Cr supplementation (300 mg / kg po) was suspended in 0.5% CMC or vehicle (CMC) twice daily for a period of 14 days. it was shown that animals on submitted to TBI showed a reduction in cognitive functions evaluated by 15 days object recognition task after TBI. The animals that received creatine supplementation did not have their compromised functions. Our biochemical data revealed that the activity of the enzyme creatine kinase was increased fifteen days after trauma, in the same period the TBI did not alter the expression of AMPK however creatine supplementation increased its expression, suggesting a connection between CK and AMPK after TBI, since the creatine supplementation was effective in raising the activity of CK while increased expression of AMPK also caused a significant increase in the ratio of CREB and p-CREB in animals that were supplemented. We also note the participation of BDNF, whose expression this increases the animals submitted to the TBI and were supplemented with creatine, protection evidenced by creatine in lesion volume induced by the TBI. / Por definição o Traumatismo Cranioencefálico (TCE) é um acometimento comum em todas as sociedades e abrange todo o conjunto de processos que sozinhos ou em combinação podem danificar o encéfalo. Em crianças e adolescentes o TCE representa uma interrupção em seu desenvolvimento normal, com estimativas que variam de 200 a 500 casos para cada 100.000 ao ano. A maioria dos casos é caracterizada como leve, com poucas consequências a longo prazo, entretanto, uma porção significativa de jovens sofrerá ferimentos mais graves. Além disso, o TCE juvenil é a principal causa de morte e incapacidade em crianças e adolescente. Neste sentido, chama-se a atenção traumas sofridos, principalmente por jovens durante pratica de esportes de contato como as artes marciais, o futebol americano, hóquei no gelo, baseball. Devido a grande variedade de condições associadas ao TCE, há um considerável interesse no desenvolvimento e posterior aplicação de marcadores bioquímicos que relacionem a gravidade do dano cerebral com o desenvolvimento de problemas neurológicos, como déficits de memória e aprendizado. Neste contexto, o presente trabalho teve como objetivo, verificar se o se os animais jovens submetidos ao TCE apresentavam déficit cognitivo quinze dias após a lesão e se a suplementação com creatina possui efeito protetor, alterando a atividade da enzima CK, modulando a expressão das proteínas AMPK, CREB, p-CREB e BDNF envolvidas no déficit cognitivo e no dano histológico gerado pelo TCE. Para tal o presente estudo utilizou ratos Wistar jovens machos aos 35 dia de vida submetidos ao TCE ou submetido a todos os processos exceto o TCE, foram divididos em quatro grupos onde foram aleatoriamente separados, para receber a suplementação com Cr (300 mg / kg, p.o), suspensa em CMC a 0,5% ou veículo (CMC) duas vezes ao dia por um período de 14 dias. Foi evidenciado que os animais submetidos ao TCE apresentaram uma redução nas funções cognitivas avaliadas pela tarefa de reconhecimento de objeto 15 dias após o TCE. Já os animais que receberam a suplementação com creatina não tiveram suas funções comprometidas. Nossos dados bioquímicos revelaram que a atividade da enzima creatina quinase estava aumentada quinze dias pós-trauma, no mesmo período o TCE não alterou a expressão de AMPK porem a suplementação com creatina aumentou sua expressão, sugerindo uma conexão entre CK e AMPK após o TCE, uma vez que a suplementação com creatina foi efetiva em elevar a atividade da CK ao mesmo tempo que elevou a expressão de AMPK, também causou um aumento significativo na razão entre CREB e p-CREB nos animais que foram suplementados. Observamos também a participação do BDNF, cuja expressão esta aumenta nos animais que foram submetidos ao TCE e foram suplementados com creatina, na proteção evidenciada pela creatina no volume da lesão induzida pelo TCE.

O paradigma intruso-residente vem sendo intensamente empregado em estudos para avaliar a memória de reconhecimento social em roedores. Tipicamente, ratos adultos, denominados residentes, são expostos a dois encontros sucessivos, de 5 minutos cada, com um mesmo rato juvenil ou com ratos juvenis diferentes, denominados intrusos; o intervalo de tempo entre encontros é 30 minutos. A quantidade de comportamentos sociais do residente (no segundo encontro) em relação a um intruso familiar é substancialmente menor do que o observado no primeiro encontro, o que não ocorre quando o segundo encontro envolve um juvenil novo; esse resultado caracteriza a memoria de reconhecimento social. Se o intervalo de tempo entre os encontros é aumentado para 60 minutos, a redução da investigação social do intruso familiar por parte do residente desaparece, levando à conclusão de que a memória de reconhecimento social seria um mecanismo para retenção temporária de informações. O objetivo central do presente trabalho foi contribuir para o entendimento da memória de reconhecimento social em ratos. Foram realizados três experimentos. No primeiro experimento avaliou-se se a expressão de comportamentos sociais e também da memória de reconhecimento social estão sujeitos à modulação temporal. No segundo experimento avaliou-se em que extensão o aumento do tempo de exposição ao intruso durante o primeiro encontro resulta num aumento da duração da memoria de reconhecimento social. No terceiro experimento avaliou-se se um procedimento de rotina na maioria dos laboratorios, o transporte dos animais da sala de experimentos para o biotério, interfere na memória de reconhecimento social, quando realizado 0,5 ou 6 horas após o primeiro encontro. Os resultados mostraram que (1) a expressão de comportamentos sociais e a memória de reconhecimento social estão sujeitos à modulação temporal, sendo mais intensos quando os testes são realizados na fase inativa (Capítulo 2), de modo que este fator deve ser levado em consideração quando do planejamento de experimentos envolvendo sociabilidade, (2) o aumento da duração do primeiro encontro para 2 horas ou mais revelou uma memória de reconhecimento social que dura pelo menos 24 horas (Capítulo 3), permitindo questionar que se trate de um dispositivo de curta duração, e (3) o transporte dos animais para o biotério 0,5 horas, mas não 6 horas, depois do primeiro encontro, prejudica a memória de reconhecimento social (Capítulo 4), indicando que se deve estar atento às rotinas laboratoriais pois as mesmas podem interferir no desempenho dos animais em testes de memória. Em associação com essas relevantes observações experimentais, foram propostas estratégias de análise dos dados gerados com esse tipo de experimentação e também discussões conceituais sobre a caracterização da memória de reconhecimento social, que contribuem marcadamente para essa área de estudos. / The intruder-resident paradigm has been extensively employed in studies of social recognition memory in rodents. Typically, adult rats, named residents, are exposed to two 5-min successive encounters with the same juvenile intruder or with two different juveniles; the time interval between the encounters is 30 min. The amount of social behaviors exhibited by the resident rats towards the same intruder juvenile in the second encounter is substantially smaller when compared to both that seen in the first encounter and that seen towards a different juvenile; these results characterize social recognition memory. When the time interval between encounters is increased to 60 min, that reduction of the investigation towards the familiar juvenile intruder vanishes, which is seen as evidence that social recognition memory corresponds to a short-term memory mechanism. The aim of this study was to contribute for our understanding of social recognition memory in rats. Three experiments were run. The first experiment evaluated to which extent both social behaviors and social recognition memory are influenced by temporal phase effects. The second experiment evaluated to which extent the increase in the duration of the first encounter renders social recognition memory longer. The third experiment evaluated to which extent the transportation of the resident rats from the experimental room to the animal facilities either 0.5 or 6 hours after the first encounter, interferes with social recognition memory. The results showed that (1) the expression of social behaviors and of the social recognition memory are modulated temporal phase effects, being stronger when animals are tested in their inactive phase (Chapter 2); thus, this aspect has to be considered in studies on sociability, (2) the increase of the first encounter duration for 2 hours or longer renders social recognition memory to last at least 24 hours (Chapter 3); this allows to question that social recognition memory corresponds to a short-term memory mechanism, and (3) transportation of the resident rats to the animal facilities 0.5, but not 6 hours, after the end of the first encounter disrupts social recognition memory (Chapter 4), indicating that one has to be cautious about usual laboratory routines, because they may interfere with performance of the memory tasks when executed a short time after training the animals.Associated with these relevant experimental observations, these studies allowed proposing novel strategies for data analysis and discussing conceptual issues about the characterization of social recognition memory that give a substantial contribution for this area.

Le récepteur aux cannabinoïdes de type 1 (CB1) est un récepteur couplé aux protéines G, abondamment exprimé dans le cerveau et régulant plusieurs processus physiologiques. Cependant, les mécanismes cellulaires par lesquels les CB1 régulent ces processus n’ont été que peu analysés. Bien que les CB1 localisés dans les membranes plasmiques sont connus pour induire la transduction de signal; une partie de ces récepteurs sont aussi fonctionnels au niveau des mitochondries (mtCB1), où leur stimulation réduit la respiration mitochondriale. L’objectif de cette thèse fut d’évaluer l’impact de l’activation des récepteurs mtCB1 du cerveau sur les effets connus des cannabinoïdes. Afin de distinguer la fonction des mtCB1 de celle des autres populations de récepteurs, nous avons développé des outils basés sur la signalisation induite par les mtCB1. Dans les mitochondries isolées de cerveau, l’activation des protéines Gαi/o, dépendante des mtCB1 diminue l’activité de l’adénylyl cyclase soluble (sAC). L'inhibition locale de l’activité de sAC prévient l’amnésie, la catalepsie et partiellement l’hypolocomotion induite par les cannabinoïdes. De plus, nous avons généré une protéine fonctionnelle mutante CB1 (DN22-CB1) dépourvue des 22 premiers acides aminés des CB1 ainsi que de sa localisation mitochondriale. Contrairement aux CB1, l'activation des DN22-CB1 n’affecte pas l'activité mitochondriale. Enfin, l’expression des DN22-CB1 dans l’hippocampe bloque à la fois la diminution de la transmission synaptique et l’amnésie induites par les cannabinoïdes. Ces travaux démontrent l’implication des mtCB1 dans certains effets des cannabinoïdes et le rôle clé des processus bioénergétiques contrôlant les fonctions cérébrales. / Type-1 cannabinoid receptor CB1 is a G protein-coupled receptor (GPCR), widely expressed in the brain, which regulates numerous physiological processes. However, the cellular mechanisms of CB1-mediated control of these functions are poorly understood. Although CB1 are known to signal at the plasma membrane, a portion of these receptors are also present in mitochondria (mtCB1), where mtCB1 activation decreases mitochondrial activity. The goal of this thesis was to dissect the impact of brain mtCB1 signaling in known behavioral effects induced by cannabinoids. To distinguish the functions of mtCB1 from other receptor pools, we developed tools based on the characterization of the intra-mitochondrial molecular cascade induced by mtCB1 receptors. In isolated brain mitochondria, we found that intra-mitochondrial decrease of soluble-adenylyl cyclase (sAC) activity links mtCB1- dependent activation of Gαi/o proteins to decrease cellular respiration. Local brain inhibition of sAC activity blocks cannabinoid-induced amnesia, catalepsy and contributes to the hypolocomotor effect of cannabinoids. In addition, we generated a functional mutant CB1 protein (DN22-CB1) lacking the first 22 amino acid of CB1 and its mitochondrial localization. Differently from CB1, activation of DN22-CB1 does not affect mitochondrial activity. Hippocampal in vivo expression of DN22-CB1 abolished both cannabinoid-induced impairment of synaptic transmission and amnesia in mice. Together, these studies couple mitochondrial activity to behavioral performances. The involvement of mtCB1 in the effects of cannabinoids on memory and motor control highlights the key role of bioenergetic processes as regulators of brain functions.

Un nombre croissant de travaux chez l’animal et chez l’homme suggèrent que les différentes structures composant le lobe temporal interne (LTI) contribuent de manière différentielle à la mémoire déclarative. Chez l’homme, deux réseaux neuraux impliquant le LTI sont décrits : un réseau mésiotemporal antérieur, constitué de structures pour lesquelles les études chez les patients cérébro-lésés indiquent qu’elles contribueraient à la mémoire décontextualisée (mémoire des objets et mémoire sémantique ou mémoire du « quoi ») ; un réseau mésiotemporal postérieur, constitué d’autres structures pour lesquelles ces études suggèrent plutôt une implication dans la mémoire contextualisée (mémoire spatiale, épisodique ou mémoire du «où » et du « quand»). Dans la Maladie d’Alzheimer (MA), les dégénérescences neurofibrillaires, dont la distribution topographique est corrélée à la nature des déficits cognitifs, se développent initialement dans les cortex sous-hippocampiques - transentorhinal et entorhinal - qui sont des composants du réseau mésiotemporal antérieur, avant de s’étendre à l’hippocampe. Les éventuels déficits cognitifs en relation avec l’atteinte de cette région ne sont pas clairement identifiés dans la MA. Les travaux présentés dans ce mémoire sont centrés sur l’étude des cortex sous-hippocampiques avec les méthodes de la neuropsychologie et la neuroimagerie. Ils suggèrent que la MA aux stades les plus précoces pourrait représenter un « modèle » d’étude privilégié des systèmes mnésiques auxquels contribue le LTI. Ces résultats sont en faveur de l’utilité de l’évaluation de la mémoire décontextualisée dans le diagnostic de la MA débutante. / There is increasing evidence from experiments in rodents and non-human primates, as well as from human studies, to suggest that the different structures within the medial temporal lobe (MTL) differentially contribute to declarative memory. In the human brain, two neural networks implicating MTL structures have been described: an anterior MTL network that includes brain areas that contribute to context-free memory (object memory and semantic memory or memory for « what ») and a posterior MTL network that contributes to context-rich memory (spatial memory, episodic memory or memory for “where” and “when”). In Alzheimer’s disease (AD), neurofibrillary tangles (NFT), associated with cognitive signs, initially appear in the sub-hippocampal (transentorhinal and entorhinal) cortex, which are part of the anterior MTL network, before reaching the hippocampus. Potential cognitive deficits related to the dysfunction of this brain area in AD are not clearly identified. In the presented studies, the emphasis is placed on the investigation of sub-hippocampal corteces using a neuropsychological approach and neuroimaging techniques. Our findings suggest that the very earliest stages of AD could represent a “model” leading to a better understanding of memory systems that involve the MTL. They also provide evidence that evaluating context-free memory may be useful in the diagnosis of early AD.

睡眠是否能鞏固陳述性記憶目前尚無定論。過去研究一致較支持睡眠能增進相關字詞配對的學習，但睡眠是否能增進無關字詞配對的學習，目前仍存在不一致的發現。造成該差異的原因可能是：過去研究多採用的行為測量指標，或許無法充分反映出睡眠促進記憶新聯結（new association）產生的效果。事件關聯電位（Event-related potential, ERP）的N400反映出語意記憶系統內每個字詞彼此的相關程度，因此本研究使用N400來探討睡眠強化無關字詞配對形成新聯結的電生理歷程。30名健康受試者（15位男性與15位女性，平均年齡為20.7歲） 隨機分派至睡眠組或清醒組，第一晚在學習80組無關字詞配對後，接受第一次再認記憶測驗，同時進行ERP的記錄。隨後睡眠組接受睡眠記錄（PSG），清醒組則接受整晚的睡眠剝奪，兩組受試者皆在第二晚給予8小時的躺床時間，使他們有機會充足睡眠以恢復精神，於第三天早上接受第二次再認記憶測驗及ERP記錄。在記憶測驗時，無關字詞配對分別組成促發字（prime）與目標字（target）先後出現，受試者需判斷先後出現的字詞是否為先前學過的完整配對，在測試階段同時記錄腦電波訊號。行為測量結果顯示睡眠過後，再認表現的正確率顯著提高且反應時間明顯縮短，但在睡眠剝奪後則顯示相反的結果。電生理測量發現睡眠組的N400振幅在睡眠過後較清醒組明顯降低。另外，睡眠組較清醒組有較高的正確率與較短的反應時間。睡眠組再認測驗的進步量與慢波睡眠呈現負相關，而慢波睡眠與第一次再認測驗的正確率呈現正相關，根據二階段睡眠記憶鞏固理論，慢波睡眠涉及重新組織記憶的歷程（系統性固化），因此學習表現較佳的受試者出現較多的深度睡眠，可能反應其經歷系統性固化。本研究結果顯示睡眠對於產生新聯結有明顯的增強效果，而且慢波睡眠可能參與了記憶表徵重新分配的歷程。 / The effect of sleep on declarative memory remains contradictory. Prior studies show that sleep benefits the learning of related word pairs consistently, while the learning of unrelated word pairs, however, show mixed results. It is possible that the behavioral measures used in previous studies are not sensitive enough to reveal subtle effects of sleep on new associations. N400, an event-related potential (ERP) component reflecting relatedness among words in semantic memory, was used in the present study to investigate the effect of sleep on the physiological process underlying new associations of unrelated word pairs. Participants were randomly assigned to either a Sleep group or a Wakefulness group. In the learning phase, participants were asked to memorize 80 visually presented unrelated word-pairs, followed by a pre-test phase with a recognition task. The participants then underwent either a night of nocturnal sleep (Sleep group) or sleep deprivation (Wakefulness group). A post-test was conducted after subjects had one night of recovery sleep. During both pre-test and post-test sessions, prime and target words were presented successively for the subjects to judge whether they were among the original pairs or new pairs. ERPs were recorded during both test phases. The behavioral data show that differences in improvement of recognition and decreases in reaction time from pre-test to post-test are significant between Sleep and Wakefulness groups. N400 peak amplitude attenuated significantly after sleep but not after wakefulness. The improvement of recognition negatively correlates with slow wave sleep (SWS). The number of word-pairs acquired in the learning phase, however, correlates positively with SWS. According to the two-stage memory consolidation theory of sleep, SWS involves in redistribution of memory (systematic consolidation). Therefore, that the participants with high performance showed more SWS may reflect the process of systematic consolidation. These results suggest that the sleep has an enhancing effect on the formation of novel association, and SWS may be involved in the process of redistributing memory representations.

Indiana University-Purdue University Indianapolis (IUPUI) / Methamphetamine (MA) is a widely abused psychostimulant that has been shown to evoke an array of neurobiological abnormalities and cognitive deficits in humans and in rodent models (Marshall & O'Dell, 2012). Alterations in cognitive function after repeated drug use may lead to impaired decision-making, a lack of behavioral control, and ultimately the inability to abstain from drug use. Human studies have shown that alterations in neurobiology resulting from prolonged MA use may lead to a number of cognitive deficits, including impairments in executive function, learning, memory, and impulsivity. These impairments, specifically those that engage the prefrontal cortex (PFC) or hippocampus (HC), may persist or recover based on the duration of abstinence. In rodents, repeated intermittent injections of MA yield protracted changes in neurobiology and behavior, which have been shown to effectively model a number of the biological and cognitive abnormalities observed in addiction. In order to assess the temporal evolution of impaired cognitive function throughout abstinence, sensitization was first induced in rats (7 x 5.0 mg/kg MA over 14 days). MA-treated rats initially exhibited a robust increase in locomotion that transitioned to stereotypy as the induction phase progressed. Then, the effects of MA sensitization on social interaction (SI), temporal order recognition (TOR) and novel object recognition (NOR) was assessed at one-day and 30-days post induction. No differences were observed in SI in either group or after a single injection of MA. However, an acute injection of 5.0 mg/kg of MA 30-minutes prior to testing dramatically reduced SI time. Impairments in TOR and NOR were observed in MA-treated rats after one day of abstinence, and impairments in TOR, but not NOR, were observed on day 30 of abstinence. No differences in TOR and NOR after a single injection of MA or saline were observed. These data establish that after 30 days of abstinence from a sensitizing regimen of MA, the ability to recall the temporal sequence that two stimuli were encountered was impaired and that was not attributable to impaired novelty detection. These data also suggest that at least some of the neurocognitive abnormalities caused by chronic MA administration may normalize after prolonged abstinence, since the ability to detect novelty recovered after 30 days of abstinence. These data provide compelling support that, since MA-sensitization caused temporal deficits in memory, PFC and HC function may be differentially impaired throughout the time course of abstinence.