Information is believed to be stored in the brain by constructing new neural circuits, and these circuits are shaped by changes in the strength of the synaptic connections between the neurons making up the circuit. According to most theories of memory, new circuits can be formed by either increasing or decreasing the strength of synaptic connections. Bidirectional modifications in synaptic efficacy are also central components in recent computer simulations of learning and memory. While long-term potentiation (LTP) has been the focus of extensive research into the mechanisms underlying information storage in the mammalian brain, long-term depression (LTD) and depotentiation, its depressive counterparts, have not. Furthermore, most of the LTD research has involved the use of anaesthetized animals and in vitro slice preparations, making it more difficult to determine the role of this synaptic phenomenon in learning and memory in the intact behaving animal. This thesis provides the first detailed examination of: 1) the induction and decay of both LTD and depotentiation in the neocortex of the awake, freely moving animal; 2) the effects of N-methyl D-Aspartate receptor (NMDAR) blockade on the induction of LTD, LTP, and depotentiation (NMDA receptor activation is known to play a major role in most forms of LTP); and 3) the interactions between these synaptic phenomena. LTD was expressed as a significant reduction in the amplitude of both short and long-latency field potential components. Depotentiation was expressed as a long lasting decrease in the amplitude of a previously enhanced late component. LTD was found to be greater in magnitude and longer lasting when the conditioning stimulation was repeated. However, unlike LTP induction, the conditioning stimulation was equally effective whether spaced over hours or days. NMDA receptor antagonism blocked LTP induction and instead produced a depression effect similar to LTD. Unlike LTP, LTD and depotentiation were found to be NMDAR-independent in the neocortex of the freely moving rat. LTP and LTD are both reversible phenomena and LTD-inducing stimulation can modulate the effects of LTP-inducing stimulation. LTD-inducing stimulation, when delivered following to LTP-inducing stimulation, attenuates the induction rate for potentiation. LTD and depotentiation may play important roles in the ongoing experience-induced modification of neuronal connectivity. Furthermore, these results are consistent with the hypothesis that potentiation and depression reflect the physiological instantiation of a bidirectional learning rule. / Thesis / Doctor of Philosophy (PhD)

Learning and memory storage is believed to occur at the synaptic connections between neurons. During the last decades it has become clear that synapses are plastic at short and long time scales. Furthermore, experiments have shown that short and long-term synaptic plasticity interact. It remains unclear, however, how is this interaction implemented and how does it impact information processing and learning in cortical networks. In this thesis I present results on the mechanisms and function of this interaction. On the mechanistic level this form of plasticity is known to rely on a presynaptic coincidence mechanism, which requires the activation of presynaptic NMDA receptors (preNMDARs). In a collaborative effort I used mathematical modeling combined with experiments to show that preNMDARs reroute information flow in local circuits during high-frequency firing, by specifically impacting frequency-dependent disynaptic inhibition mediated by Martinotti cells. In order to accurately characterize how do preNMDARs regulate the release machinery, I developed a probabilistic inference framework that provides a distribution over the relevant parameter space, rather than simple point estimates. This approach allowed me to propose better experimental protocols for short-term plasticity inference and to reveal connection-specific synaptic dynamics in the layer-5 canonical microcircuit. This framework was then extended to infer short-term plasticity from preNMDAR pharmacological blockade data. The results show that preNMDARs up-regulate the baseline release probability and the depression time-constant, which is consistent with experimental analysis and that their impact appears to be connection-specific. I also show that a preNMDAR phenomenological model captures the frequency-dependence activation of preNMDARs. Furthermore, preNMDARs increase the signal-to-noise ratio of synaptic responses. These results show that preNMDARs specifically up-regulate high frequency synaptic information transmission. Finally, I introduce a pre- and postsynaptic unified mathematical model of spike-timing- dependent synaptic plasticity. I show that this unified model captures a wide range of short-term and long-term synaptic plasticity data. Functionally, I demonstrate that this segregation into pre- and postsynaptic factors explains some observations on receptive field development and enable rapid relearning of previously stored information, in keeping with Ebbinghaus’s memory savings theory.

Made available in DSpace on 2014-06-12T18:08:18Z (GMT). No. of bitstreams: 3 arquivo8047_1.pdf: 1992919 bytes, checksum: 57d424bed65e6b9de5a2871e338a68ec (MD5) arquivo8047_2.pdf: 10283231 bytes, checksum: f15b859b779fd47ee1dedfaf5d8331b5 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2002 / Neste trabalho, estudamos o modelo de rede neural para áreas do neocórtex cerebral humano, proposto por L. Ingber (1992) para explicar a atividade neocortical de duração entre centenas de milisegundos e vários segundos. O modelo permite a simulação de grandes regiões neocorticais, pelo fato de resumir em cada nó centenas de graus de liberdade correspondentes a vários neurônios. O conjunto de suas unidades básicas, chamadas mesocolunas, é modelado através de um autômato celular que evolui no tempo de acordo com regras locais estocásticas, determinadas por interações de tipo não-linear entre os nós através de conexões limitadas (de alcance finito) entre eles, uma constatação decorrente das pesquisas biológicas experimentais

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20756号 / 医博第4286号 / 新制||医||1024(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邉 大, 教授 伊佐 正, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p> Alterations in neural tissues associated with environmental variables have been studied for many years. Anatomical changes in the neocortex of rats in response to exposure to complex environments were observed and replicated in a number of studies both within and across species. These changes are not dependent on the age of the animal or on the duration of exposure, and have been demonstrated in structures outside of the cortex. Due to the undisputed involvement of both the neocortex and the hippocampus in learning and memory, researchers applied a widely used model system of a synaptic mechanism for learning, long-term potentiation (LTP), to the environmental enrichment paradigm and demonstrated significant enhancements in hippocampal field potentials in enriched rats. The present study examines whether the neocortex also showed evidence of plasticity in synaptic transmission. No effects for environmental enrichment were observed on the maximum amplitude of neocortical field responses evoked from the corpus callosum. To assess the plasticity of the chronic preparation used in the study, the animals were exposed to trains of pulses previously shown to induce electrical LTP in the cortex, but revealed only a slight, although significant, depression of the evoked response amplitude. An alteration in the stimulation parameters did not result in an enhanced response. Cortical depth measures suggested that the enriched environment was indeed sufficient to produce plastic changes in anatomy, if not in the efficacy of synaptic transmission. The importance of these findings in the neocortex leads us to question the validity of the LTP model of learning and memory.</p> / Thesis / Master of Science (MSc)

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23464号 / 医博第4771号 / 新制||医||1053(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 林 康紀, 教授 伊佐 正, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Thesis (MScMedSc (Biomedical Sciences. Molecular Biology and Human Genetics. Medical Biochemistry))--University of Stellenbosch, 2009. / The mammalian neocortex contributes to the increasing functional complexity of the mammalian brain, partly because of its striking organisation into distinct neuronal layers. The development of the neocortex has been well studied because disrupted neurodevelopment results in several human diseases. The basic principles of neocortical development have been well established for some time; however the molecular mechanisms have only recently been identified. One major advance in our understanding of these molecular mechanisms was the discovery of Reelin, an extracellular matrix protein that directs the migration of neurons to their final positions in the developing neocortex. Reelin is a large multi-domain protein that exerts its functions by binding to its ligands on the cell surface and initiating a signal transduction cascade that ultimately results in cytoskeletal rearrangements. Several investigations have been undertaken to elucidate the functions of each of these domains to gain a better understanding reelin’s functions. We have previously identified the WR40 repeat protein 47 (WDR47), a protein of unknown function, as a novel putative ligand for the N-terminal reeler domain of reelin. To gain better understanding into the functional significance of this interaction, the present study sought to identify novel WDR47- interacting proteins. In order to achieve this, a cDNA encoding a polypeptide that contains the two N-terminal domains of WDR47, i.e. the Lis homology and the C-terminal Lis homology domain (CTLH) was used as bait in a Y2H screen of a foetal brain cDNA library. Putative WDR47 ligands were subsequently verified using 3D in vivo co-localisation. Results of these analyses showed that SCG10, a microtubule destabilizing protein belonging to the stathmin family of proteins, interacted with the N-terminal of WDR47. The identification of SCG10 as a novel WDR47 interacting protein not only sheds some light on the role and function of WDR47 but also aids in a better understanding of the reelin pathway and cortical lamination. Moreover, the data presented here, may also provide researchers with new avenues of research into molecular mechanisms involved in neuronal migration disorders.

This thesis investigates how through experience the brain acquires and stores memories, and uses these to extract and modify knowledge. This question is being studied by both computational and experimental neuroscientists as it is of relevance for neuroscience, but also for artificial systems that need to develop knowledge about the world from limited, sequential data. It is widely assumed that new memories are initially stored in the hippocampus, and later are slowly reorganised into distributed cortical networks that represent knowledge. This memory reorganisation is called systems consolidation. In recent years, experimental studies have revealed complex hippocampal-neocortical interactions that have blurred the lines between the two memory systems, challenging the traditional understanding of memory processes. In particular, the prior existence of cortical knowledge frameworks (also known as schemas) was found to speed up learning and consolidation, which seemingly is at odds with previous models of systems consolidation. However, the underlying mechanisms of this effect are not known. In this work, we present a computational framework to explore potential interactions between the hippocampus, the prefrontal cortex, and associative cortical areas during learning as well as during sleep. To model the associative cortical areas, where the memories are gradually consolidated, we have implemented an artificial neural network (Restricted Boltzmann Machine) so as to get insight into potential neural mechanisms of memory acquisition, recall, and consolidation. We analyse the network's properties using two tasks inspired by neuroscience experiments. The network gradually built a semantic schema in the associative cortical areas through the consolidation of multiple related memories, a process promoted by hippocampal-driven replay during sleep. To explain the experimental data we suggest that, as the neocortical schema develops, the prefrontal cortex extracts characteristics shared across multiple memories. We call this information meta-schema. In our model, the semantic schema and meta-schema in the neocortex are used to compute consistency, conflict and novelty signals. We propose that the prefrontal cortex uses these signals to modulate memory formation in the hippocampus during learning, which in turn influences consolidation during sleep replay. Together, these results provide theoretical framework to explain experimental findings and produce predictions for hippocampal-neocortical interactions during learning and systems consolidation.

Recent evidence indicates that the mature neocortex retains a higher degree of plasticity than traditionally assumed. Up- and down-regulation of synaptic strength, long-term potentiation (LTP) and long-term depression (LTD), is thought to be the primary mechanism mediating experience-dependent plasticity of cortical networks. The present thesis investigate factors that regulate adult cortical plasticity, focusing on the role of neuromodulators, recent sensory experience, and different anatomical divisions of the cortex in influencing synaptic strength. First, I investigated the role of the neuromodulator histamine in gating plasticity in the primary visual cortex (V1) of urethane anesthetized adult rats. Histamine applied locally in V1 produced an enhancement of LTP elicited by theta burst stimulation (TBS) of dorsal lateral geniculate nucleus (dLGN) and allowed a sub-threshold TBS to produce stable LTP. Second, the impact of visual deprivation on LTP in V1 was assessed. Animals that received 2 and 5 hr dark exposure showed greater potentiation of field potentials when stimulated though retinal light flashes or weak TBS of the dLGN, which failed to induce LTP in control animals kept in continuous light. Third, I performed a detailed characterization of LTP induced by different TBS protocols, recording in either the monocular or binocular segment of both V1 hemispheres (i.e., ipsi- and contralateral to the stimulated dLGN). Stronger, NMDA receptor-independent LTP was found in the contralateral V1. Interestingly, weak TBS induced LTD that was NMDA receptor-dependent in the ipsilateral V1. Furthermore, a lower LTP induction threshold was observed in the binocular than the monocular segment of ipsilateral V1. Lastly, I investigated cholinergic modulation of sensory-induced activity in the barrel cortex. Basal forebrain stimulation enhanced multi-unit activity elicited by whisker deflection, an effect that was more pronounced for weaker response driven by a secondary whisker than principal whisker deflection. This thesis demonstrates that neocortical plasticity consists of multiple forms of synaptic modification. Adult cortical plasticity is greatly influenced by preceding activity of the synapse by various neuromodulator systems, and by anatomical subdivisions within primary sensory cortex fields. Together, these mechanisms may facilitate the detection, amplification, and storage of inputs to primary sensory fields of the neocortex. / Thesis (Ph.D, Psychology) -- Queen's University, 2010-04-29 14:02:30.742

Les récepteurs NMDA (NMDARs) sont des canaux cationiques activés par le glutamate. Les NMDARs participent au développement cérébral, à la plasticité synaptique, à l'apprentissage, à la mémoire et aux fonctions cognitives supérieures. Des variants pathogènes de GRIN2A, codant pour la sous-unité GluN2A des NMDARs, peuvent causer des épilepsies focales et encéphalopathies épileptiques de l'enfance avec troubles du langage et de la parole, connue sous le nom de spectre des épilepsies-aphasies (EAS). Les caractéristiques communes de l'EAS comprennent une activité épileptiforme âge-dépendante activée pendant le sommeil lent associées à des troubles de la parole, de la cognition et du comportement qui peuvent persister à l'âge adulte. Afin de commencer à identifier les événements précoces possiblement associés aux altérations de GluN2A, nous avons exploré le modèle correspondant de souris knock-out (KO) du gène Grin2a. Nous avons notamment recherché des altérations précoces de la communication vocale, de la (micro)structure cérébrale, et de l'activité électrique néocorticale. Nos données démontrent l'existence de plusieurs altérations à ces différents niveaux, parfois transitoirement à des stades spécifiques. De plus, les enregistrements néocorticaux mettent en évidence des anomalies de divers types liées au sommeil lent. Nos résultats indiquent également un rôle de GluN2A dans la communication vocale, dans l'organisation de la microstructure cérébrale, et dans la maturation des activités d’ondes lentes. Ces données suggèrent que les souris KO Grin2a représentent un modèle fiable pour appréhender les mécanismes physiopathologiques associés à l’EAS et leur séquence temporelle. / NMDA receptors (NMDARs) are cation channels that are gated by glutamate - the major excitatory neurotransmitter of the central nervous system. NMDARs participate in brain development, synaptic plasticity, learning, memory and high cognitive functions. Pathogenic variants in the GRIN2A gene, which encodes the GluN2A subunit of the NMDARs, can cause a group of childhood focal epilepsies and epileptic encephalopathies with speech and language dysfunction, known as the epilepsy-aphasia spectrum (EAS). Features shared in common by EAS disorders include age-dependent epileptiform activity activated in sleep associated with speech, neuropsychological and behavioral deficits that may persist in adulthood. In order to start in deciphering the early events possibly associated with the dysfunctioning of GluN2A-containing NMDARs, we have explored the corresponding Grin2a knock-out (KO) mouse model. That consisted in looking for early alterations of vocal communication, of brain (micro)structure, and of neocortical electrical activity. Our data demonstrated the existence of several alterations at those various levels. Some alterations were transient only, being detected at selective stages; also, neocortical recordings pointed for sleep-related anomalies of various types. Our data also indicated a role for GluN2A-containing NMDA receptors in vocal communication, fine organization of brain microstructure, and proper maturation of slow wave activity in sleep. Altogether, our data suggest that the Grin2a KO mice represent a reliable model to further elucidate the pathophysiological mechanisms associated with the disorders of EAS and their temporal sequences.