No description available.

No description available.

Oscillatory states in the Electroencephalogram (EEG) reflect the rhythmic synchronous activation in large networks of neurons. Time-frequency methods quantify the spectral content of the EEG as a function of time. As such, they are well suited as tools for the study of spontaneous and induced changes in oscillatory states. We have used time-frequency techniques to analyze the flow of activity patterns between two strongly connected brain structures: the entorhinal cortex and the hippocampus, which are believed to be involved in information storage. EEG was recorded simultaneously from the entorhinal cortex and the hippocampus of behaving rats. During the recording, low-intensity trains of electrical pulses at frequencies between 1 and 40 Hz were applied to the olfactory (piriform) cortex. The piriform cortex projects to the entorhinal cortex, which then passes the signal on to the hippocampus. Several time-frequency methods, including the short-time Fourier transform (STFT), Wigner-Ville distribution (WVD) and multiple window (MW) time-frequency analysis (TFA), were used to analyse EEG signals. To monitor the signal transmission between the entorhinal cortex and hippocampus, the time-frequency coherence functions were used. The analysed results showed that stimulation-related power in both sites peaked near 15 Hz, but the coherence between the EEG signals recorded from these two sites increased monotonically with stimulation frequency. Among the time-frequency methods used, the STFT provided time-frequency distributions not only without cross-terms which were present in the WVD, but also with higher resolutions in both time and frequency than the MW-TFA. The STFT seems to be the most suitable time-frequency method to study the stimulation-induced signals presented in this thesis. The MW-TFA, which gives low bias and low variance estimations of the time-frequency distribution when only one realization of data is given, is suitable for stochastic and nonstationary signals such as spontaneous EEG. We also compared the performance of the MW-TFA using two different window functions: Slepian sequences and Hermite functions. By carefully matching the two window functions, we found no noticeable difference in time-frequency plane between them. / Thesis / Master of Engineering (ME)

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L'objectif de cette thèse est d'étudier l'implication de deux structures de la formation hippocampique, le cortex entorhinal latéral (CEL) et l'hippocampe dorsal (DH), dans les processus sous-tendant la formation et la flexibilité d'associations entre deux stimuli de modalités sensorielles différentes : l'olfaction et le toucher. Pour cela, une tâche bimodale olfacto-tactile (OT) est développée chez le rat. Dans celle-ci, l'animal doit apprendre à identifier une combinaison "odeur-texture" spécifique parmi les trois proposées afin d'obtenir un renforcement (ex: O1T1+ O2T1 O1T2, + désignant la combinaison renforcée). Aucun indice spatial ou contextuel n'est pertinent pour résoudre cette tâche. Suite à l'acquisition de deux tâches différentes, les stimuli sont réassociés sous forme de combinaisons inédites dans une troisième tâche appelée « recombinaison ». La manipulation pharmacologique de l'activité du CEL a mis en évidence l'implication des systèmes glutamatergique NMDA et cholinergique de cette structure dans les processus sous-tendant ces deux types de tâche. En revanche, si le DH n'est pas indispensable pour l'acquisition, son système cholinergique est critique pour la recombinaison. En comparaison avec l'acquisition, l'étude électrophysiologique a montré que la recombinaison repose sur un découplage de la synchronisation entre les activités oscillatoires du CEL et celles du DH dans la bande thêta (5-12 Hz). De plus, cet apprentissage est associé à une augmentation de l'amplitude des oscillations bêta (15-45 Hz) dans le CEL. Ces travaux montrent que le CEL et le DH interviennent dans les processus sous-tendant la flexibilité des représentations bimodales / The goal of this thesis is to study the involvement of two structures of the hippocampal formation, the lateral entorhinal cortex (LEC) and the dorsal hippocampus (DH), in the processes underlying the formation and the flexibility of associations of stimuli between two different sensory modalities. To this aim, a new olfactory-tactile (OT) bimodal task has been developed in the rat. To solve the task, animals have to identity one “odor-texture” combination between three in order to obtain a reinforcement (ex: O1T1+ O2T1 O1T2, + for the baited cup). This procedure excludes the use of any spatial or contextual cues for solving the task. After the acquisition of two different tasks, the familiar stimuli used in acquisition were recombined in a third task (called “recombination”). The pharmacological manipulation of the LEC showed that the NMDA glutamatergic and cholinergic system in this structure are involved in the processes underlying the acquisition and the recombination. In contrast, the cholinergic system in the DH is selectively and critically involved in the recombination processes. Compared to acquisition, our electrophysiological data showed that the recombination is based on a desynchronization between the oscillatory activities of the LEC and of the DH in the theta band (5-12 Hz). Moreover, this task is associated with increased amplitude of beta oscillations (15-45 Hz) in the LEC. These data demonstrated that the LEC and the DH are critically involved in the processes underlying the flexibility of bimodal representations

L’apnée obstructive du sommeil (AOS) est l’un des troubles du sommeil les plus fréquents chez l’adulte et sa prévalence augmente avec l’âge. Elle se caractérise par des arrêts répétés de la respiration au cours du sommeil, menant à la présence de fragmentation du sommeil et à de l’hypoxémie intermittente. Lorsque non traité, ce trouble peut mener à diverses conséquences non négligeables sur la santé des individus qui en sont atteints, incluant sur la santé du cerveau. L’AOS est d’ailleurs de plus en plus reconnue comme étant un possible facteur de risque de déclin cognitif et de démence. Dans ce contexte, quelques études transversales ont caractérisé le volume de la substance grise cérébrale chez des adultes vieillissants atteints d’AOS, avec des résultats variables. En effet, certaines études ont noté de plus grands volumes de substance grise chez les personnes avec une AOS plus sévère, alors que d’autres ont retrouvé des plus petits volumes chez cette même population. Ce qui explique la variabilité entre les études demeure à ce jour mal compris, bien que certaines hypothèses aient émergé. Ainsi, cette thèse vise à évaluer l’association entre la sévérité de l’AOS et le volume de substance grise cérébrale chez des personnes d’âge moyen et âgées de manière transversale et longitudinale. La première étude de cette thèse se base sur des techniques de neuroimagerie afin d’évaluer les liens entre la sévérité de l’AOS et le volume de la substance grise cérébrale des sous-régions du lobe temporal médian, soit l’hippocampe, le cortex entorhinal et le cortex parahippocampique. Celles-ci ont été ciblées puisqu’elles peuvent être affectées tôt dans la progression de la pathologie de la maladie d’Alzheimer (MA). De plus, nous avons testé l’effet d’une correction de la portion d’eau libre sur les volumes cérébraux. Finalement, nous avions comme objectif de mieux comprendre si certaines caractéristiques démographiques ou cliniques de nos participants pouvaient avoir un impact sur les associations observées. Nous avons observé qu’une AOS plus sévère était associée à des volumes de substance grise plus grands de certaines sous-régions du lobe temporal médian (hippocampe et cortex entorhinal), mais seulement chez des groupes de participants spécifiques, soit les femmes, les participants plus âgés et ceux présentant un trouble cognitif léger de type amnésique. Le fait d’apporter une correction pour la portion d’eau libre aux volumes mesurés a rendu non significatives les associations observées. Il est donc possible que la présence accrue d’eau extracellulaire, suggérant de l’œdème cérébral, puisse expliquer la présence de plus grands volumes chez les participants présentant une AOS plus sévère. La deuxième étude visait quant à elle à évaluer les changements structurels des sous-régions du lobe temporal médian associés à la sévérité de l’AOS chez des personnes d’âge moyen et âgées sur une période d’environ 2 ans. Nous avons démontré que chez nos participants n’ayant pas utilisé un traitement pour l’AOS, la présence d’interaction entre la sévérité de l’AOS et l’âge permettait d’expliquer les changements annuels de volume de substance grise. De fait, les participants plus jeunes de notre échantillon (< 65 ans) avec une AOS plus sévère présentaient un plus grand taux de changement annuel de volume de substance grise, soulignant la présence d’hypertrophie dans ce sous-groupe. Ceci a été mis en lumière pour l’ensemble des sous-régions du lobe temporal médian. Chez les participants âgés entre 65 et 75 ans, aucune association entre la sévérité de l’AOS et les changements de volume au fil du temps n’a pu être soulignée. Les participants plus âgés (> 75 ans) avec une plus grande sévérité d’AOS présentaient quant à eux une plus grande atrophie au fil du temps dans certaines régions, soit l’hippocampe et le cortex entorhinal. Ces résultats supportent donc une hypothèse biphasique des changements au niveau de la substance grise cérébrale chez les gens présentant de l’AOS, avec une première phase caractérisée par des augmentations de volume chez les adultes plus jeunes, menant éventuellement à de l’atrophie chez les personnes plus âgées. Cette thèse permet d’avoir un portrait plus clair sur la nature des changements et des mécanismes impliqués dans l’association entre la sévérité de l’AOS et les volumes de substance grise. L’un des apports importants est l’utilisation d’une nouvelle méthodologie afin d’obtenir une portion d’eau libre, ce qui a permis de mieux comprendre l’apport potentiel de mécanismes pouvant sous-tendre les changements structuraux observés, notamment l’œdème cérébral. De plus, l’évaluation des caractéristiques individuelles des participants a permis d’expliquer partiellement les incongruences entre les études précédentes. Dans le cadre des études incluses dans cette thèse, nous avons observé des changements plus marqués chez les femmes. Nous avons également pu démontrer que l’âge des individus atteints d’AOS pouvait influencer significativement le patron de changements observés. Les résultats de cette thèse pourraient donc permettre de mieux cibler les personnes avec AOS qui pourraient le plus bénéficier d’un traitement pour maintenir leur santé cérébrale. / Obstructive sleep apnea (OSA) is one of the most common sleep disorders in adults, and its prevalence increases with age. It is characterized by repeated pauses in breathing during sleep, leading to sleep fragmentation and intermittent hypoxemia. If left untreated, this disorder can have numerous consequences, including on the brain’s health. OSA is increasingly recognized as a risk factor for cognitive decline and dementia. In this context, cross-sectional studies have characterized brain gray matter volume in aging adults with OSA, with variable results. Indeed, some studies have noted greater gray matter volumes in people with more severe OSA, while others have found smaller volumes in this same population. What explains the variability between studies remains poorly understood, although some hypotheses have emerged. Thus, this thesis aims to assess the association between OSA severity and cerebral gray matter volume in middle-aged and elderly individuals using cross-sectional and longitudinal designs. The first study in this thesis uses neuroimaging techniques to assess the links between OSA severity and cerebral gray matter volume of the medial temporal lobe subregions, i.e. the hippocampus, entorhinal cortex and parahippocampal cortex. These were chosen as they can be affected early in the progression of Alzheimer's disease (AD) pathology. We also corrected our brain volumes for free-water portion. Finally, we aimed to better understand whether certain demographic or clinical characteristics of our participants might have an impact on the associations observed. We noted that more severe OSA was associated with larger gray matter volumes in certain subregions of the medial temporal lobe (hippocampus and enthorinal cortex), but only in specific groups of participants: women, older participants and those with amnestic mild cognitive impairment. Correcting our volumes for free-water portion rendered the associations nonsignificant. It is therefore possible that the presence of extracellular water, suggestive of cerebral edema, could explain the presence of larger volumes in participants with more severe OSA. The second study aimed to assess longitudinal structural changes associated with OSA severity in middle-aged and elderly people over a period of around 2 years. We found that in participants who did not use treatment for OSA, the presence of interactions between OSA severity and age were associated with the annual changes in gray matter volume. Indeed, younger participants (< 65 years old) in our sample with more severe OSA showed a greater rate of annual change in gray matter volume, highlighting the presence of hypertrophy in this subgroup. This was underlined in all medial temporal lobe subregions. In participants aged between 65 and 75, no association between OSA severity and volume changes over time could be highlighted. Older participants (>75 years old) with greater OSA severity showed greater hippocampal and entorhinal cortex atrophy over time. These results therefore support a biphasic hypothesis of changes in cerebral gray matter in people with OSA, with an initial phase characterized by volume increases in younger adults, eventually leading to atrophy in older people. This thesis provides a clearer picture of the nature of the changes and mechanisms involved in the association between OSA severity and gray matter volumes. An important contribution is the use of a new methodology to obtain a free-water portion, which allows to better understand the potential contribution of mechanisms that may underlie the structural changes observed, notably cerebral edema. In addition, the assessment of participants' individual characteristics helped to partially explain incongruities between previous studies. Indeed, in the studies included in this thesis, we observed more marked changes in certain subgroups of participants, notably women. We were also able to demonstrate that the age of individuals with OSA could significantly influence the pattern of changes observed, either gray matter hypertrophy or atrophy. The results of this thesis could therefore make it possible to target specific subgroups of individuals suffering from OSA who may be at greater risk of displaying changes in gray matter structure, and thus promote screening and treatment when necessary.

Tauopathy, which results from the oligomerization of misfolded tau protein in neurons, is a feature present in a number of neurodegenerative diseases and a hallmark of Alzheimer’s Disease (AD). Tau is an important phosphoprotein that regulates the assembly of microtubules, but tauopathy can occur when tau becomes hyperphosphorylated. Phosphorylation prevents tau from binding to tubulin, which results in cytosolic accumulation of tau and eventual oligomerization. This abnormal accumulation of tau leads to the spreading of hyperphosphorylated tau to downstream synaptically connected neurons through an unknown mechanism. In AD, the hippocampus is one of the first brain structures to be affected by tauopathy in humans. According to previous research, tauopathy occurs primarily between principal cells in the hippocampus. The involvement of local inhibitory interneurons in tauopathy and their potential role in AD is more controversial. Previous research suggests that tau pathogenesis primarily affects principal cells; however, given the importance, diversity, and function of interneurons in the hippocampus, it is important to gain a better understanding of the interneuron subtypes that may be impacted by the spread of trans-synaptic tau into the hippocampus. Understanding the involvement of interneurons in trans-synaptic tau transmission is important to understanding neurodegeneration in AD and other neurodegenerative disorders. To investigate this, both male and female genetically-modified mice underwent surgery to examine the trans-synaptic spread of pathogenic tau (EGFP-Tau P301L) from the entorhinal cortex to hippocampal neurons. Histology and imaging analysis of brain sections were performed to examine the hippocampal cells impacted by trans-synaptic spread of tau. Results show that pathogenic tau can trans-synaptically spread from presynaptic neurons in the entorhinal cortex into downstream hippocampal interneurons and also that hippocampal interneurons are capable of trans-synaptically spreading tau. Future studies examining the specific subtypes of hippocampal interneurons vulnerable to trans-synaptic spread of tau will be important for a better understanding of disease progression, which could lead to uncovering new therapeutic targets for neurodegenerative diseases, like AD, which are associated with tauopathy.

Alzheimer’s disease (AD) is a degenerative disorder where the distribution of pathology throughout the brain is not random but follows a predictive pattern used for pathological staging. While the involvement of defined functional systems is fairly well established for more advanced stages, the initial sites of degeneration are still ill defined. The prevailing concept suggests an origin within the transentorhinal and entorhinal cortex (EC) from where pathology spreads to other areas. Still, this concept has been challenged recently suggesting a potential origin of degeneration in nonthalamic subcortical nuclei giving rise to cortical innervation such as locus coeruleus (LC) and nucleus basalis of Meynert (NbM). To contribute to the identification of the early site of degeneration, here, we address the question whether cortical or subcortical degeneration occurs more early and develops more quickly during progression of AD. To this end, we stereologically assesses neurone counts in the NbM, LC and EC layer-II in the same AD patients ranging from preclinical stages to severe dementia. In all three areas, neurone loss becomes detectable already at preclinical stages and is clearly manifest at prodromal AD/MCI. At more advanced AD, cell loss is most pronounced in the NbM > LC > layer-II EC. During early AD, however, the extent of cell loss is fairly balanced between all three areas without clear indications for a preference of one area. We can thus not rule out that there is more than one way of spreading from its site of origin or that degeneration even occurs independently at several sites in parallel.

The brain processes information sensed from the environment and guides behaviour. A fundamental component in this process is the storage and retrieval of past experiences as memories, which relies on the hippocampal formation. Although there has been a great progress in understanding the underlying neural code by which neurons communicate information, there are still open questions. Neural activity can be measured extracellularly as either spikes or field potentials. Isolated spikes and bursts of high-frequency spikes followed by silent periods can transmit messages to distant networks. The local field potential (LFP) reflects synaptic activity within a local network. The interplay between the two has been linked to cognitive functions, such as memory, attention and decision making. However, the code by which this neural communication is achieved is not well understood. We investigated a mechanism by which local network information contained in LFP rhythms can be transmitted to distant networks in the formof spike patterns fired by bursting neurons. Since rhythms within different frequency bands are prevalent during behavioural states, we studied this encoding during different states within the hippocampal formation. In the first paper, using a computational model we show that bursts of different size preferentially lock to the phase of the dominant rhythm within the LFP.We also present examples showing that bursting activity in the subiculum of an anaesthetised rat was phase-locked to delta or theta rhythms as predicted by the model. In the second paper, we explored possible neural codes by which bursting neurons can encode features of the LFP.We used the computational model reported in the first paper and analysed recordings from the subiculum of anaesthetised rats and the medial entorhinal cortex of an awake behaving rat. We show that bursting neurons encoded information about the instantaneous voltage, phase, slope and/or amplitude of the dominant LFP rhythm (delta or theta) in their firing rate. In addition, some neurons encoded about 10-15% of this information in intra-burst spike counts. We subsequently studied how the interactions between delta or theta rhythms can transfer information between different areas within the hippocampal formation. In the third paper, we show that delta and theta rhythms can act as separate routes for simultaneously transferring segregate information between the hippocampus and the subiculum of anaesthetised mice. We found that the phase of the rhythms conveyed more information than amplitude. We next investigated whether neurodegenerative pathology affects this information exchange. We compared information transfer within the hippocampal formation of young transgenic mice exhibiting Alzheimer’s disease-like pathology and healthy aged-matched control mice and show that at early stages of the disease the information transmission by LFP rhythm interactions appears to be intact but with some differences. The outcome of this project supports a burst code for relaying information about local network activity to downstream neurons and underscores the importance of LFP phase, which provides a reference time frame for coordinating neural activity, in information exchange between neural networks.

In dieser Arbeit werden Struktur-Funktionsbeziehungen in der medialen entorhinalen Hirnrinde untersucht. Schicht 2 Neurone im medialen entorhinalen Cortex unterteilen sich in calbindin-positive Pyramidenzellen und calbindin-negative Sternzellen. Calbindin-positive Pyramidenzellen bündeln ihre apikalen Dendriten zusammen und formen Zellhaufen, die in einem hexagolen arrangiert sind. Das Gitter von calbindin-positiven Pyramidenzellhaufen ist an Schicht 1 Axonen und dem Parasubiculum ausgerichtet und wird durch cholinerge Eingänge innerviert. Calbindin-positive Pyramidenzellen zeigen stark theta-modulierte Aktivität. Sternzellen sind vertreut in der Schicht 2 angeordnet und zeigen nur schwach theta-modulierte Aktivität, ein Befund, der gegen eine Rolle von zell-intrinsischen Oszillationen in der Entstehung von Theta-Modulation spricht. In der Arbeit wurden Methoden entwickelt, um durch die juxtazelluläre Färbung und Identifikation von Zellen, die räumlichen Feuermuster von Schicht 2 Sternzellen und Pyramidenzellen zu bestimmen. Insbesondere wird gezeigt, dass die zeitlichen Feuermuster von Sternzellen und Pyramidenzellen so unterschiedlich sind, dass auch Daten von nichtidentifizierten extrazellulär abgeleiteten Zellen Sternzellen und Pyramidenzellen zugeordnet werden können. Die Ergebnisse zeigen, dass Gitterzell (engl. grid cell) Feuermuster relativ selten sind und in der Regel in Pyramidenzellen beobachtet werden. Grenzzell (engl. border cell) Feuermuster sind dagegen meistens in Sternzellen zu beobachten. Weiterhin wurde die Anatomie und Physiologie des Parasubiculums untersucht. Die Ergebnisse deuten auf die Existenz eines hexagonalen ‘Gitterzell-gitters’ in der entorhinalen Hirnrinde hin und sprechen für starke Struktur-Funktionsbeziehungen in diesem Teil der Hirnrinde. / Little is known about how medial entorhinal cortical microcircuits contribute to spatial navigation. Layer 2 principal neurons of medial entorhinal cortex divide into calbindin-positive pyramidal cells and dentate-gyrus-projecting calbindin-negative stellate cells. Calbindin-positive pyramidal cells bundled dendrites together and formed patches arranged in a hexagonal grid aligned to layer 1 axons, parasubiculum and cholinergic inputs. Calbindin-positive pyramidal cells were strongly theta modulated. Calbindin-negative stellate cells were distributed across layer 2 but avoided centers of calbindin-positive pyramidal patches, and were weakly theta modulated. We developed techniques for anatomical identification of single neurons recorded in trained rats engaged in exploratory behavior. Furthermore, we assigned unidentified juxtacellular and extracellular recordings based on spike phase locking to field potential theta. In layer 2 of medial entorhinal cortex, weakly hexagonal spatial discharges and head direction selectivity were observed in both cell types. Clear grid discharges were predominantly pyramidal cells. Border cells were mainly stellate neurons. Thus, weakly theta locked border responses occurred in stellate cells, whose dendrites sample large input territories, whereas strongly theta-locked grid discharges occurred in pyramidal cells, which sample small input territories in patches organized in a hexagonal ‘grid-cell-grid’. In addition, we investigated anatomical structures and neuronal discharge patterns of the parasubiculum. The parasubiculum is a primary target of medial septal inputs and parasubicular output preferentially targeted patches of calbindin-positive pyramidal cells in layer 2 of medial entorhinal cortex. Parasubicular cells were strongly theta modulated and carried mostly head-direction and border information, and might contribute to shape theta-rhythmicity and the (dorsoventral) integration of information across entorhinal grid scales.