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.

A growing interest for Cannabidiol (CBD), a component of Cannabis Sativa, has occurred over the past years. The medical potential of the component is yet to be better characterized, as its effects on sleep, and in particular memory, are to date not well understood or consistently characterized. This master thesis project focuses on analysing the effect of CBD on an anaesthesia-induced sleep-like state in rats, and its effects on the hippocampal sharp-wave-ripples, which have been shown to be associated with memory replay during sleep, and hence system consolidation. The hippocampus and prefrontal cortex, the two structures involved in memory consolidation, were recorded in 19 rats, split in two groups (CBD and vehicle). From these recordings, an automated sleep scorer using principal component analysis was developed to obtain the animals’ hypnograms, which were analysed to study sleep-like structure. From the recordings of the hippocampal pyramidal layer, and an additionnal layer deeper under it, respectively ripples and sharp waves were detected in all animals, and characterized for each group. We observed and demonstrated that CBD changes the sleep-like structure by shortening both REM and NREM bouts, resulting in an increase in transitions between both states. Additionally, we observed that, although ripples are not significantly different between both groups, sharp waves tend to be smaller among CBD animals. Lastly we noticed that both sharp wave and ripple activity, after increasing upon transition to NREM, decreases as the bout last. This finding suggests that vehicle animals, who have longer bouts and less transitions, would display less sharp wave and ripple activity, although we found no significant difference in the amount of both brain events. This paradox suggests that there is still more to characterize in order to understand if CBD enhances or not memory consolidation. In sum, CBD changes anaesthesia-induced sleep by shortening the duration of both NREM and REM bouts, resulting in an increase in transitions between both state. As for sleep events, sharp waves appeared shorter among CBD animals, although the same difference was not observed for ripples. Finally, sharp wave and ripple activity appear to peak upon transition from REM to NREM sleep, and decreases as the NREM bout lasts longer, however, no effect of CBD on this observation was highlighted.

Visual attention improves sensory processing, as well as perceptual readout and behavior. Over the last decades, many proposals have been put forth to explain how attention affects visual neural processing. These include the modulation of neural firing rates and synchrony, neural tuning properties, and rhythmic, subthreshold activity. Despite the wealth of knowledge provided by previous studies, the way attention shapes interactions between cortical layers within and between visual sensory areas is only just emerging. To investigate this, we studied neural signals from macaque V1 and V4 visual areas, while monkeys performed a covert, feature-based spatial attention task. The data were simultaneously recorded from laminar electrodes disposed normal to cortical surface in both areas (16 contacts, 150 μm inter-contact spacing). Stimuli presentation was based on the overlap of the receptive fields (RFs) of V1 and V4. Channel depths alignment was referenced to laminar layer IV, based on spatial current source density and temporal latency analyses. Our analyses mainly focused on the study of Local Field Potential (LFP) signals, for which we applied local (bipolar) re-referencing offline. We investigated the effects of attention on LFP spectral power and laminar interactions between LFP signals at different depths, both at the local level within V1 and V4, and at the inter-areal level across V1 and V4. Inspired by current progress from literature, we were interested in the characterization of frequency-specific laminar interactions, which we investigated both in terms of rhythmic synchronization by computing spectral coherence, and in terms of directed causal influence, by computing Granger causalities (GCs). The spectral power of LFPs in different frequency bands showed relatively small differences along cortical depths both in V1 and in V4. However, we found attentional effects on LFP spectral power consistent with previous literature. For V1 LFPs, attention to stimuli in RF location mainly resulted in a shift of the low-gamma (∼30-50 Hz) spectral power peak towards (∼3-4 Hz) higher frequencies and increases in power for frequency bands above low-gamma peak frequencies, as well as decreases in power below these frequencies. For V4 LFPs, attention towards stimuli in RF locations caused a decrease in power for frequencies < 20 Hz and a broad band increase for frequencies > 20 Hz. Attention affected spectral coherence within V1 and within V4 layers in similar way as the spectral power modulation described above. Spectral coherence between V1 and V4 channel pairs was increased by attention mainly in the beta band (∼ 15-30 Hz) and the low-gamma range (∼ 30-50 Hz). Attention affected GC interactions in a layer and frequency dependent manner in complex ways, not always compliant with predictions made by the canonical models of laminar feed-forward and feed-back interactions. Within V1, attention increased feed-forward efficacy across almost all low-frequency bands (∼ 2-50 Hz). Within V4, attention mostly increased GCs in the low and high gamma frequency in a 'downwards' direction within the column, i.e. from supragranular to granular and to infragranular layers. Increases were also evident in an ‘upwards’ direction from granular to supragranular layers. For inter-areal GCs, the dominant changes were an increase in the gamma frequency range from V1 granular and infragranular layers to V4 supragranular and granular layers, as well as an increase from V4 supragranular layers to all V1 layers.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and DBS of the pedunculopontine nucleus (PPN) have been shown to be effective surgical therapies for Parkinson’s disease (PD). To better understand the PPN and STN as DBS targets for PD, this research compares the anatomy, electrophysiology, and motor control roles of these nuclei. PPN and STN connections were examined in vivo in human subjects and in the non-human primate using probabilistic diffusion tractography. Both the PPN and STN were connected with each other and with the motor cortex (M1) and basal ganglia. After studying these anatomical connections in primates, their functional significance was further explored in an anesthetized rat model of PD. Examination of the electrophysiological relationship between the PPN and basal ganglia in the presence of slow cortical oscillatory activity suggested that excitatory input from the STN may normally modulate PPN spike timing but that inhibitory oscillatory input from the basal ganglia output nuclei has a greater effect on PPN spike timing in the parkinsonian brain. To examine transmission and modulation of oscillatory activity between these structures at higher frequencies, LFP activity was recorded from the PPN and STN in PD patients performing simple voluntary movements. Movement-related modulation of oscillatory activity predominantly occurred in the α (8-12 Hz) and low β (12-20 Hz) frequencies in the STN but in the high β (20-35 Hz) frequencies in the PPN, supporting observations from rodent studies suggesting that oscillatory activity is not directly transmitted from the STN to the PPN in PD. Finally, to better understand the roles of the STN and PPN in large-scale movement, the effects of STN and PPN DBS on gait abnormalities in PD patients were studied. DBS of the STN appeared to improve gait by optimising executive gait control while DBS of the PPN appeared to restore autonomic gait control. These results have several implications for DBS patient selection, surgical targeting, and for understanding the mechanisms underlying DBS efficacy.

Le rythme lent lié à la respiration est une caractéristique proéminente de l’activité du bulbe olfactif de rat. Il se définit par des oscillations de grande amplitude du potentiel de champ local, une activité de décharge des cellules mitrales/ à panache (M/P) synchronisée à la respiration et des oscillations lentes de leur potentiel de membrane (OPLM). Des relations spécifiques entre ces activités détermineraient la participation d’une cellule M/P au traitement de l’information olfactive. Jusqu’à présent, il n'existait que très peu de données sur ces relations. L’objectif de cette thèse a été de caractériser les OLPM des cellules M/P et d’étudier les relations qu’elles entretiennent avec l’activité de décharge et l’activité du réseau bulbaire. Pour répondre à cet objectif, nous avons mis au point une technique d’enregistrements simultanés de l’activité intracellulaire des cellules M/P et du potentiel de champ local du bulbe olfactif chez l’animal anesthésié et libre de respirer. Nous montrons que plusieurs types d’OLPM existent. Des relations spécifiques s’établissent entre ces OLPM et la synchronisation de l’activité de décharge à la respiration. Nous observons également l’existence de relations complexes entre les OLPM et les oscillations du réseau bulbaire. L’ensemble de ces résultats nous permet d’intégrer la dynamique lente, et plus particulièrement celle du potentiel de membrane, à un schéma général du traitement de l’information olfactive et de proposer son implication dans la formation d’assemblée de neurones. / The respiration-related slow rhythm strongly shapes the activity of the olfactory bulb. This rhythm is characterized by high amplitude oscillations in the local field potential, respiration synchronization of mitral/tufted (M/T) cell discharge and slow oscillation of M/T cell membrane potential (OLPM). Specific relationships between these activities could determine the M/T cell participation to olfactory processing. However, little is known on these relationships. The aim of my thesis has been to characterize M/T cell OLPM and to study the relationships between OLPM and both discharge and bulbar network activities. In this way, we recorded simultaneously intracellular activity of M/T cell and local field potential of olfactory bulb in anesthetized freely breathing rat. We showed that several types of OLPM can be distinguished and exhibited specific relationship with the respirations ynchronization of M/T cell discharge activity. We observed also specific and complex relationships between OLPM and local field potential oscillation. Taken together, our results allowed us to integrate slow rhythm, and more particularly OLPM, in the more general scheme of olfactory processing.

Chez les mamifères terrestres, l’échantillonnage des odeurs (flairage) est inextricablement lié à la respiration. Le flairage contraint à la fois le décours temporel et l’intensité de l’input olfactif. Or le flaireage est un acte dynamique, il peut varier aussi bien en fréquence qu’en débit. Dans une 1ère partie de mon travail de thèse, nous avoins souhaité caractériser l’impact des variations de fréquence et de débit respiratiore sur l’activité du bulbe olfactif. Pour cela, nous avons mis au point une méthode de double trachéotomie chez le rat anesthésié nous permettant de contrôler précisément les flux d’air ans la cavité nasale. En paralèlle, nous avons enregistrer l’acitivité unitaire et de réseau du bulbe olfactif. Nous montrons que les variations de flairage modulent la représentation neuronale bulbaire des odeurs en modifiant à la fois l’activité de décharge des cellules principales et l’occurence des oscillaations du potentiel de champ local. Dans une 2e partie de ma thèse, nous avons souhaitécomprendre quel pouvait être le rôle du flairage chez un animal qui se comporte. Nous avons posé l’hypothèse qu’un animal pouvait adapter sa façon de flaireer en fonction de la qualité des molécules odorantes. Pour tester cette hypothèse, nous avons mis au point un système d’enregeistrement non invasif de la respiration couplé à une tâche de discrimination olfactive chez le rat. Nous montrons non seulement que les animaux peuvent adapter leur flairage en fonction des molécules odorantes masi également en focntion du contexte dans lequel l’odeur est présentée. L’ensemble de ces résultats s’intègre donc dans la problématique plus générale de l’intégration sensori-motrice. / In terrestrial mammals, an inextricable link between olfaction and respiration exists due to the periodic sampling of odorant molecules by inhalation. The features of sniffing (or breathing) constrain both the timing and the intensity of the input to the olfactory structures. But rather than being fixed, sniffing in the bahavingrodent is highly dynamic and varies both in frequency and flow rate. During the firs stage of my PhD, I asked to what extent sniffing parameters (frequency and flow rate) variations could affect the olfactory bulb activity. To address this question, I developped a double tracheotomy protocol in anesthetized rats to precisely control and modify the nasal airflow. In parallel, I recorded oldfactory bulbactivities, single-unit activity and local field potentials. We showed that, at the olfactory bulb level, the neutral representation of an odor is highly modified by sampling variations. In fact both the mitral/tufted cell discharge patterns and local field potentials oscilliations were affected by sniffing variations. In the second stage, we wanted to understand the role of sniffing variations in behaving animals. We hypothesized tha t an animal could adapt its sniffing strategy relative to the quality of the odorant molecules. To test this hypothesis, we developped a tool to record sniffing in a non invasive way, and combined it to an olfactory discrimination task in the rat. We showed that animals not only adapted their sniffing relative to the odorant quality but also to the odorant context. Taken together, these results fit into the broader context of sensory-motor integration.

Durch Kreuzkorrelation von ECoG- und EEG-Signalen hoher Bandbreite (10 - 400 Hz) mit dem Muster eines Amplituden - Zeit - Templates von 10 ms Dauer können Subpotentiale (SP) selektiert werden, die dem sogenannten ?local field potential? ähnlich sind.Diese Ähnlichkeit ergibt sich i. durch den Vergleich mit dem ermittelten Amplituden - Zeit - Template des SP. ii. durch den Vergleich mit der Lage der Quellstrukturen zur ableitenden Elektrode. Die SP - Modulanalyse liefert Potentialverteilung für jede untersuchte Elektrode. Diese ist stets in ein Nahfeld und Fernfelder organisiert, wobei die Polarität des Nahfeld der Polarität des Trigger- SP entspricht und das Fernfeld von entgegengesetzter Polarität ist. Diese Quellstrukturen sind um so kleiner, je geringer der Elektrodenabstand ist. iii. aus der Kohärenz von SP, die im Ableitfeld auftreten. Dafür wurde die SP- Zweikanalkopplungsanalyse entwickelt.Die einzelnen Schritte dieser SP - Methode, die sich aus der SP - event-, SP - Modul- und SP - Zweikanalkopplungsanalyse zusammensetzt, werden beschrieben und an einem Beispiel einer 30 kanaligen subduralen interiktalen ECoG - Ableitung eines Patienten mit fokaler Epilepsie unter drei verschiedenen Bedingungen (normales ECoG, ECoG mit spikes bzw. ECoG mit slow waves) sowie am Beispiel einer 30 kanaligen EEG-Ableitung eines Probanden unter drei verschiedenen kognitiven Anforderungen (relaxierte Wachheit, Kopfrechnen, beim Anhören eines Hörspiels) vergleichend demonstriert. Beide Beispiele sind repräsentativ für zwei größere Untersuchungsreihen. / We obtained subpotentials (SP), similar to so called ?local field potentials? by application of cross - correlation on ECoG- and EEG- Signals with large band width (10 - 400 Hz) with the pattern of an amplitude-time-template with a duration of 10ms. This similarity is given by i. the comparison with obtained amplitude-time-template of the SP ii. the comparison with the position of source- structures to the deriving electrode. The potential distribution is given by the SP - moduleanalysis for each investigated electrode. This SP - module - analysis is always organised in a near- and in a far-field. The polarity of the near-field corresponds to the trigger-SP and the far-field to the opposite. The smaller the source-structure, the lower the distance of the electrodes iii.the coherence of SP in the deriving array The SP - method, consisting of SP - event, SP - module and SP ?two-channel-coupling -analysis? is described. The comparison between an example of an 30 channel subdural interictal derived ECoG of a patient, who was suffering from focal epilepsy, under three conditions (normal ECoG, ECoG with spikes and ECoG with slow-waves) and one of an 30 channel derived EEG of a candidate under three different cognitive demands (relaxed vigilance, doing mental arithmetic, listening to a radio serial) is demonstrated an discussed. Both examples are representatives for two extensive serials.

Neurons can respond to input by firing isolated action potentials or spikes. Sequences of spikes have been linked to the encoding of neuron input. However, many neurons also fire bursts; mechanistically distinct responses consisting of brief high-frequency spike firing. Bursts form separate response symbols but historically have not been thought to encode input. However, recent experimental evidence suggests that bursts can encode input in parallel with tonic spikes. The recognition of bursts as distinct encoding symbols raises important questions; these form the basic aims of this thesis: (1) What inputs do bursts encode? (2) Does burst structure provide extra information about different inputs. (3) Is burst coding robust against the presence of noise; an inherent property of all neural systems? (4) What mechanisms are responsible for burst input encoding? (5) How does burst coding manifest in in-vivo neurons. To answer these questions, bursting is studied using a combination of neuron models and in-vivo hippocampal neuron recordings. Models ranged from neuron-specific cell models to models belonging to three fundamentally different burst dynamic classes (unspecific to any neural region). These classes are defined using concepts from non-linear system theory. Together, analysing these model types with in-vivo recordings provides a specific and general analysis of burst encoding. For neuron-specific and unspecific models, a number of model types expressing different levels of biological realism are analysed. For the study of thalamic encoding, two models containing either a single simplified burst-generating current or multiple currents are used. For models simulating three burst dynamic classes, three further models of different biological complexity are used. The bursts generated by models and real neurons were analysed by assessing the input they encode using methods such as information theory, and reverse correlation. Modelled bursts were also analysed for their resilience to simulated neural noise. In all cases, inputs evoking bursts and tonic spikes were distinct. The structure of burst-evoking input depended on burst dynamic class rather than the biological complexity of models. Different n-spike bursts encoded different inputs that, if read by downstream cells, could discriminate complex input structure. In the thalamus, this n-spike burst code explains informative responses that were not due to tonic spikes. In-vivo hippocampal neurons and a pyramidal cell model both use the n-spike code to mark different LFP features. This n-spike burst may therefore be a general feature of bursting relevant to both model and in-vivo neurons. Bursts can also encode input corrupted by neural noise, often outperforming the encoding of single spikes. Both burst timing and internal structure are informative even when driven by strongly noise-corrupted input. Also, bursts induce input-dependent spike correlations that remain informative despite strong added noise. As a result, bursts endow their constituent spikes with extra information that would be lost if tonic spikes were considered the only informative responses.

Par sa connectivité directe avec le cortex, le noyau subthalamique (NST) représente une des structures d'entrée du système des ganglions de la base, et se trouve impliqué dans différents aspects du comportement (contrôle moteur, cognitif et limbique). Néanmoins, les corrélats électrophysiologiques de ces processus restent débattus. Les études effectuées dans le cadre de cette thèse visent à éclaircir le rôle possible du NST dans trois fonctions exécutives, à savoir l'inhibition réactive (suppression d'un mouvement programmé), l'inhibition proactive (préparation à inhiber son mouvement) et l'attention soutenue. Pour ce faire, les activités extracellulaires et/ou en potentiels de champs locaux du NST ont été enregistrées chez 28 patients parkinsoniens pendant qu'ils effectuaient des taches cognitives, visant à dissocier les corrélats de ces différentes fonctions exécutives. Dans une première étude, les activités en potentiel de champs locaux du NST lors de l'inhibition réactive et proactive ont été étudiées à l'aide d'un paradigme modifié du « stop signal ». L'inhibition réactive se caractérise par une augmentation rapide de synchronisation relative de l'activité du NST dans la bande de fréquence β (13-35 Hz), tandis que l'inhibition proactive se caractérise par la maintenance tonique d'un niveau élevé d'activité β qui prédit les performances des patients lors de l'inhibition réactive. Dans la seconde étude, nous avons montré qu'une population neuronale (n=7 neurones) augmente rapidement sa fréquence de décharge lors de l'inhibition réactive. Enfin, dans la troisième étude, nous avons utilisé un paradigme permettant de moduler le niveau attentionnel requis pour réaliser un comportement simple. Nos résultats indiquent qu'une baisse d'activité β est observée uniquement lorsque le sujet maintient une attention soutenue pour encoder, retrouver en mémoire une information afin de produire une réponse. L'ensemble de ces résultats nous ont permis d'apporter des preuves électrophysiologiques de l'implication du NST dans ces différentes fonctions et de clarifier la dynamique temporelle des activités neuronales supportant ces processus. Ils suggèrent ainsi l'hypothèse d'une implémentation de différents aspects du contrôle exécutif dans le NST via des mécanismes communs et interactifs dont la dynamique temporelle permettrait la modulation fine du comportement. / The subthalamic nucleus (STN) is an input structure of the basal ganglia implicated in many behavioral processes (motor, cognitive and limbic control). However the electrophysiological correlates of these processes remain unclear. This thesis aims to clarify the role of the STN during 3 executive functions: reactive inhibition (suppression of a prepotent move), proactive inhibition (preparation to inhibit a move) and sustained attention. To this end, extracellular and local field potential activities were recorded in 28 patients with Parkinson's disease while they performed cognitive tasks, aiming to dissociate the neural correlates of these executive functions In a first study, local field potentials β (13-35 Hz) activity was recorded in the STN during reactive and proactive inhibition. Reactive Inhibition was related to a relative increase of β activity, while proactive inhibition was related to maintenance of a tonic level of β activity predictive of reactive inhibitory performances. In a second study, we showed that reactive inhibition is related to a phasic increase of firing rate in a neuronal subpopulation (n=7 neurons). In a third study, we recorded Local field potentials in the STN while patients performed a sustained attention-demanding task (combining a visual search and a delayed match-to-sample paradigm) and found a systematic suppression of 15-35 Hz activity during each repetition of the task directly related to the amount of attention allocated by the participants. Altogether, these results present electrophysiological evidences of the implication of the STN in these functions and clarify the temporal dynamics of neuronal activities supporting these processes. These results may suggest an implementation of various executive functions in the STN via common and interactive mechanisms which temporal dynamics would mediate behavioral control.

Gamma oscillations of local field potentials (LFP) in the basal ganglia and thalamus had not been studied during saccades. Eleven patients were studied during deep brain stimulation (DBS); 6 were in the subthalamic nucleus (STN); 3 in the globus pallidus interna (GPi); and 2 in the thalamic ventralis intermedius nucleus (Vim). Patients performed horizontal saccades to visual targets while LFPs from DBS electrodes, scalp electroencephalogram (EEG), and electrooculogram (EOG) were recorded. Wavelet spectrograms were generated and saccade onset and event-related gamma synchronizations (ERS) were compared to baseline without eye motion. ERS were recorded at and after saccade onset in the STN, GPi and Vim, EEGs and EOGs; but were absent during target light illumination without saccades. ERS were symmetric in all DBS contacts and appeared identical in DBS LFPs, frontal EEGs and EOGs. These findings indicate their origin from extraocular muscle spike potentials rather than brain neural activity.