Theta activity is one of the most prominent rhythms in the brain and appears to be conserved among mammals.  These 4-12 Hz oscillations have been predominantly studied in the dorsal hippocampus where they are correlated with a broad range of voluntary and exploratory behaviors. Theta activity has been also implicated in a number of mnemonic processes, long-term potentiation (LTP) induction and even acting as a global synchronizing mechanism. Moving along the dorso-ventral axis theta activity is reduced in power and desynchronized from the dorsal part. However, theta activity can also be generated in the ventral hippocampus itself during anxiety- and fear-related behaviors. Until now it was unknown which hippocampal cell population was capable to generate theta activity and it was controversial if its origin was local, in the hippocampus, or driven by other brain regions. In this thesis I present compelling in vitro and in vivo  evidence that   a subpopulation of OLM interneurons (defined by the Chrna2-cre line)  distinctively enriched  in the CA1 region of  the ventral hippocampus is implicated in LTP function (paper I,II), information control (paper V) and the induction of theta activity that is under cholinergic  control (paper IV). Importantly, a concomitant effect of the optogenetically induced theta activity is reduction in anxiety (Paper IV). Another innovation of this work was the development of a methodological approach to avoid artefactual signals when combining electrophysiology with light activation during optogenetic experiments (Paper III). In summary, the work presented in this thesis elucidates the role of a morphologically and electrophysiologially identified cell population, OLMα2 interneurons, first on the cellular, then on the circuit and ultimately on the behavioral level.

The hippocampus is a brain structure involved in episodic memory and spatial cognition. Neuronal activity within the hippocampus exhibits intricate temporal patterning, including oscillatory and sequential dynamics, which are believed to underlie these cognitive processes. In individual cells, a temporal activity pattern called phase precession occurs which leads to the organisation of neuronal populations into sequences. These sequences are hypothesised to form a substrate for episodic memory and the representation of spatial trajectories during navigation. In this thesis, I present a novel theory of the phenomenological properties of these neuronal activity sequences. In particular, I propose that the sequential organisation of population activity is governed by the independent phase precession of each cell. By comparison of models in which cells are independent and models in which cells exhibit coordinated activity against experimental data, I provide empirical evidence to support this hypothesis. Further, I show how independent coding affords a vast capacity for the generation of sequential activity patterns across distinct environments, allowing the representation of episodes and spatial experiences across a large number of contexts. This theory is then extended to account for grid cells, whose activity patterns form a hexagonal lattice over external space. By analysing simple forms of phase coding in populations of grid cells, I show how previously undocumented constraints on phase coding in two dimensional environments are imposed by the symmetries of grid cell firing fields. To overcome these constraints, I propose a more complex phenomenological model which can account for phase precession in both place cells and grid cells in two dimensional environments. Using insights from this theory, I then propose a biophysical circuit mechanism for hippocampal sequences. I show that this biophysical circuit model can account for the proposed phenomenological coding properties and provide experimentally testable predictions which can distinguish this model from existing models of phase precession. Finally, I outline a scheme by which this biophysical mechanism can implement supervised learning using spike time dependent plasticity in order to learn associations between events occurring on behavioural timescales. The models presented in this thesis challenge previous theories of hippocampal circuit function and suggest a much higher degree of flexibility and capacity for the generation of sequences than previously believed. This flexibility may underlie our ability to represent spatial experiences and store episodic memories across a seemingly unlimited number of distinct contexts.

The amygdala, in particular its basolateral part (BLA), plays a critical role in binding affective qualities to otherwise neutral stimuli, and in eliciting emotional behaviors. Plasticity of inputs to BLA projection neurons involved in emotional memory has been extensively studied. However, how BLA neurons collectively process sensory information to encode and stabilize emotional memories is unknown. Precise coordination of BLA network activities seems critical. Specifically, timed integration of salient stimuli, and synchrony with hippocampal theta oscillations appear to be important. Recent reports suggest that GABAergic neurons may be instrumental in shaping ensemble activity in the BLA. Studies of neocortex and hippocampus showed that diverse GABAergic interneuron types play highly specific roles in coordinating network operations. The presence of similar interneuron populations in the BLA suggests comparable mechanism may govern its activities. However, GABAergic cell types and their functions have not been characterized.

The subthalamic nucleus (STN), which is the most common target for deep brain stimulation for Parkinson's disease, is known to be crucially involved in motor control. Recent appreciation of the potential non-motor side effects of STN deep brain stimulation, however, has led to speculation that the importance of this nucleus may also relate to processes involved in decision- making, particularly during high conflict scenarios. This thesis concerns itself with investigating the STN's role in action selection during conflict. I begin by recording local field potentials directly from the STN of Parkinson's disease patients while they perform a flanker task that has been shown to elicit theta (4-8 Hz) band activity in areas of the prefrontal cortex involved in cognitive control. I report that like the prefrontal cortex, the STN demonstrates elevated theta activity during conflict. I then test whether STN theta activity is related to that of the prefrontal cortex by recording from both sites simultaneously while patients perform a novel task that temporally separates conflict from stimulus onset or movement. This reveals that theta activity indeed becomes synchronized during conflict, with cortical oscillations driving those of the STN. Thirdly, I investigate how STN oscillations may affect firing rate dynamics by intra-operatively recording local field potentials and single unit activity from patients performing the flanker task. I report that both theta and beta (15-30 Hz) oscillations entrain STN neurons, but only during conflict. Finally, I record cortical and STN activity while a fourth group of patients performs the flanker task. This experiment confirms that cortico-STN theta synchrony is elevated during conflict and may also relate to across-trial adaptations to conflict and errors. Taken together these studies shed light on the mechanisms by which cortical structures may influence the STN during conflict and why STN deep brain stimulation may result in impulsivity.

<p>Forebrain cholinergic projection systems innervate the entire cortex and hippocampus. These cholinergic systems are involved in a wide range of cognitive and behavioral functions, including learning and memory, attention, and sleep-waking modulation. However, the <italic>in vivo</italic> physiological mechanisms of cholinergic functions, particularly their fast dynamics and the consequent modulation on the hippocampus and cortex, are not well understood. In this dissertation, I investigated these issues using a number of convergent approaches.</p><p> First, to study fast acetylcholine (ACh) dynamics and its interaction with field potential theta oscillations, I developed a novel technique to acquire second-by-second electrophysiological and neurochemical information simultaneously with amperometry. Using this technique on anesthetized rats, I discovered for the first time the tight <italic>in vivo</italic> coupling between phasic ACh release and theta oscillations on fine spatiotemporal scales. In addition, with electrophysiological recording, putative cholinergic neurons in medial setpal area (MS) were found with firing rate dynamics matching the phasic ACh release. </p><p> Second, to further elucidate the dynamic activities and physiological functions of cholinergic neurons, putative cholinergic MS neurons were identified in behaving rats. These neurons had much higher firing rates during rapid-eye-movement (REM) sleep, and brief responses to auditory stimuli. Interestingly, their firing promoted theta/gamma oscillations, or small-amplitude irregular activities (SIA) in a state-dependent manner. These results suggest that putative MS cholinergic neurons may be a generalized hippocampal activation/arousal network. </p><p> Third, I investigated the hypothesis that ACh enhances cortical and hippocampal immediate-early gene (IEG) expression induced by novel sensory experience. Cholinergic transmission was manipulated with pharmacology or lesion. The resultant cholinergic impairment suppressed the induction of <italic>arc</italic>, a representative IEG, suggesting that ACh promotes IEG induction. </p><p> In conclusion, my results have revealed that the firing of putative cholinergic neurons promotes hippocampal activation, and the consequent phasic ACh release is tightly coupled to theta oscillations. These fast cholinergic activities may provide exceptional opportunities to dynamically modulate neural activity and plasticity on much finer temporal scales than traditionally assumed. By the subsequent promotion of IEG induction, ACh may further substantiate its function in neural plasticity and memory consolidation.</p> / Dissertation

The perception of self-motion draws on inputs from the visual, vestibular and proprioceptive systems. Decades of behavioural research has shed light on constructs such as multisensory weighting, heading perception, and sensory thresholds, that are involved in self-motion perception. Despite the abundance of knowledge generated by behavioural studies, there is a clear lack of research exploring the neural processes associated with full-body, multisensory self-motion perception in humans. Much of what is known about the neural correlates of self-motion perception comes from either the animal literature, or from human neuroimaging studies only administering visual self-motion stimuli. The goal of this thesis was to bridge the gap between understanding the behavioural correlates of full-body self-motion perception, and the underlying neural processes of the human brain. We used a high-fidelity motion simulator to manipulate the interaction of the visual and vestibular systems to gain insights into cognitive processes related to self-motion perception. The present line of research demonstrated that theta, alpha and beta oscillations are the underlying electrophysiological oscillations associated with self-motion perception. Specifically, the three empirical chapters combine to contribute two main findings to our understanding of self-motion perception. First, the beta band is an index of visual-vestibular weighting. We demonstrated that beta event-related synchronization power is associated with visual weighting bias, and beta event-related desynchronization power is associated with vestibular weighting bias. Second, the theta band is associated with direction processing, regardless of whether direction information is provided through the visual or vestibular system. This research is the first of its kind and has opened the door for future research to further develop our understanding of biomarkers related to self-motion perception. / Dissertation / Doctor of Philosophy (PhD) / As we move through the environment, either by walking, or operating a vehicle, our senses collect many different kinds of information that allow us to perceive factors such as, how fast we are moving, which direction we are headed in, or how other objects are moving around us. Many of our senses take in very different information, for example, the vestibular system processes information about our head movements, while our visual system processes information about incoming light waves. Despite how different all of this self-motion information can be, we still manage to have one smooth perception of our bodies moving through the environment. This smooth perception of self-motion is due to our senses sharing information with one another, which is called multisensory integration. Two of the most important senses for collecting information about self-motion are the visual and vestibular systems. To this point, very little is known about the biological processes in the brain while the visual and vestibular systems integrate information about self-motion. Understanding this process is limited because until recently, we have not had the technology or the methodology to adequately record the brain while physically moving people in a virtual environment. Our team developed a ground-breaking set of methodologies to solve this issue, and discovered key insights into brainwave patterns that take place in order for us to perceive ourselves in motion. There were two critical insights from our line of research. First, we identified a specific brainwave frequency (beta oscillations) that indexes integration between the visual and vestibular systems. Second, we demonstrated another brainwave frequency (theta oscillation) that is associated with perceiving which direction we are headed in, regardless of which sense this direction information is coming from. Our research lays the foundation for our understanding of biological processes of self-motion perception and can be applied to diagnosing vestibular disorders or improving pilot simulator training.

La douleur sociale est une forme de douleur non physique dérivant de la perception de l'exclusion sociale. L'importance de la compréhension de ses modulations comportementales et neuronales est fondamentale, car ses conséquences sur le long terme peuvent être très néfastes. Dans ce travail de thèse, j'ai exploré ces aspects à travers une étude comportementale à l‟aide d‟enregistrements par SCR (Skin Conductance Recording), et trois études en iEEG (électro-encéphalographie intracrânienne) chez des patients épileptiques. La première étude comportementale a exploré la direction dans laquelle l'exclusion sociale est influencée par une récompense et ses réactions sur le long terme. Ainsi, la récompense monétaire altère l'équilibre social et augmente l‟activité électrodermale. La personne ayant été exclue met alors en oeuvre des mécanismes de vengeance en défavorisant la personne qui l‟a exclue précédemment. Les études en iEEG ont été une fenêtre unique d'exploration du cerveau lors de différentes types de modulation de l'exclusion. Dans la première étude en iEEG, nous avons observé que la douleur sociale produit une activation des oscillations thêta (3-7 Hz), lors de d'exclusion, dans l'insula, l'ACC, le cortex préfrontal et le gyrus fusiforme. La deuxième étude iEEG s'est intéressée aux modulations produites par la douleur sociale dans BA 19 et BA 17 présentant des P1 d'amplitude majeure lors de l'observation des photos du joueur qui exclut. La troisième étude en iEEG a exploré la réponse neuronale de l'influence d'une variable monétaire lors de l'exclusion. Nos résultats démontrent que l'insula postérieure présente une activation thêta indépendante du fait que l'exclusion soit positive (exclusion et gain d'argent) ou encore négative (exclusion et perte d'argent), à la différence de l'insula antérieure, active seulement lors d'une exclusion négative / Pain is a form of social non-physical pain arising from the perception of social exclusion. The importance of understanding its behavioral and neuronal modulations has a critical value, since its long lasting consequences can be extremely harmful. In this thesis I firstly explored these issues through a behavioral SCR study (Skin Conductance Recording), and successively through three iEEG studies in patients with epilepsy (intracranial EEG). The SCR study explored the direction in which social exclusion is influenced by a reward and its long lasting reactions. Money affects social equilibrium and increases the SCR pics. The excluded individual implements revenge attitudes toward the person who excluded in a previuous interaction. The iEEG studies were a unique window for exploring the brain during different types of social pain modulations. In the first iEEG study, we found that social pain produced activation of theta oscillations (3-7 Hz) during exclusion in the insula, in the ACC, in the prefrontal cortex and in the fusiform face area. The second iEEG study wanted to explore deeply the primitive modulations produced by social pain in visual area. We found in BA 19 and BA 17 greater P1 peak amplitude during excluder pictures presentation. The third iEEG study investigated the neuronal modulations produced by a monetary reward during social pain. These results demonstrated that the posterior insula has a theta activation independent of whether the exclusion is positive (excluded but gaining money) or more negative (excluded but losing money), whereas the anterior insula, has a theta activation only during a negative exclusion

Les processus d'apprentissage et de mémoire sont contrôlés par des circuits et éléments neuronaux spécifiques. De nombreuses études ont récemment mis en évidence que les circuits corticaux jouent un rôle important dans la régulation des comportements de peur, cependant, leurs caractéristiques anatomiques et fonctionnelles restent encore largement inconnues. Au cours de ma thèse, en utilisant des enregistrements unitaires et des approches optogénétiques chez la souris libre de se comporter, nous avons pu montrer que les interneurones inhibiteurs du cortex auditif et du cortex préfrontal médian forment un microcircuit désinhibiteur permettant respectivement l'acquisition et l'expression de la mémoire de peur conditionnée. Dans les deux cas, les interneurones parvalbuminergiques constituent l'élément central du circuit et sont inhibés de façon phasique. D’un point de vue fonctionnel, nous avons démontré que cette inhibition était associée à la désinhibition des neurones pyramidaux par un mécanisme de réduction de l'inhibition continue exercée par les interneurones parvalbuminergiques. Ainsi, les interneurones parvalbuminergiques peuvent contrôler temporellement l'excitabilité des neurones pyramidaux. En particulier, nous avons montré que l'acquisition de la mémoire de peur conditionnée dépend du recrutement d'un microcircuit désinhibiteur localisé dans le cortex auditif. En effet, au cours du conditionnement de peur, la présentation du choc électrique induit l'inhibition des interneurones parvalbuminergiques, ce qui a pour conséquence de désinhiber les neurones pyramidaux du cortex auditif et de permettre l’apprentissage du conditionnement de peur. Dans leur ensemble, ces données suggèrent que la désinhibition est un mécanisme important dans l'apprentissage et le traitement de l'information dans les circuits corticaux. Dans un second temps, nous avons montré que l'expression de la peur conditionnée requière l'inhibition phasique des interneurones parvalbuminergiques du cortex préfrontal médian. En effet, leur inhibition désinhibe les cellules pyramidales préfrontales et synchronise leur activité en réinitialisant les oscillations thêta locales. Ces résultats mettent en évidence deux mécanismes neuronaux complémentaires induits par les interneurones parvalbuminergiques qui coordonnent et organisent avec précision l’activité neuronale des neurones pyramidaux du cortex préfrontal pour contrôler l'expression de la peur conditionnée. Ensemble, nos données montrent que la désinhibition joue un rôle important dans les comportements de peur en permettant l’association entre des informations comportementalement pertinentes, en sélectionnant les éléments spécifiques du circuit et en orchestrant l'activité neuronale des cellules pyramidales. / Learning and memory processes are controlled by specific neuronal circuits and elements. Numerous recent reports highlighted the important role of cortical circuits in the regulation of fear behaviour, however, the anatomical and functional characteristics of their neuronal components remain largely unknown. During my thesis, we used single unit recordings and optogenetic manipulations of specific neuronal elements in behaving mice, to show that both the auditory cortex and the medial prefrontal cortex contain a disinhibitory microcircuit required respectively for the acquisition and the expression of conditioned fear memory. In both cases, parvalbumin-expressing interneurons constitute the central element of the circuit and are phasically inhibited during the presentation of the conditioned tone. From a functional point of view, we demonstrated that this inhibition induced the disinhibition of cortical pyramidal neurons by releasing the ongoing perisomatic inhibition mediated by parvalbumin-expressing interneurons onto pyramidal neurons. Thereby, this disinhibition allows the precise temporal regulation of pyramidal neurons excitability. In particular, we showed that the acquisition of associative fear memories depend on the recruitment of a disinhibitory microcircuit in the auditory cortex. Fear-conditioning-associated disinhibition in auditory cortex is driven by foot-shock-mediated inhibition of parvalbumin-expressing interneurons. Importantly, pharmacological or optogenetic blockade of pyramidal neuron disinhibition abolishes fear learning. Together, these data suggest that disinhibition is an important mechanism underlying learning and information processing in cortical circuits. Secondly, in the medial prefrontal cortex, we demonstrated that expression of fear behaviour is causally related to the phasic inhibition of prefrontal parvalbumin-expressing interneurons. Inhibition of parvalbumin-expressing interneuron activity disinhibits prefrontal pyramidal neurons and synchronizes their firing by resetting local theta oscillations, leading to fear expression. These results identify two complementary neuronal mechanisms both mediated by prefrontal parvalbumin-expressing interneurons that precisely coordinate and enhance the neuronal efficiency of prefrontal pyramidal neurons to drive fear expression. Together these data highlighted the important role played by neuronal disinhibition in fear behaviour by binding behavioural relevant information, selecting specific circuit elements and orchestrating pyramidal neurons activity.

Um eine Folge von Ereignissen aus unserem Gedächtnis abzurufen, ist zunächst ein Mechanismus erforderlich, der geordnete Sequenzen abspeichert. Hierbei stehen wir vor dem Problem, dass Ereignisse in unserem Leben auf einer Zeitskala von Sekunden oder mehr stattfinden. Auf der anderen Seite basiert das Lernen von Sequenzen auf der Plastizität von Synapsen im Gehirn, die durch die Abfolge von Aktionspotentialen von Nervenzellen im Millisekunden-Bereich gesteuert wird. Um dieses zeitliche Problem zu lösen, betrachten wir den Hippocampus, eine Struktur im Gehirn von Vertebraten, die für das explizite Gedächtnis (Fakten, Ereignisse, Sequenzen) entscheidende Bedeutung hat. In Nagetieren ist der Hippocampus sehr gut untersucht. Dort wurden Neurone gefunden, die nur dann aktiv sind, wenn das Tier innerhalb einer bestimmten Region seiner Umgebung ist: im sogenannten “Ortsfeld” des entsprechenden Neurons. Während der Bewegung durch ein Ortsfeld verschiebt sich die Phase der Nervenimpulse zu immer früheren Phasen der EEG-Oszillation. Dieses Phänomen wird als “Phasenpräzession” bezeichnet. Theoretische und experimentelle Untersuchungen zeigen, dass Phasenpräzession eine Lösung für unser Dilemma bietet: es führt zu einer zeitlich komprimierten Darstellung der Sequenz von Orten. In der vorliegenden Arbeit untersuche ich den Mechanismus und die Funktion von Phasenpräzession im Hinblick auf die Ausbreitung neuronaler Aktivität von einer Hirnregion zu einer anderen. Phasenpräzession konnte bereits in mehreren Regionen des Gehirns beobachtet werden. Bisher war unklar, ob Phasenpräzession in jeder dieser Regionen eigenständig entsteht, oder ob die Phasenpräzession von einer vorgeschalteten Population von Neuronen “vererbt” werden kann. Schliesslich diskutiere ich auf Grundlage der aktuellen Literatur, ob Phasenpräzession das Verhalten beeinflusst und gebe einen Ausblick auf zukünftige Forschungsmöglichkeiten auf diesem Gebiet. / The process of faithfully retrieving episodes from our memory requires a neural mechanism capable of initially forming ordered and reliable behavioral sequences. These behavioral sequences take place on a timescale of seconds or more, whereas the timescale of neural plasticity and learning is in the order of tens of milliseconds. To shed light on this dilemma, we turn to studies of hippocampal place cells in rodents, i.e., cells that selectively increase their firing rates in locations of the environment known as the place fields. Within a field, the firing phases of a place cell precess monotonically relative to the ongoing theta rhythm. This phenomenon, termed "phase precession", leads to a temporally compressed representation of the behavioral sequences experienced by the rodent, and the compressed timescale matches the requirements of neural plasticity. In this thesis, I study the mechanisms and functions of phase precession by proposing a framework that relies on the concept of inheritance: the simple idea that patterns of neural activity can be propagated from one region to another. Indeed, phase precession has been observed in several regions of the hippocampus and entorhinal cortex, and an important open question is whether phase precession emerges independently in each region, or conversely, whether phase precession can be "inherited" from an upstream neu ronal population. These results suggest that the presence of phase precession in different stages of the hippocampal circuit and other regions of the brain is indicative of a common source, a fact that can help us better understand the temporal spiking patterns in the brain. Finally, I critically review the current evidence for a behavioral role for phase precession and suggest a roadmap for future research in this field.

Title from first page of PDF document. Includes bibliographical references (p. 22-31).