This dissertation explores the relationships between self-motion, place field size, and theta phase precession with a primary focus on providing insight into the interactions between theta phase precession and place field size. The present data indicate that place field size increases along the dorsal to ventral axis of the hippocampus. Pyramidal neurons of the middle hippocampus, with larger place fields, exhibit a lower intrinsic burst frequency compared to dorsal place cells. Moreover, the firing rate of neurons in the middle hippocampus show a weaker relationship with running velocity compared with cells in the dorsal CA1 region suggesting that there is a decrease in the self-motion input to this region. By defining place fields as phase shifts up to, but not exceeding 360 degrees, the rate of phase precession is found to significantly correlate with place field size. Moreover, this definition revealed that approximately 10% of the pyramidal neurons will have place fields that overlap in space. Applying this critereon to interneurons reveals that a subset shows a similar spatial metric to those of pyramidal cells, inheriting the activity profiles and spike-phase relationships of the pyramidal cells that they are putatively monosynaptically coupled to. Finally, a reliable reconstruction of the look-ahead phenomenon provides preliminary evidence that suggests an increase in place field size as velocity increases.The results are presented to imply that the influence of the self-motion signals is graded along the dorsal-ventral axis of the hippocampus. These self-motion signals are capable of influencing the neuronal spike times of both pyramidal cells and interneurons on short-time scales of a theta cycle or less. Despite these short-time scale spike timing control mechanisms, preliminary data is presented that the influence of self-motion information with velocity is not enough to maintain a fixed place field size.

Spatial navigation in humans correlates with activity of cells in hippocampus that respond when we traverse specific locations in our environment. Hippocampal pyramidal cells in rodents called "place cells" may contribute to episodic memory by encoding location in physical space. Place cells display plasticity by "remapping" or altering their firing rates and patterns of activity in response to changes in spatial environment. Impaired remapping may underlie age-related deficits in spatial memory tasks. Using in vivo high-density electrophysiology to record place cell activity in awake, behaving rats, we tested the hypothesis that CA3 neuron hyperactivity in aged animals could be normalized by pharmacotherapy. Results show that acute, systemic administration of low dose levetiracetam and sodium valproate ameliorates deficits in the aged hippocampal network by reducing firing rates, decreasing place field area, and increasing the spatial selectivity of CA3 place cells. We then tested the hypothesis that place cell activity, field area, and spatial selectivity may be an indicator for therapeutic enhancement of spatial memory in young adult rats. The results demonstrate that α5IA enhances hippocampal-dependent spatial memory as measured by the location novelty recognition task in rats, consistent with the previously established action of α5IA as an enhancer of spatial memory in the water maze test. Electrophysiological recordings on the same animals carried out in parallel demonstrate that α5IA increases place cell firing rates, reduces field area, and increases spatial selectivity. Together, these results suggest that reducing place field area and enhancing spatial selectivity correlate with the age-independent therapeutic improvement of spatial memory. The increase in place cell firing rates by α5IA likely results from its known action as a negative allosteric modulator of α5-subunit-containing receptors (α), which are located extrasynaptically at the base of dendritic spines on CA1 and CA3 pyramidal cells. Thus, to potentially target extrasynaptic tonic inhibition in the hippocampus, we synthesized and validated two α specific miRNAs as a platform for future attempts to improve spatial memory in young adult and aging animals via molecular genetics.

Les neurones pyramidaux sont constamment bombardés par une activité GABAergique spontanée qui régule le comportement de la décharge neuronale. Des résultats récents ont montré que cette activité spontanée GABAergique pouvait moduler l'excitabilité mais aussi la fidélité temporelle de décharge d'un neurone définie comme sa capacité à reproduire à l'identique un patron de décharge lors de la présentation répétée d'un même stimulus. D'autre part, de nombreuses études ont caractérisé l'existence d'une plasticité à court-terme de l'activité GABAergique médiée par les endocannabinoïdes. Ce phénomène, connu sous le nom de DSI (Depolarization-induced Suppression of Inhibition) a été décrit dans de nombreuses structures comme le cervelet, le cortex ou encore l'hippocampe.Au cours de ma thèse, j'ai étudié quelles pouvaient être les conséquences fonctionnelles de la production d'endocannabinoïdes sur l'activité neuronale et en particulier sur la fidélité temporelle de la décharge. Dans un premier temps nous avons montré que le profil de décharge in vivo des cellules de lieu de l'hippocampe pouvait induire, quand il était rejoué in vitro, le phénomène de DSI. Nous avons observé ensuite que cette diminution transitoire de la transmission GABAergique était associée à une amélioration de la fidélité temporelle de la décharge.En conclusion, nos travaux suggèrent que l'activité des cellules de lieu de la région CA1 de l'hippocampe peut provoquer, par la synthèse et la libération rétrograde d'endocannabinoïdes, une diminution à court-terme de l'activité GABAergique reçue par ces cellules avec pour conséquence des modifications de la précision temporelle de la décharge neuronale. / Pyramidal neurons are constantly bombarded by spontaneous GABAergic activity that regulates their firing behaviour. Recent results have shown that this spontaneous GABAergic activity can modulate both the excitability and the temporal fidelity of action potential discharge (Caillard, 2011). Many studies have characterized the existence of short-term plasticity of GABAergic activity mediated by endocannabinoids. This phenomenon, known as DSI (Depolarization-induced Suppression of Inhibition) has been described in many brain structures such as the cerebellum, cortex or hippocampus (for review see Freund et al., 2003; Kano et al. 2009).During my PhD thesis, I have evaluated the functional consequences of the endocannabinoid production on neuronal activity and in particular on the spike-time precision of the CA1 pyramidal neurons. As a first step we have shown that the in vivo firing pattern of place cells could induce, when replayed in vitro, a decrease in spontaneous GABA release by the endocannabinoid signalling pathway. We then observed that this transient depression of GABAergic transmission improved spike-time precision of CA1 pyramidal neurons.In conclusion, our work suggests that, in the hippocampus, CA1 place cell firing can induce, following the synthesis and retrograde release of endocannabinoids, a short-term decrease in the GABAergic activity received by these cells that consequently affects their spike-time precision.

Animals learn from past experience to guide future behavior and improve survival. This ability relies in part on specific episodic memories of past events encoded by neuronal activity and stored by updated connectivity between neurons. The unique architecture and activity of the hippocampus and related cortical regions are crucial for supporting these episodic memories. Hippocampal models propose the need for a pattern separation function to disambiguate similar memories and a pattern completion function to recall the full breadth of an experience from a partial cue. Past work suggests that neuronal activity in the dentate gyrus (DG) of hippocampus contributes to memory-guided navigation and plays a role in pattern separation. We tested the role of specific DG neuronal ensembles (i.e. engrams) in supporting the pattern separation function and altering downstream neural activity and, ultimately, behavior. To that end, we used an activity-dependent labeling paradigm to identify and manipulate engram ensembles during navigational and contextual fear conditioning (CFC) tasks. The results of our first experiment revealed that the DG partially disambiguates specific maze trajectories while still exhibiting greater overlap than chance levels. These findings suggest that the DG contributes to memory-guided navigation by both pattern separation and completion. Our second experiment manipulated nonspecific memory-related DG populations to assess the functional role of these cells in task generalization across contexts and ongoing spatial working memory. Optogenetic activation of these ensembles disrupted performance accuracy and exhibited a time-dependent impairment effect suggesting a role of the DG in task generalization between contexts. The final experiments investigated the physiological ramifications of artificial memory ensemble reactivation during ongoing navigation behavior. We recorded local field potential (LFP) and single unit responses in mouse DG and CA1 during artificial reactivation of a DG-mediated CFC memory engram. Stimulation of the DG entrained LFP and individual cell spiking in a subpopulation of CA1 pyramidal cells. Their spatial information was disrupted by stimulation despite stable navigational representation before and after the manipulation. Further, the presence of stimulation could be reliably decoded by the firing rate of the network, suggesting that engram reactivation forced the CA1 to adopt a repeatable state, perhaps to support behavioral expression of memories. In summary, my dissertation work presents empirical and theoretical evidence for the role of the dentate gyrus as a single node of an extended separation/completion circuit distributed anatomically and temporally as a neural mechanism supporting episodic memory.

Tesi realitzada a l'Equip de Neurociència de Sistemes - IDIBAPS / The generation of cognitive maps is influenced by different senses such as vision, audition or smell. However, the tactile information system -a highly developed system in the rat- and its influence on spatial processing, has hardly been studied. The availability of precise tactile information in the hippocampus (Pereira et al., 2007) is highly suggestive of a possible influence of tactile information on spatial processing. In this study we aimed to test if somatosensory information contributes to the cognitive map creation and spatial representation. The deprivation of the tactile sense without the possibility of using other senses (total darkness, homogeneous odour and uniform white noise), should then affect the coding of spatial information and could be detected as an alteration in place cell properties such as firing rate, location and/or extension of the firing fields. These types of changes would demonstrate that somatosensory inputs are involved in the cognitive map creation. To carry out this study we developed three kinds of experiments. First, we developed a paradigm (Gener et al., 2009) to temporarily deprive the tactile input using locally applied local anaesthesia (lidocaine). In a second part, we demonstrate that this deprivation was effective in the awake animal, altering the behaviour during tactile discrimination protocols and reducing successful trials from 88% to chance (48%). Finally, we applied the deprivation technique to characterise the cognitive map creation. With that purpose, we first demonstrated that place cells recorded in a controlled environment were sensitive to tactile cues, such that the rotation of the cues induce the rotation of the firing fields. Next, when tactile information was deprived, the place cells’ fields showed changes in their compactness and size. The results of this study suggest that somatosensory input information transduced by the whiskers contributes to the cognitive map creation. Those findings respond to some of the questions about hippocampus integration’s of sensory information.

Neurons are sensitive to specific aspects of natural stimuli, which are according to different statistical criteria an optimal representation of the natural sensory input. Since these representations are purely sensory, it is still an open question whether they are suited to generate meaningful behavior. Here we introduce an optimization scheme that applies a statistical criterion to an agent s sensory input while taking its motor behavior into account. We first introduce a general cognitive model, and second develop an optimization scheme that increases the predictability of the sensory outcome of the agent s motor actions and apply this to a navigational paradigm.In the cognitive model, place cells divide the environment into discrete states, similar to hippocampal place cells. The agents learned the sensory outcome of its action by the state-to-state transition probabilities and the extent to which these motor actions are caused by sensory-driven reflexive behavior (obstacle avoidance). Navigational decision making integrates both learned components to derive the actions that are most likely to lead to a navigational goal. Next we introduced an optimization process that modified the state distributions to increase the predictability of the sensory outcome of the agent s actions.The cognitive model successfully performs the navigational task, and the differentiation between transitions and reflexive processing increases both behavioral accuracy, as well as behavioral adaptation to changes in the environment. Further, the optimized sensory states are similar to place fields found in behaving animals. The spatial distribution of states depends on the agent s motor capabilities as well as on the environment. We proofed the generality of predictability as a coding principle by comparing it to the existing ones. Our results suggest that the agent s motor apparatus can play a profound role in the formation of place fields and thus in higher sensory representations.

Die sequenzielle Aktivität von Ortszellen im Hippocampus entspricht vielfach früheren Erlebnissen, was auf eine Rolle in Gedächtnisprozessen hinweist. Jüngere experimentelle Befunde zeigen allerdings, dass Zielorte in sequenzieller Aktivität überrepräsentiert sind. Dies legt eine Rolle dieser Aktivitätsmuster in der Verhaltensplanung nahe, wobei ein detailliertes Verständnis sowohl des Ursprungs als auch der Funktion von Ortszellsequenzen im Hippocampus bislang fehlt. Insbesondere ist nicht bekannt, welcher Mechanismus solche Sequenzen auf adaptive und konstruktive Weise generiert, wodurch effizientes Planen ermöglicht würde. Um der Beantwortung dieser Fragen näher zu kommen, stelle ich ein neu entwickeltes pulscodiertes Netzwerkmodell vor, in dem räumliches Lernen und die Generierung von Sequenzen untrennbar voneinander abhängig sind. Anhand von Simulationen zeige ich, dass dieses Modell die Erzeugung von noch nicht erlebten Sequenztrajektorien in bekannten Umgebungen erklärt, was deren Nutzen für flexible Pfadplanung hervorhebt. Zusätzlich stelle ich die Ergebnisse eines detaillierten Vergleichs zwischen simulierten neuronalen Pulsfolgen und experimentellen Daten auf der Ebene der Populationsdynamik vor. Diese Resultate zeigen, wie sequenzielle räumliche Repräsentationen durch die Interaktion zwischen lokaler oszillatorischer Dynamik und externen Einflüssen geprägt werden.:1. Introduction 2. Neurobiological and theoretical accounts of hippocampal function 3. A computational model of place-cell sequences for goal-finding 4. A statistical note on step size decoding in place-cell sequences 5. Summary and Discussion Bibliography / Hippocampal place-cell sequences observed during awake immobility often represent previous experience, suggesting a role in memory processes. However, recent reports of goals being overrepresented in sequential activity suggest a role in short-term planning, although a detailed understanding of the origins of hippocampal sequential activity and of its functional role is still lacking. In particular, it is unknown which mechanism could support efficient planning by generating place-cell sequences biased toward known goal locations, in an adaptive and constructive fashion. To address these questions, I propose a spiking network model of spatial learning and sequence generation as interdependent processes. Simulations show that this model explains the generation of never-experienced sequence trajectories in familiar environments and highlights their utility in flexible route planning. In addition, I report the results of a detailed comparison between simulated spike trains and experimental data, at the level of network dynamics. These results demonstrate how sequential spatial representations are shaped by the interaction between local oscillatory dynamics and external inputs.:1. Introduction 2. Neurobiological and theoretical accounts of hippocampal function 3. A computational model of place-cell sequences for goal-finding 4. A statistical note on step size decoding in place-cell sequences 5. Summary and Discussion Bibliography