In real world environments, animals need to organize their behavior relative to other moving animals or objects; when hunting a predator, when migrating in groups or during various social interactions. In all of these situations, the animal needs to orient relative to another moving animal/object. To understand the role of the hippocampus in this ability we adopted a two-step approach. We developed a task that would mimic important elements of this behavior in the laboratory. The task required the rats to assess not only their distance from the moving object but also their position relative to the object. We further studied how neurons in the hippocampal CA1 subfield encode the subject, the moving object and the environment in the behavioral paradigm and how do these representations interact among themselves. In rats, we aimed to characterize spatial behaviors relative to moving objects and to explore the cognitive mechanisms controlling these behaviors. Three groups of animals were trained to avoid a mild foot-shock delivered in one of three positions: either in front, on the left side, or the right side of a moving robot. Using different variations of the task, we also probed whether avoidance was simply due to increased noise level or size of the retinal image or appearance of the robot. As the...

The hippocampal formation has been implicated in spatial formation for many decades. The hippocampus proper has received the most attention but other regions of the hippocampal formation contribute largely to spatial cognition. This thesis concentrated on one such region, the postsubiculum. The postsubiculum is considered important because it contains head direction cells and because it thought to be a major input to the hippocampus, via the entorhinal cortex. This thesis aims to test the functional role of the rat postsubiculum under two types of situation: one where the rat must rely on idiothetic cues for navigation, and another where the rat has visual cues present and can rely on these for orientation. The thesis also investigates hippocampal place cells and their stability over time after short exposures to novel environments. Chapter 3 of this thesis aimed to test whether the postsubiculum is necessary for path integration during a homing task. Rats were trained on a homing task on a circular platform maze. Once the task was acquired, rats were given lesions of the postsubiculum or sham lesions and then re-tested on the path integration task. The homing performance of rats with lesions of the postsubiculum was as good as that of the sham rats. A series of manipulations suggests that the rats were homing by path integration, confirmed by probe tests. The rats were then tested on a forced-choice delayed alternation T-maze task that revealed a significant impairment in alternation with delays of 5, 30, and 60 seconds. This suggests that the postsubiculum is not necessary for path integration in a homing task but is necessary for avoiding previously visited locations as is necessary in an alternation task. The experiments in Chapters 4 and 5 of this thesis aimed to investigate the effects of postsubiculum pharmacological inactivation on hippocampal CA1 place cells when rats were introduced to a novel environment with visual cues. A necessary first step was to assess place cells without any manipulation of the postsubiculum (Chapter 4) and then use information gained from this in the design of experiments in Chapter 5. Rats chronically implanted with recording electrodes in the CA1 region of the hippocampus were exposed to novel cue-rich environments whilst place fields were recorded. Following delays of 3, 6, or 24 hours, the same cells were recorded again in the same environment but with the cues rotated by 90°. Pixel-by-pixel correlations of the place fields show that stability of the place fields was significantly lower at 24 hours than at 3 hours. Stability after 6 hours was not significantly different from 3 hours. In the third set of experiments, rats were implanted with drug infusion cannulae in the postsubiculum and recording electrodes in CA1. Following infusions of either the AMPA receptor antagonist CXQX, the NMDA receptor antagonist D-AP5 or a control infusion of ACSF, place field stability was assessed as rats were exposed to a cylindrical environment with a single polarising cue card for 3 x 10 minute sessions and then again 6 hours later. There were no differences in place field correlations between the 3 drug conditions, although there was evidence of larger changes in spatial information content between cells in the CNQX and AP5 drug condition, but not the ACSF condition. The results suggest that, under the present testing conditions, place fields stability did not depend upon AMPA receptor-mediated transmission nor did it depend on NMDA receptor-mediated synaptic plasticity.

Actualment, no hi ha consens científic respecte a la informació representada en la activitat de les célules del hipocamp. D'una banda, experiments amb humans sostenen una visión de la funció de l'hipocamp com a un sistema per l'emmagatzematge de memóries episódiques, mentre que la recerca amb rodents enfatitza una visió com a sistema cognitiu espacial. Tot i que existeix abundant evidència experimental que indica una possible sobreposició d'ambdues teories, aquesta dissociació també es manté en part en base a dades fisiològiques aparentment incompatibles. Aquesta tèsi poposa que l'hippocamp té un rol funcional que s'hauría d'analitzar en termes de la seva estructura i funció, enlloc de mitjança estudis correlació entre activitat neuronal i comportament. La identificació d'un codi a l'hipocamp, es a dir, el conjunt de principis computacionals que conformen les transformacions d'entrada i sortida de l'activitat neuronal, hauría de proporcionar un explicació unificada de la seva funció. En aquesta tèsi presentem un model teòric que descriu quantitativament i que interpreta la selectivitat de certes regions de l'hipocamp en funció de variables espaials i no-espaials, tal i com observada en experiments amb rates. Aquest resultat suggereix que multiples aspectes de la memòria expressada en humans i rodents deriven d'uns mateixos principis. Per aquest motius, proposem nous principis per la memòria, l'auto-completat de patrons i plasticitat. A més, mitjançant aplicacions robòtiques, creem d'un nexe causal entre el circuit neural i el comportament amb el que demostrem la naturalesa conjuntiva de la selectivitat neuronal observada en el hipocamp es necessària per la solució de problemes pràctics comuns, com per example la cerca d'aliments. Tot plegat, aquests resultats avancen en l'idea general de que el codi de l'hipocamp es genèric i aplicable als diversos tipus de memòries estudiades en la literatura. / There is no consensual understanding on what the activity of the hippocampus neurons represents. While experiments with humans foster a dominant view of an episodic memory system, experiments with rodents promote its role as a spatial cognitive system. Although there is abundant evidence pointing to an overlap between these two theories, the dissociation is sustained by conflicting physiological data. This thesis proposes that the functional role of the hippocampus should be analyzed in terms of its structure and function rather than by the correlation of neuronal activity and behavioral performance. The identification of the hippocampus code, i.e. the set of computational principles underlying the input-output transformations of neural activity, might ultimately provide a unifying understanding of its role. In this thesis we present a theoretical model that quantitatively describes and interprets the selectivity of regions of the hippocampus to spatial and non-spatial variables observed in experiments with rats. The results suggest that the multiple aspects of memory expressed in human and rodent data are derived form similar principles. This approach suggests new principles for memory, pattern completion and plasticity. In addition, by creating a causal tie between the neural circuitry and behavior through a robotic control framework we show that the conjunctive nature of neural selectivity observed in the hippocampus is needed for effective problem solving in real-world tasks such as foraging. Altogether, these results advance the concept that the hippocampal code is generic to the different aspects of memory highlighted in the literature.

Existing computational cognitive models of spatial memory often neglect difficulties posed by the real world, such as sensory noise, uncertainty, and high spatial complexity. On the other hand, robotics is unconcerned with understanding biological cognition. This thesis takes an interdisciplinary approach towards developing cognitively plausible spatial memory models able to function in realistic environments, despite sensory noise and spatial complexity. We hypothesized that Bayesian localization and error correction accounts for how brains might maintain accurate location estimates, despite sensory errors. We argued that these mechanisms are psychologically plausible (producing human-like behaviour) as well as neurally plausible (implementable in brains). To support our hypotheses, we reported modelling results of neural recordings from rats (acquired outside this PhD), constituting the first evidence for Bayesian inference in neurons representing spatial location, as well as modelling human behaviour data. In addition to dealing with uncertainty, spatial representations have to be stored and used efficiently in realistic environments, by using structured representations such as hierarchies (which facilitate efficient retrieval and route planning). Evidence suggests that human spatial memories are structured hierarchically, but the process responsible for these structures has not been known. We investigated features influencing them using data from experiments in real-world and virtual reality environments, and proposed a computational model able to predict them in advance (based on clustering in psychological space). We have extended a general cognitive architecture, LIDA (Learning Intelligent Distribution Agent), by these probabilistic models of how brains might estimate, correct, and structure representations of spatial locations. We demonstrated the ability of the resulting model to deal with the challenges of realistic environments by running it in high-fidelity robotic simulations, modelled after participants' actual cities. Our results show that the model can deal with noise, uncertainty and complexity, and that it can reproduce the spatial accuracies of human participants.

Bisherige Forschung hat zwischen zwei Gedächtnissystemen unterschieden: dem sog. deklarativen Gedächtnis (DG), welches sich durch die Fähigkeit vergangene Lebensereignisse bewusst zu erinnern auszeichnet und mit dem lobus temporalis medialis (MTL) in Verbindung steht, und dem prozeduralen Gedächtnis (PG), welches erlernte Fertigkeiten beinhaltet und mit dem Corpus striatum assoziiert ist. Weitere Studien haben ergeben, dass Alterung von neurologischen Schäden in beiden Systemen, erhöhter Aktivität im MTL und einer relativ geringeren Beeinträchtigung des PG begleitet ist. Hyperaktivität im MTL wurde dabei sowohl mit verbesserten als auch verschlechterten Gedächtnisleistungen in Verbindung gebracht. Die hier vorgelegte Dissertation befasst sich mit dem Einfluss von Alterung auf die Beziehungen zwischen o. g. Hirnnetzwerken und prozeduralen bzw. deklarativen Gedächtnisfähigkeiten. Studie I zeigte, dass Altersunterschiede in einer prozeduralen Gedächtnisaufgabe graduell im Verlaufe des Trainings entstehen und vmtl. mit negativen Einflüssen von Alterung auf den Übergang von PG zu DG in Zusammenhang stehen. Zwei striatal-dopaminerge genetische Polymorphismen, rs907094 auf DARPP-32 und VNTR auf DAT, wirkten sich dabei auf das DG älterer aber nicht jüngerer Erwachsener aus. In Studie II wurden Beeinträchtigungen im neuronalen Vorhersagefehler, einem neuronales Lernsignal im Striatum, in älteren Probanden gefunden. Studie III konnte teilweise intaktes PG in einer räumlichen Gedächtnisaufgabe demonstrieren, wobei der Polymorphismus rs17070145 auf WWC1, der sich auf Lanzeitpotenzierung im MTL auswirkt, diese Altersunterschiede modulierte. In Studie IV wurden neuronale Repräsentationen und Komputationen während einer räumlichen Gedächtnisaufgabe untersucht. Während jüngere Probanden in dieser Studie Anzeichen von MTL-basiertem DG zeigten, zeigten ältere Teilnehmer Evidenz von PG. Die neuronalen Signaturen älterer Erwachsener wurden jedoch am stärksten im MTL beobachtet. / Previous research has distinguished between a declarative memory system that stores flexible representations and is subserved by the medial-temporal lobe (MTL) and a procedural memory system that expresses past experiences through skills and is based mainly on the striatum. Investigations into age-related changes in these memory systems indicated a complex pattern of neural degradation in both systems, elevated MTL activity as well as partially spared procedural memory functions in older adults. A literature review further suggests that MTL overactivity can be caused by factors which are either beneficial or detrimental for memory. The present dissertation investigated the effects of human aging on the relations of brain functions to declarative and procedural memory. In Study I, age differences in a procedural memory task gradually emerged over the course of training and were linked to negative effects of aging on the transition from procedural to declarative memory. In addition, this study showed that striatal dopaminergic genetic polymorphisms, rs907094 on DARPP-32 and VNTR on DAT, affected declarative knowledge in older but not younger adults. Study II indicated that prediction error signals in the human brain, a neural computation associated with striatal learning functions, were partially impaired in older adults. Study III demonstrated partially intact procedural memory in older adults in a spatial memory task, whereby age differences were modulated by a polymorphism influencing long-term potentiation in the MTL (rs17070145 on WWC1). Finally, Study IV showed hat that neural representations and computations subserving spatial memory qualitatively differed between younger and older adults. The performance and neural activation of younger adults showed unique properties of MTL-dependent declarative memory. Older adults, in contrast, showed behavioral and neural indications of procedural memory but the localization of the neural signatures peaked in the MTL.

Diese Doktorarbeit führt ein hierarchisches Modell für das unüberwachte Lernen aus quasi-natürlichen Videosequenzen ein. Das Modell basiert auf den Lernprinzipien der Langsamkeit und Spärlichkeit, für die verschiedene Ansätze und Implementierungen vorgestellt werden. Eine Vielzahl von Neuronentypen im Hippocampus von Nagern und Primaten kodiert verschiedene Aspekte der räumlichen Umgebung eines Tieres. Dazu gehören Ortszellen (place cells), Kopfrichtungszellen (head direction cells), Raumansichtszellen (spatial view cells) und Gitterzellen (grid cells). Die Hauptergebnisse dieser Arbeit basieren auf dem Training des hierarchischen Modells mit Videosequenzen aus einer Virtual-Reality-Umgebung. Das Modell reproduziert die wichtigsten räumlichen Codes aus dem Hippocampus. Die Art der erzeugten Repräsentationen hängt hauptsächlich von der Bewegungsstatistik des simulierten Tieres ab. Das vorgestellte Modell wird außerdem auf das Problem der invaranten Objekterkennung angewandt, indem Videosequenzen von simulierten Kugelhaufen oder Fischen als Stimuli genutzt wurden. Die resultierenden Modellrepräsentationen erlauben das unabhängige Auslesen von Objektidentität, Position und Rotationswinkel im Raum. / This thesis introduces a hierarchical model for unsupervised learning from naturalistic video sequences. The model is based on the principles of slowness and sparseness. Different approaches and implementations for these principles are discussed. A variety of neuron classes in the hippocampal formation of rodents and primates codes for different aspects of space surrounding the animal, including place cells, head direction cells, spatial view cells and grid cells. In the main part of this thesis, video sequences from a virtual reality environment are used for training the hierarchical model. The behavior of most known hippocampal neuron types coding for space are reproduced by this model. The type of representations generated by the model is mostly determined by the movement statistics of the simulated animal. The model approach is not limited to spatial coding. An application of the model to invariant object recognition is described, where artificial clusters of spheres or rendered fish are presented to the model. The resulting representations allow a simple extraction of the identity of the object presented as well as of its position and viewing angle.

La locomotion spontanée a une forte influence sur l’état du réseau hippocampique et joue un rôle crucial lors de l’intégration de l'information spatiale. Différents états d'attention ou de comportement au cours de l'éveil peuvent modifier la réponse des neurones aux stimuli sensoriels ainsi que les performances dans les tâches associées. Au cours du mouvement (mov.) le potentiel de champ local de l’hippocampe est caractérisé par des oscillations de fréquence thêta et les cellules pyramidales (CPs) présentent une décharge spécifique à la localisation de l'animal dans un environnement donné. Cependant, les déterminants intracellulaires liés à l'activation des cellules pyramidales de CA1 pendant du mov. sont peu connus. Dans ce travail de thèse, nous avons enregistré le potentiel de membrane (Vm) des CPs de CA1 chez des souris qui alternaient spontanément entre des périodes de mov. et des périodes d’immobilité lors d’une tâche de navigation spatiale virtuelle. Nous avons trouvé une modulation opposée du Vm entre les CPs de CA1 qui déchargeaient de manière régulière par rapport à celles qui déchargeaient en bouffées de potentiels d’action. Les cellules qui déchargeaient de manière régulière étaient plus dépolarisées et déchargeaient plus pendant le mov.comparé à l’immobilité. Les cellules déchargeant en bouffées de potentiels d’action, préférentiellement inhibées pendant les sharp wave-ripples, étaient hyperpolarisées de façon dépendante à la vitesse pendant le mov.. Cette inhibition dépendante de la vitesse pourrait permettre d’augmenter le rapport signal sur bruit afin de coder l’information spatiale de manière plus efficace pendant le mov.. / Spontaneous locomotion strongly influences the state of the hippocampal network and is critically important for spatial information coding. In neocortex, different attentional or behavioral states during arousal can modify neurons responses to sensorial stimuli and associated task performance. During locomotion, the local field potential of the hippocampus is characterized by theta frequency oscillations (5-12 Hz) and the pyramidal neurons present a specific discharge to the localization of the animal in environments. However, the intracellular determinants of CA1 pyramidal cells activation during locomotion are poorly understood. Here we recorded the membrane potential of CA1 pyramidal cells (PCs) while non-overtrained mice spontaneously alternated between periods of movement and immobility during a virtual spatial navigation task. We found opposite membrane polarization between bursting and regular firing CA1 PCs during movement. Regular firing CA1 PCs were more depolarized and fired at higher frequency during movement compared to immobility while bursting CA1 PCs, preferentially inhibited during sharp wave ripples, were hyperpolarized during movement in a speed dependent manner. This speed-dependent suppression of a subpopulation of CA1 PCs could enhance signal to noise ratio for efficient spatial coding during locomotion.

<p>Navigation is a very important area of spatial information research that presents researchers with a number of challenges. One of these challenges concerns the nature of spatial information encoding itself: is such encoding the result of a single mechanism system, a two-mechanism system or possibly a mixed system? One possible avenue of insight into this problem centers on the disorientation effect as described in Wang & Spelke (2000). A quick survey of basic findings, terminating with Waller & Hodgson (2006), indicates that there seem to be two systems at work. Moreover, the results obtained are based upon experiments carried out in actual reality. A virtual reality experiment was designed in an attempt to replicate the findings described in Waller & Hodgson (2006). The experiment is described in detail and its results are presented. These were found to be sufficiently reliable to justify pointing to a potentially rich field for future research, including such techniques as combining VR with fMRI to achieve more fine-grained results that cannot currently be obtained from the direct use of actual reality only. Underlying factors such as experimental control and data presentation are briefly described in the discussion section.</p> / Master of Science (MS)

The neural circuitry responsible for memory consists of complex components with dynamic interactions. In hippocampal area CA1, interactions between excitatory pyramidal cells and inhibitory interneurons shape ensemble activity which encodes sequential experience. An extremely diverse set of inhibitory interneurons, with variation in gene expression, synaptic targeting, state-dependent activity, and connectivity, contribute substantially to circuit activity, such as theta and sharp wave-ripple oscillations. The precise roles of each interneuron group is not well understood, though characterization of their activity reveals mechanisms underlying hippocampal circuit computation. In this dissertation, I aim to identify and disrupt interactions between pyramidal cells and local interneurons to clarify their role in shaping cell assembly activity. We characterized axo-axonic cell activity in sharp wave-ripples, and compared their control of pyramidal cell activity and ripple events to parvalbumin expressing neurons. We identified pyramidal cell-interneuron interactions during ripples, suggesting they serve as lateral inhibitors between cell assemblies. We additionally developed and implemented a novel neural device to explore the role of cannabinoid disruption of hippocampal oscillations and organization of assemblies in vivo in awake animals. We demonstrate that cannabinoid receptor type 1 within CA1 is responsible for suppression of theta and SPW-Rs. We also found that cannabinoid activation within CA1 circuitry, regardless of muted input from CA3, was sufficient to disrupt sharp wave-ripples, likely through interference of pyramidal cell-interneuron interactions. The work in this dissertation provides insight suggesting that interneuron activity must be studied at the spiking timescale to characterize their control over cell assembly activity. / Doctor of Philosophy / Understanding how the brain creates memory remains one of the greatest questions in the field of neuroscience. Coordinated brain activity serves to build communication on large and small scales, across brain regions and within circuits consisting of small groups of neurons. Precise coordination of activity and communication across neurons and regions is thought to build salient experience, which is achieved through the timing of neuron action potentials, or spikes. Neurons receive thousands of inputs that control their spiking activity. "Go and stop" signals from excitatory and inhibitory interneurons act to conduct synchronized activity, which is required for proper circuit function. Importantly, coordinated spiking across large groups of neurons is responsible for observed "brain waves", or oscillations, which reflect organized activity. In CA1 of the hippocampus, there are >20 subtypes of interneurons that all make distinct contributions to memory function, and the roles of these interneurons have not been fully studied within behaving animals. As engineers develop new tools, new methods become available to study and classify how unique groups of interneurons play a part in circuit activity. Thus, we sought to characterize the role of axo-axonic cells, a specialized interneuron with strong control over spiking activity, in hippocampal oscillations that are responsible for memory encoding and consolidation. We identified a new role for axo-axonic cells in the regulation of pyramidal cell spiking in sharp wave-ripple oscillations. Additionally, we developed a novel neural device that allowed us to investigate the mechanisms that underlie cannabinoids, molecules found in Cannabis sativa, and memory dysfunction. We leveraged the multifunctionality of our T-DOpE probe to focally deliver synthetic cannabinoid into the hippocampus in combination with optical control of circuits, with simultaneous recording of activity. We found that cannabinoids acting within CA1 sufficiently disrupt hippocampal oscillations, likely through hindering pyramidal cell-interneuron interactions. Together, these findings suggest that the spatial and temporal resolution required to study diverse roles of interneurons is high, and experiments designed to explore interneuron activity should especially emphasize fine time-scales.

It has been proposed that as animals explore their environment they build and maintain a cognitive map, an internal representation of their surroundings (Tolman, 1948). We tested this hypothesis using a task designed to assess the ability of rats to make a spatial inference (take a novel shortcut)(Roberts et al., 2007). Our findings suggest that rats are unable to make a spontaneous spatial inference. Furthermore, they bear similarities to experiments which have been similarly unable to replicate or support Tolman’s (1948) findings. An inability to take novel shortcuts suggests that rats do not possess a cognitive map (Bennett, 1996). However, we found evidence of alternative learning strategies, such as latent learning (Tolman & Honzik, 1930b) , which suggest that rats may still be building such a representation, although it does not appear they are able to utilise this information to make complex spatial computations. Neurons found in the hippocampus show remarkable spatial modulation of their firing rate and have been suggested as a possible neural substrate for a cognitive map (O'Keefe & Nadel, 1978). However, the firing of these place cells often appears to be modulated by features of an animal’s behaviour (Ainge, Tamosiunaite, et al., 2007; Wood, Dudchenko, Robitsek, & Eichenbaum, 2000). For instance, previous experiments have demonstrated that the firing rate of place fields in the start box of some mazes are predictive of the animal’s final destination (Ainge, Tamosiunaite, et al., 2007; Ferbinteanu & Shapiro, 2003). We sought to understand whether this prospective firing is in fact related to the goal the rat is planning to navigate to or the route the rat is planning to take. Our results provide strong evidence for the latter, suggesting that rats may not be aware of the location of specific goals and may not be aware of their environment in the form of a contiguous map. However, we also found behavioural evidence that rats are aware of specific goal locations, suggesting that place cells in the hippocampus may not be responsible for this representation and that it may reside elsewhere (Hok, Chah, Save, & Poucet, 2013). Unlike their typical activity in an open field, place cells often have multiple place fields in geometrically similar areas of a multicompartment environment (Derdikman et al., 2009; Spiers et al., 2013). For example, Spiers et al. (2013) found that in an environment composed of four parallel compartments, place cells often fired similarly in multiple compartments, despite the active movement of the rat between them. We were able to replicate this phenomenon, furthermore, we were also able to show that if the compartments are arranged in a radial configuration this repetitive firing does not occur as frequently. We suggest that this place field repetition is driven by inputs from Boundary Vector Cells (BVCs) in neighbouring brain regions which are in turn greatly modulated by inputs from the head direction system. This is supported by a novel BVC model of place cell firing which predicts our observed results accurately. If place cells form the neural basis of a cognitive map one would predict spatial learning to be difficult in an environment where repetitive firing is observed frequently (Spiers et al., 2013). We tested this hypothesis by training animals on an odour discrimination task in the maze environments described above. We found that rats trained in the parallel version of the task were significantly impaired when compared to the radial version. These results support the hypothesis that place cells form the neural basis of a cognitive map; in environments where it is difficult to discriminate compartments based on the firing of place cells, rats find it similarly difficult to discriminate these compartments as shown by their behaviour. The experiments reported here are discussed in terms of a cognitive map, the likelihood that such a construct exists and the possibility that place cells form the neural basis of such a representation. Although the results of our experiments could be interpreted as evidence that animals do not possess a cognitive map, ultimately they suggest that animals do have a cognitive map and that place cells form a more than adequate substrate for this representation.