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DISC1 is an established susceptibility gene for schizophrenia. To gain insight on the neural mechanisms responsible for hippocampal deficits in schizophrenia, we sought to characterize place cell activity and theta rhythm in our Disc1-L100P mouse strain that we have previously shown to express deficits in spatial working memory. Our findings suggest that the rate code of place cells is intact. We found that Disc1-L100P mice have deficits in theta rhythm, increased neural noise, and lower levels of PV+ interneurons in the hippocampus. Our findings are supportive of impaired temporal coding in Disc1-L100P place cells. We found that Disc1-L100P place cell waveforms were broader than those of wild-type mice and putative interneuron waveforms were narrower. These findings suggest that ion-channel function and expression in the hippocampus is altered in Disc1-L100P mice. In schizophrenic subjects deficits in working memory are associated with aberrant oscillatory activity, increased noise, and lower PV+ interneuron expression.

DISC1 is an established susceptibility gene for schizophrenia. To gain insight on the neural mechanisms responsible for hippocampal deficits in schizophrenia, we sought to characterize place cell activity and theta rhythm in our Disc1-L100P mouse strain that we have previously shown to express deficits in spatial working memory. Our findings suggest that the rate code of place cells is intact. We found that Disc1-L100P mice have deficits in theta rhythm, increased neural noise, and lower levels of PV+ interneurons in the hippocampus. Our findings are supportive of impaired temporal coding in Disc1-L100P place cells. We found that Disc1-L100P place cell waveforms were broader than those of wild-type mice and putative interneuron waveforms were narrower. These findings suggest that ion-channel function and expression in the hippocampus is altered in Disc1-L100P mice. In schizophrenic subjects deficits in working memory are associated with aberrant oscillatory activity, increased noise, and lower PV+ interneuron expression.

The importance of the hippocampus in the formation and retrieval of episodic memory has been famously demonstrated in the case of patient H.M. Subsequent studies conducted in animal models have provided considerable insight into the specific functions of the individual components of the hippocampus. In the rodent, the pyramidal neurons of the CA1 and CA3 regions of the hippocampus have typically been associated with the encoding of visuo-spatial cues and their utilization in navigation. These ‘place cells’ fire when the animal is in a specific part of its environment (its place field). However, these cells also encode non-spatial information from other sensory inputs, such as olfaction and audition. This study was conducted to find out how contextual odor cues are represented in the firing of CA1 place cells and whether these cues could drive stable spatial representations. One group of mice was first extensively familiarized to a cylinder containing both visual cues and preserved, self-generated odor cues. Then, after assessing place field stability across a six hour delay, the visual and odor cues were rotated in opposite directions by ninety degrees (counter-rotated). Another group of mice was familiarized only to the visual cues that were subsequently rotated. The next day stability and rotation were re-assessed in a novel cylinder. However, the odor cues of the two groups were switched: the preserved odor cues of the first group were removed, and the odor cues of the second group were now preserved across the three sessions. In a separate experiment, a third group of animals was familiarized only to the odor cues. Firstly, we found that contextual odor cues attenuated rotation with the visual cues, but only following extensive familiarization. Secondly, the removal of familiar odor cues impaired long-term stability of place fields. Third and finally, the self-generated odor cues alone were not sufficient for the generation of stable place fields in a free, open-field exploration paradigm. We therefore conclude that although they are not as dominant as discrete visual cues, highly familiarized odor cues exert a significant effect on the representation of space of the mouse CA1 place cell, illustrating the role of contextually relevant information in navigating an ever-changing world.

This thesis aims to explore the two dominant functional roles of the hippocampal formation, in the relational encoding of episodic memory and the neural representation of allocentric space, using a combination of pharmaceutical manipulations and single-unit recording techniques in rodents. The first part of this thesis focuses on episodic-like memory, defined by the original episodic memory triad: ‘what-where-when’ (Tulving 1972), which enables the behavioural aspects of episodic memory to be tested in non-human animals. Permanent neurotoxic lesions of the hippocampus and it’s subregions were induced to assess their role in a putative episodic-like memory task developed by Eacott and Norman (2004). In view of the difficulties encountered in successfully demonstrating the temporal component of episodic-like memory in rats, this task tested integrated memory for ‘what-where-which’, where the temporal component (when) was replaced with another event specifier: context (on ‘which’ occasion). Disruption of the hippocampal circuitry led to a specific impairment in the integration of all three event components, whereas the associative recognition of any combination of these features in isolation was left intact. These results confirm the hippocampal dependence of this episodic-like memory task and further reveals the necessity of both CA3 and CA1, hypothetically due to the underlying autoassociative role of CA3 with CA1 functioning as the vital output pathway for this associated information and/or as a mismatch detector. There has been much debate over the inclusion of the temporal component and sceptics may argue that any such interpretations of task-dependence on episodic-like memory processing are invalid considering the requirement for temporal processing is absent. Due to the proposal that a temporal framework necessarily provides the foundation on which episodic memories are built, the second chapter focuses on the development of a suitable protocol in which integrated memory for the original ‘what-where-when’ episodic memory triad can be reliably tested. The other main function attributed to the hippocampus was brought to light by the fascinating revelation that it’s neurons selectively fire in different regions of an environment, termed ‘place cells’ (O’Keefe and Dostrovsky 1971). From the numerous publications resulting from this discovery it has emerged that place cells not only respond to the spatial features of the environment but are also sensitive to a multitude of non-spatial features. These characteristics support the logical assumption that the primary firing patterns of the hippocampus should underlie it’s main purported roles, leading to speculations that they reflect episodic memory processes. The second part of this thesis aims to examine the relationship between hippocampal cells and behaviour by extending the work of Ainge et al. (2007a), in which a subset of hippocampal place cells were found to encode both current and intended destination in a double Y-maze ‘win-stay’ task. The development of these ‘goal-sensitive’ cells were initially investigated during the learning phase of this task. An exciting pattern of results showed a strong positive correlation between the emergence of goal-sensitive firing and behavioural performance on the task, tempting speculations that these firing patterns may underlie spatial learning and future planning, necessary to support performance. To ensure these firing patterns were not a mere reflection of greater experience on the maze, a second study was conducted in which the task demands changed over set periods of days. A significant increase in the proportion of cells demonstrating goal-sensitive firing was revealed when the protocol shifted to incorporate the spatial memory demands of the ‘win-stay’ task, with all other parameters of the protocol remaining constant. These results support the theory that goal-sensitive firing patterns are specifically related to the learning and memory demands of the spatial task, not a result of increased exploration of the maze. The last of this series of studies assessed hippocampal-dependence of this task and revealed that bilateral hippocampal lesions induced an impairment in spatial ‘win-stay’ performance. Collectively, these experiments demonstrate that goal-sensitive firing of hippocampal cells emerge in line with behavioural performance in a hippocampal-dependent task and the emergence of these firing patterns are specific to the learning and memory demands of a spatial ‘win-stay’ protocol. The functional role of the hippocampus in allocentric spatial processing may thus underpin it’s function in episodic memory and potentially in the imagining and planning of future events, whereby the hippocampus provides a ‘space’ in which retrieved information can be integrated in a coherent context to support the fluent and flexible use of information. This hippocampal function would necessarily require visual information to be accessed, concerning the arrangement of landmarks and cues within the environment, in association with information regarding internal orientation and direction and this leads to the question assessed in the final part of this thesis of where this integration occurs. Based on anatomical evidence and the current literature, the postsubiculum, an input structure to the hippocampus, emerged as a potential site for the convergence of sensory cues into the internally generated head direction cell and place cell networks to enable hippocampal-dependent spatial processing. Thus, the effects of temporary pharmacological blockade of AMPARs and NMDARs in the postsubiculum were assessed on the encoding of spatial memory in an object recognition paradigm. The impairment revealed in the ability to recognise novel object-place configurations demonstrates a key role for NMDAR-dependent plasticity within the postsubiculum itself in the formation of allocentric spatial memory. In summary, the experimental results reported in this thesis further elucidate the critical role the hippocampal formation plays in spatial and episodic memory by combining evidence from cellular physiology and neuroanatomy to the behaving animal and extends these findings to discuss a more general role for the hippocampus in imagining both past and future events, in order to successfully navigate, learn and enable past experience to influence our intended future plans and decisions.

Place cells in the hippocampus fire in specific locations within an environment. The aim of this thesis is to investigate the different inputs to the hippocampus and what they contribute to place cell activity and performance of hippocampus-dependent tasks. Place cell activity can also be modulated by relevant features of a task such as a future destination or trajectory. Initial experiments investigated the origin and function of this trajectory-dependent activity and later experiments targeted the medial entorhinal cortex inputs to the hippocampal formation and investigated what they contributed to place cell activity and behaviour. The purpose of the first study was to determine whether trajectory dependent activity occurs in CA3 in a hippocampus-dependent serial-reversal task on the double-Y-maze and to compare it with that seen in CA1. Place cells in both CA3 and CA1 were recorded in rats trained on a serial-reversal task on a double-Y-maze. Rats were trained to run from a start box through two Y-junctions to one of four goal locations. After 10 trials the reward was moved to a new location, until all the boxes had been rewarded. Previous research has found that 44% of CA1 place cells with fields in the start areas of the maze show trajectory-dependent activity in rats trained on the task. This study found that a similar proportion of CA3 place cells also show trajectory-dependent activity in rats trained on this task and that this activity develops at the same time point as the task is learned. This result suggests that trajectory-dependent activity may be generated earlier in the circuit than CA1. Secondly, the contribution of the nucleus reuniens (N.Re) to spatial tasks was investigated. Previously, trajectory-dependent activity has been found to reach the hippocampus via N.Re, however this was shown in a hippocampus-independent task. To investigate the possible role that this input may play in behaviour, N.Re was lesioned and animals were tested on acquisition and performance of the double-Y-maze serial-reversal task described previously. Surprisingly, lesions had no effects on either learning or performance. Taken together with previous data from other studies, this suggests that trajectory dependent activity is not one unique phenomenon but is rather multiple similar phenomena which may originate in different brain regions and fulfil different roles in navigation depending on the demands of the task. In addition, animals were tested on tasks involving allocentric or egocentric navigation. Results suggest that N.Re may have a role in the selection or performance of allocentric navigation but not egocentric navigation. Thirdly, the role of inputs from the medial entorhinal cortex (MEC) to place cells was investigated. Consistent with previous research, MEC lesions resulted in larger, less precise place fields in CA1 place cells. By performing cue-rotation experiments using either distal or proximal cues it was observed that place fields in the MEC lesion animals were not anchored to distal cues but were either stable or anchored to other aspects of the environment. However, place cells in the MEC lesion group still followed proximal cues suggesting that the deficit is restricted to distal landmarks. This suggests that the MEC may process distal landmark information allowing the use of distal landmarks for orientation and self-location within an environment. This thesis contributes a better understanding of the role and origins of trajectory dependent activity as well as a novel finding that the MEC contributes information about distal landmarks to the hippocampus.

Studies of spatial memory provide valuable insight into more general mnemonic functions, for by observing the activity of cells such as place cells, one can follow a subject’s dynamic representation of a changing environment. I investigate how place cells resolve conflicting neuronal input signals by developing computational models that integrate synaptic inputs on two scales. First, I construct reduced models of morphologically accurate neurons that preserve neuronal structure and the spatial specificity of inputs. Second, I use a parallel implementation to examine the dynamics among a network of interconnected place cells. Both models elucidate possible roles for the inputs and mechanisms involved in spatial memory.

The work presented in this dissertation focuses on the use of computational and mathematical models to investigate how mammalian brains construct and maintain stable representations of space and location. Recordings of the activities of cells in the hippocampus and entorhinal cortex have provided strong, direct evidence that these cells and brain areas are involved in generating internal representations of the location of an animal in space. The emphasis of the first two portions of the dissertation are on understanding the factors that influence the scale and stability of these representations, both of which are important for accurate spatial navigation. In addition, it is argued in both cases that many of the computations observed in these systems emerge at least in part as a consequence of a particular type of network structure, where excitatory neurons are driven by external sources, and then mutually inhibit each other via interactions mediated by inhibitory cells. The first contribution of this thesis, which is described in chapter 2, is an investigation into the origin of the change in the scale of spatial representations across the dorsoventral axis of the hippocampus. Here it will be argued that this change in scale is due to increased processing of nonspatial information, rather than a dorsoventral change in the scale of the spatially-modulated inputs to this structure. Chapter 3 explores the factors influencing the dynamical stability of class of pattern-forming networks known as continuous attractor networks, which have been used to model various components of the spatial navigation systems, including head direction cells, place cells, and grid cells. Here it will be shown that network architecture, the amount of input drive, and the timescales at which cells interact all influence the stability of the patterns formed by these networks. Finally, in chapter 4, a new technique for analyzing neural data is introduced. This technique is a spike train similarity measure designed to compare spike trains on the basis of shared inhibition and bursts.

The ability to self-localize and navigate in both stable and changing environments is crucial for the survival of many species. Research conducted on the non-human mammalian hippocampus and surrounding brain structures has uncovered several classes of spatial related cells. These cells provide the rest of the brain with knowledge of the animal’s location and direction—knowledge that is subsequently used in spatial navigation. This thesis provides an overview of three types of cells underlying this ability in rodents. First, place cells located in the hippocampus encode the animal’s specific location in the environment. Second, head direction cells found throughout the Papez circuit convey the angular direction of the animal’s head. Last, grid cells in the medial entorhinal cortex generate a regular triangular grid spanning the entire explored setting. The focus of this review lies on the most salient features of these types of cells. It is also considered how the cells respond to manipulations of external and internal information, as well as how different lesions affect their activity.

Les cellules de lieu de l’hippocampe sont des neurones aux propriétés intrigantes, commele fait que leur activité soit corrélée à la position spatiale de l’animal. Il est généralementconsidéré que ces propriétés peuvent être expliquées en grande partie par les comporte-ments collectifs de modèles schématiques de neurones en interaction. La physique statis-tique fournit des outils permettant l’étude analytique et numérique de ces comportementscollectifs.Nous abordons ici le problème de l’utilisation de ces outils dans le cadre du paradigmedu “réseau attracteur”, une hypothèse théorique sur la nature de la mémoire. La questionest de savoir comment ces méthodes et ce cadre théorique peuvent aider à comprendrel’activité des cellules de lieu. Dans un premier temps, nous proposons un modèle de cellulesde lieu dans lequel la localisation spatiale de l’activité neuronale est le résultat d’unedynamique d’attracteur. Plusieurs aspects des propriétés collectives de ce modèle sontétudiés. La simplicité du modèle permet de les comprendre en profondeur. Le diagrammede phase du modèle est calculé et discuté en comparaison avec des travaux précedents.Du point de vue dynamique, l’évolution du système présente des motifs particulièrementriches. La seconde partie de cette thèse est à propos du décodage de l’activité des cellulesde lieu. Nous nous demandons quelle est l’implication de l’hypothèse des attracteurs surce problème. Nous comparons plusieurs méthodes de décodage et leurs résultats sur letraitement de données expérimentales. / Place cells in the hippocampus are neurons with interesting properties such as the corre-lation between their activity and the animal’s position in space. It is believed that theseproperties can be for the most part understood by collective behaviours of models of inter-acting simplified neurons. Statistical mechanics provides tools permitting to study thesecollective behaviours, both analytically and numerically.Here, we address how these tools can be used to understand place-cell activity withinthe attractor neural network paradigm, a theory for memory. We first propose a modelfor place cells in which the formation of a localized bump of activity is accounted for byattractor dynamics. Several aspects of the collective properties of this model are studied.Thanks to the simplicity of the model, they can be understood in great detail. The phasediagram of the model is computed and discussed in relation with previous works on at-tractor neural networks. The dynamical evolution of the system displays particularly richpatterns. The second part of this thesis deals with decoding place-cell activity, and theimplications of the attractor hypothesis on this problem. We compare several decodingmethods and their results on the processing of experimental recordings of place cells in afreely behaving rat.