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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.

The entorhinal cortex (EC) in the medial temporal lobe plays a critical role in memory formation and is implicated in several neurological diseases including temporal lobe epilepsy and Alzheimer’s disease. Despite the known importance of this brain region, little is known about the normal bioelectrical activity patterns of the EC in awake, behaving primates. In order to develop effective therapies for diseases affecting the EC, we must first understand its normal properties. To contribute to our understanding of the EC, I monitored the activity of individual neurons and populations of neurons in the EC of rhesus macaque monkeys during free-viewing of photographs using electrophysiological techniques. The results of these experiments help to explain how primates can form memories of, and navigate through, the visual world. These experiments revealed neurons in the EC that represent visual space with triangular grid receptive fields and other neurons that prefer to fire near image borders. These properties are similar to those previously described in the rodent EC, but here the neuronal responses relate to viewing of remote space as opposed to representing the physical location of the animal. The representation of visual space may be aided by another EC neuron type that was discovered, free-viewing saccade direction cells, neurons that signaled the direction of upcoming saccades. Such a signal could be used by other cells to prepare to fire according to the future gaze location. Many of these spatially-responsive neurons also represented memory for images, suggesting that they may be useful for associating items with their locations. I also examined the neuronal circuitry of recognition memory for visual stimuli in the EC, and I found that population synchronization within the gamma-band (30-140 Hz) in superficial layers of the EC was modulated by stimulus novelty, while the strength of memory formation modulated gamma-band synchronization in the deep layers and in layer III. Furthermore, the strength of connectivity in the gamma-band between different layers was correlated with the strength of memory formation, with deep to superficial power transfer being correlated with stronger memory formation and superficial to deep transfer correlated with weaker memory formation. These findings support several previous investigations of hippocampal-entorhinal connectivity in the rodent and advance our understanding of the functional circuitry of the medial temporal lobe memory system. Finally, I explored the design of a device that could be used to investigate properties of brain tissue in vitro, potentially aiding in the development of treatments for disorders of the EC and other brain structures. We designed, fabricated, and validated a novel device for long-term maintenance of thick brain slices and 3-dimensional dissociated cell cultures on a perforated multi-electrode array. To date, most electrical recordings of thick tissue preparations have been performed by manually inserting electrode arrays. This work demonstrates a simple and effective solution to this problem by building a culture perfusion chamber around a planar perforated multi-electrode array. By making use of interstitial perfusion, the device maintained the thickness of tissue constructs and improved cellular survival as demonstrated by increased firing rates of perfused slices and 3-D cultures, compared to unperfused controls. To the best of our knowledge, this is the first thick tissue culture device to combine forced interstitial perfusion for long-term tissue maintenance and an integrated multi-electrode array for electrical recording and stimulation.