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The peripheral and central mechanisms mediating the modulatory effects of glucose and acute stress in rats were investigated using two versions of an appetitive win-stay task. Post-training injections of glucose, but not fructose, enhanced retention on the closed maze task. Acquisition of this task was found to be impaired by lesions of the fimbria-fornix (FF). Further experiments showed that while the celiac ganglion and the FF normally participate in suppressing the memory-enhancing effect of an acute stressor, neither structure is involved in mediating the effect of glucose on memory. Post-training injections of glucose, but not fructose, enhanced retention on the open maze task. Although acquisition of this task was not affected by FF lesions, both the celiac ganglion and the FF participate in mediating the memory-enhancing effect of glucose. Together, the results suggest that the peripheral and central mechanisms studied here are both substance- and task-specific. The modulatory effects of different types of stress, and the issue of whether task acquisition and memory modulation are anatomically distinct are discussed.

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The experiments in this thesis examined the roles of stimulus configuration on conditioned cue preference (CCP) learning by asking what information is processed and by which neural substrates. Results from Experiments 1 and 2 showed that lesions of the lateral nucleus of the amygdala (LNA) but not of fimbria-fornix (FF) impaired CCP learning when the cues paired with food during training were distinct from those not paired with food in either of two different apparatuses. In Experiments 3 and 4 LNA lesions increased the size of the CCP when the cues paired with food and no food were ambiguous in two different apparatuses. Learning the ambiguous cue CCP required at least one session of unreinforced pre-exposure to the cues and was eliminated by FF lesions. In the last series of experiments, a latent learning effect of unreinforced pre-exposure on ambiguous cue CCP learning on the radial maze was found in normal animals that received at least 3 sessions of unreinforced pre-exposure. FF lesions made before, but not after, pre-exposure eliminated the latent learning effect. Hippocampus lesions made either before or after pre-exposure eliminated the CCP learning. Taken together, the results are consistent with the hypothesis that distinct cue CCP learning is based on conditioned approach responses to cues paired with food, mediated by a neural system that includes the LNA. The results also suggest that ambiguous cue CCP learning takes place in two phases. First spatial learning occurs during unreinforced pre-exposure, a process that requires an intact FF. Subsequently, information about the location of the reinforcer is added to the spatial information during the reinforced training trials by a process of "reconsolidation". An intact hippocampus is required for this process. The implications of these results and interpretations for latent learning and latent inhibition are considered.

It has been argued that patients with frontal lobe lesions are impaired in temporal context memory and, more generally, in retrieving the source of one's knowledge or ideas. Furthermore, it has been speculated that a failure to retrieve source information may result in an increased susceptibility to distortions of episodic memories in patients with frontal lobe lesions. The precise role of the frontal cortex, however, in source or episodic retrieval is not clear. Does this region of cortex play a primary role or a secondary, executive role in the processing of such memories? Studies of patients with temporal lobe lesions have also shown impairments in episodic memory, including difficulties in the retrieval of source information. An important issue, therefore, is whether these two brain regions make different contributions to the processing of source information and to the retrieval of episodic memories. / In the present experiments, patients with unilateral excisions restricted to frontal cortex or to the anterior temporal lobe were compared on various tasks examining source memory performance and the accurate retrieval of episodic information. The results of these studies failed to support the general contention that patients with frontal cortex excisions have source (or temporal context) memory impairments. Instead, differences between these patients and normal control subjects appeared to be contingent on whether strategic organizational or control processes were necessary for efficient processing of episodic information. The memory of patients with left temporal lobe excisions, on the other hand, was significantly impaired for both content and source information in most tasks. Furthermore, these subjects showed high rates of inaccuracies and distortions of memory. The false memories of this patient group were attributed to a combination of their poor memory for the specific items of the task and their over-reliance on semantic "gist" or on inferential knowledge about the events. Patients with right temporal lobe excisions were generally less severely impaired on the verbal memory tasks compared with those with left-sided lesions, but were impaired in their memory for the contextual aspects of an event.

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A longstanding goal in neuroscience is to provide a biological understanding of episodic memory, our conscious recollection of prior experience. While the hippocampus is thought to be a critical locus for episodic learning in the mammalian brain, the nature of its involvement is unsettled. This thesis details several investigations that attempt to probe the neural mechanisms that support the encoding and organization of new experiences into memory. Throughout the included works, we utilize in vivo two-photon fluorescence microscopy and calcium imaging to study the functional dynamics of hippocampal networks in mice during memory-guided behavior. To begin, Chapter 2 examines how neural coding in hippocampal area CA1 is modified during trace fear conditioning, a common model of episodic learning in rodents that requires linking events separated in time. We longitudinally tracked network activity throughout the entire learning process, analyzing how changes in hippocampal representations paralleled behavioral expression of conditioned fear. Our data indicated that, contrary to contemporary theories, the hippocampus does not generate sequences of persistent activity to learn the temporal association. Instead, neural firing rates were reorganized by learning to encode the relevant stimuli in a temporally variable manner, which could reflect a fundamentally different mode of information transmission and learning across longer time intervals. The remaining chapters concern place cells---neurons identified in the hippocampus that are active only in specific locations of an animals' environment. In Chapter 3, we use mouse virtual reality to explore how the hippocampus constructs representations of novel environments. Through multiple lines of analysis, we identify signatures of place cells that acquire spatial tuning through a particularly rapid form of synaptic plasticity. These motifs were enriched specifically during novel exploration, suggesting that the hippocampus can dynamical tune its learning rate to rapidly encode memories of new experiences. Finally, Chapter 4 expands a model of hippocampal computation that explains the emergence of place cells through a more general mechanism of efficient memory coding. In theory and experiment, we identified properties of place cells that systematically varied with the compressibility of sensory information in the environment. Our preliminary data suggests that hippocampal coding adapts to the statistics of experience to compress correlated patterns, a computation generically useful for memory and which naturally extends to representation of variables beyond physical space.

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The memory system is adaptive in so far as it is able to provide the most robust predictions of what will happen next in our environment. Three means through which it can do this are: arbitrating between temporally embedded recollections and generalized knowledge; rescuing remote memories that are learned to be behaviorally relevant; and updating existing memories if they provide invalid predictions of the outside world. Here, I cover three studies that probe these functions in behavior and in the brain. In Chapter 1, I show how a data-driven parcellation reveals non-linear gradients in measures of signal heterogeneity across the body of the hippocampus, suggesting novel areas of investigation into how the memory system flexibly constructs fine- and coarse-grained memories. In Chapter 2, I then explore how memories might be rescued by later aversive experiences, finding novel evidence that the online inferences participants make as to what current stimuli are relevant to their arousal subtly shapes what previous stimuli they retroactively maintain in memory. Finally, in Chapter 3, I show that signals from the ventral tegmental area modulate the effect of replaying memories on the eventual updating of those memories. Each of these provides novel pieces of evidence into the neural and behavioral markers of how memories are constructed, strengthened, or updated in the brain.