Historically, there have been two lines of research on mammalian hippocampus. The first one is concerned with the role of hippocampus in formations of new memories and owes its origin to the seminal study by Brenda Milner and William Scoville of a single memory disorder patient, widely known as H.M. The second line of research views the hippocampus as the brain area concerned with orienting and navigating in space. It started with John O’Keefe’s discovery of place cells, pyramidal neurons in the CA3 area of hippocampus, that fire when the animal enters a particular place in its environment. I argue that both lines of discoveries seem to be consistent with a more general view of hippocampus as a brain area strongly involved in the integration of sensory, and possibly internal, information. The first part of the thesis presents an investigation of the effect of limited connectivity constraint on the model network in the framework of pattern classification. It is shown that feed-forward neural classifiers with numerous long range connections can be replaced by networks with sparse feed-forward connectivity and local recurrent connectivity without sacrificing the classification performance. The limited connectivity constraint is relevant for most biological networks, and especially for the hippocampus. The second part describes a decoding analysis from the calcium signal recorded in mouse dentate gyrus. The animal’s position can be decoded with approximately 10cm accuracy and the neural representation of position in the dentate gyrus have close to maximal dimensionality. The analysis also suggests that cells with single firing field and cells with multiple firing fields contribute approximately equal amount of information to the decoder.

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Current concepts of hippocampal circuitry assume a large population of excitatory principal neurones whose activity is largely governed by a network of local-circuit GABAergic interneurones. The diversity of hippocampal local-circuit neurones and their synaptic control over principal cell activity was investigated in vitro, in order to define their synaptic connections and functional roles. Single and dual intracellular recordings were made from local-circuit neurones and pyramidal cells in area CA1 of the rat hippocampal slice. Interneurones were tentatively distinguished from pyramidal cells based on their firing as well as their membrane properties. Intracellular labelling of recorded cells with the marker biocytin revealed a diversity of cell types based on differential dendritic and axonal morphology and synaptic connections. The physiological data revealed that all types of interneurone tested evoked inhibitory postsynaptic potentials (IPSPs) in simultaneously recorded pyramidal cells. The IPSPs had fast rise and decay kinetics and the ones tested pharmacologically, were mediated by GABA_A receptors. Similarly, individual interneurones were also shown to innervate other local-circuit interneurones in addition to pyramidal cells, the evoked effects being qualitatively similar in both types of postsynaptic targets. The postsynaptic effect and functional role of one type of hippocampal interneurone, the basket cell, was investigated in greater detail. Basket cell-evoked IPSPs were reliable, but showed some frequency-dependent attenuation. Moreover, basket cell IPSPs were found to interact with intrinsic pyramidal cell conductances to elicit rebound depolarisations and facilitate action potential generation. More detailed investigation showed that basket and axo-axonic cells were particularly effective in entraining pyramidal cell firing and sub-threshold membrane potential oscillations. Through these powerfully tuned mechanisms, sub-types of local-circuit interneurone provide a powerful mechanism to synchronise the activity of pyramidal cells. These results demonstrate a remarkable diversity of GABAergic local-circuit neurones in the hippocampal CA1 area and suggest that specific subtypes of cell mediate different functions.

Experimentally naive rats exhibit varying degrees of novelty exploration. Some rats display high rates of locomotor reactivity to novelty (high responders; HR), and others display low rates (low responders; LR). The novelty-seeking phenotype (LRHR) is introduced as a model of stress responsiveness. In this thesis I examined effects of chronic variable physical and social stress or control handling on the levels of various neurotrophins in the hippocampus, and changes in mossy fibre terminal fields in LRHR rats. A positive correlation is seen between histone deacetylase 2 and brain-derived neurotrophic factor (BDNF) levels both of which are oppositely regulated in LRHR CA3 fields in response to chronic social stress. Increase in BDNF levels in CA3 field accompanied increase in supra-pyramidal mossy fibre terminal field size (SP-MF) in HRs, and decrease in BDNF levels accompanied decrease in SP-MF volume in LRs. Epigenetic regulation of neurotrophic support underlying these structural changes is discussed. / by Ozge Oztan. / Thesis (M.S.)--Florida Atlantic University, 2009. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2009. Mode of access: World Wide Web.

Adult hippocampal neurogenesis—a unique form of plasticity in the dentate gyrus (DG)—is regulated by experience, and when manipulated can have specific effects on behavior. Different methods have been used over the years to study new neurons’ functional role in the hippocampus, many of which focus on ablating neurogenesis. While ablation methods can test the necessity of adult-born granule cells (abGCs) for behavior, these techniques remove all abGCs from the circuit and thus do not allow one to determine which properties of abGCs are required for behavior. Such information is required to understand the mechanism of their action. Thus, new strategies are needed to determine what properties of young abGCs allow them to distinguish themselves from their mature counterparts and uniquely impact behavior. Recent hypotheses have suggested that the enhanced synaptic plasticity exhibited by 4–6-week-old abGCs allows them to uniquely contribute to hippocampal circuit function, and thus behavior. The primary goal of this thesis was to explore the contribution young abGCs’ heightened synaptic plasticity makes to hippocampal function. This was achieved using a transgenic mouse approach that allowed for the conditional deletion of NR2B from abGCs. Overall, iNR2BNes mice generated the same number of new neurons in adulthood as control mice at baseline. These neurons survived and matured with only a slight reduction in dendritic complexity. However, a potentially important electrophysiological property of these neurons—their enhanced synaptic plasticity—had been eliminated. From an electrophysiological standpoint, iNR2BNes mice resemble mice with ablated neurogenesis, while from all other neurogenic standpoints examined they most closely resemble wild-type mice. Consequently, these mice provided a novel model to test the extent to which young abGCs’ enhanced plasticity contributes to hippocampal-dependent behaviors. The results reveal that eliminating NR2B-containing NMDA receptors from abGCs does not alter baseline anxiety or antidepressant (AD)-like behavior. However, iNR2BNes mice differed from controls in measures of cognitive function. These mice were able to learn in the contextual fear conditioning test, but were impaired in the more difficult contextual fear discrimination test. Mice also exhibited a decreased novelty exploration phenotype that impaired their performance in the novel object recognition test. Together, these results indicate that the NR2B-dependent heightened plasticity exhibited by 4–6-week-old abGCs is necessary for responses to novelty and fine contextual discrimination, but does not contribute to baseline anxiety or emotionality. AD treatment increases levels of adult neurogenesis in the hippocampus, and these newborn neurons have been shown to be necessary for some of the behavioral effects of ADs seen in rodents. In addition, the maturation timeline of adult neurogenesis correlates with the onset of behavioral responses to ADs. ADs also enhance a neurogenesis-dependent form of long-term potentiation (LTP) in the DG evoked by medial perforant path stimulation under intact GABAergic tone called ACSF-LTP. Thus, a potential mechanism by which abGCs may contribute to AD behavioral efficacy is by providing extra plastic units to the DG circuit. This theory was tested by once again using the mouse line in which NR2B can be conditionally deleted from abGCs in the DG. Here, we found that deletion of the NR2B subunit significantly attenuated a neurogenesis-dependent behavioral response to fluoxetine in the novelty suppressed feeding test, and additionally blocked fluoxetine’s ability to enhance young abGCs’ maturation and subsequent integration into the hippocampal network. This suggests that eliminating abGCs’ enhanced plasticity decreases their ability to influence DG output resulting in an AD response that is less robust than seen in control mice. Control experiments revealed the specificity of this effect, as NR2B deletion did not impact the effect of fluoxetine in a neurogenesis-independent behavioral assay (tail suspension test) or in an assay that was insensitive to fluoxetine in this strain of mice (elevated plus maze). Our efforts to isolate the contribution of abGCs’ unique physiology from the neurogenic effects of fluoxetine were not entirely successful as the results presented here also revealed slight group differences in neurogenesis between control mice and mice lacking NR2B in young neurons. Yet, this data still supports the idea that fluoxetine increases the ability of abGCs to participate in DG output by increasing the chance that new neurons will be activated during DG stimulation. This may be achieved either by increasing their overall number, increasing their potential to make synaptic connections, or increasing their ability to strengthen their connections. However, due to the close link between activity and maturation that appears to be enhanced with fluoxetine treatment, a different approach with greater temporal resolution is needed to separate the neurogenic effects of fluoxetine from the physiological contribution abGCs make to hippocampal output. With this in mind, a mouse line in which abGCs could be temporally inhibited was also generated. Cellular and behavioral characterization of mice conditionally expressing hM4Di—a mutated muscarinic acetylcholine receptor that is insensitive to endogenous acetylcholine, but can be activated by the biologically inert, highly bioavailable compound, clozapine N-oxide (CNO)—has begun. Results show that acute CNO treatment in mice expressing this designer receptor exclusively activated by a designer drug (DREADD) in DG granule cells can impair encoding of contextual fear memory. Chronically treating these mice had an anxiogenic effect in the open field test, but otherwise anxiety and emotionality in these mice were comparable to controls. Chronic CNO treatment in mice expressing hM4Di in young abGCs effectively decreased these cells’ dendritic complexity, but did not alter proliferation or early survival. Thus, hM4Di DREADDs represent a novel tool that can be used to modulate activity of neurons in a temporally restricted manner, allowing for both acute and chronic manipulations of hippocampal granule cells. The experiments put forth in this thesis will highlight the importance of abGCs enhanced plasticity. The utility as well as potential pitfalls of the mouse models used here to test theories of abGC function will also be explored. Hopefully this analysis will provide an improved framework in which future experiments can be developed with the aim of uncovering novel insights into the hippocampal circuitry that underlies learning and memory and discovering new strategies for the treatment of neurological and psychiatric disorders.

The purpose of the current thesis was twofold: (1) to examine various factors that might be contributing to age-related learning and memory deficits specifically related to the hippocampus, and (2) to validate our rat model of aging, employing a multilevel analysis. We found age-related deficits on both spatial and non-spatial hippocampus-dependent taks that were accompanied by structural alterations observed in vivo (volune, but not neuronal metabolic function) and post mortem (neuronal density and neurogenesis, but not synaptic or mitochondrial density). Furthermore, our results suggest that the observed hippocampal structural changes, named decreased volume and neurogenesis, predict learning and memory deficits, and both can be accounted for by neurogenic reduction. In addition, the above-mentioned pattern of age-related deficits closely resembles that seen in humans, suggesting the present rat version of aging to be a very useful model for investigating hippocampal aging in humans. / iii, 236 leaves : ill. (some col.) ; 29 cm.

Different events usually contain similar elements that can contribute to interference during memory encoding and retrieval. The hippocampus (HPC), a structure that is critically involved in some forms of memory, has been hypothesized to reduce interference between memories with overlapping content, thus facilitating correct recall. Pattern separation is one hypothetical process whereby input ambiguity is reduced. Here we test the hypothesis that the HPC and/or dentate gyrus (DG) are important for pattern separation by measuring performance by rats with damage in tasks that require discrimination between visual stimuli that share systematically varying numbers of common elements. Rats with HPC damage were slower to resolve discriminations with minimal degrees of overlap. Lesions of the DG did not affect the ability of rats to deal with overlap, suggesting a dissociation between the HPC and DG. Our results provide partial support for the idea that the HPC contributes to the pattern separation process. / ix, 84 leaves : ill. ; 29 cm.

This thesis investigates the role of the hippocampus in object memory. Currently, the role of the hippocampus in object recognition is unclear, with some studies demonstrating a delay-dependent impairment after hippocampal damage, others showing no impairment. The present thesis used the novel object recognition task and its variants to investigate various types of object memory in hippocampal lesion rats. In the first study, impairments were observed in discriminating object order and associating objects with contexts, while no impairment was observed in novel object recognition. In the second study, it was found that encountering another object shortly prior to or after encountering a target object impairs the recognition of the target object. In a control procedure, encountering a novel context either shortly before or after encountering the target object did not impair object recognition. In sum, in the absence of the hippocampus, object memory becomes vulnerable to interference, rendering rats unable to discern memories of multiple objects. The present thesis concludes that the hippocampus discriminates multiple objects via pattern separation. A stimulus-response model relating the role of the hippocampus to object memory is proposed. / vii, 150 leaves : ill. ; 29 cm. --

Bibliography: 197-226 p. / xiv, 226 p. : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines the alterations in electrophysiological function during hypoxia in the rat hippocampal slice, in particular those alterations induced by extracellular accumulation of adenosine. / Thesis (Ph.D.)--University of Adelaide, Faculty of Science, 1996

Experimentally naive rats show variance in their locomotor reactivity to novelty, some displaying higher (HR) while others displaying lower (LR) reactivity, associated with vulnerability to stress. LRHR phenotype is proposed as an antecedent to the development of stress hyper responsiveness. Results presented here show emergence of antidepressive-like behavior following peripubertal-juvenile exposure to chronic variable physical (CVP) and chronic variable social stress (CVS) in HR rats, and depressive-like behavior following CVP in the LRs. The antidepressive-like behavior in HR rats was accompanied by increased levels of acetylated Histone3 (acH3) and acetylated Histone4 (acH4) at the hippocampal brain-derived neurotrophic factor (BDNF) P2 and P4 promoters respectively. This effect may mediate increased mossy fibre (MF) terminal field size, particularly the suprapyramidal mossy fibre projection volume (SP-MF), in the HR animals following both stress regimens. These findings show that chronic variable stress during adolescence induces individual differences in molecular, neuromorphological and behavioral parameters between LRs and HRs, which provides further evidence that individual differences in stress responsiveness is an important factor in resistance or vulnerability to stress-induced depression and/or anxiety. / by Ozge Oztan. / Thesis (Ph.D.)--Florida Atlantic University, 2013. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.