published_or_final_version / abstract / Pharmacology / Master / Master of Philosophy

published_or_final_version / Biological Sciences / Master / Master of Philosophy

published_or_final_version / Biological Sciences / Master / Master of Philosophy

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.

Male C7BL/6J mice were implanted with bilateral dorsal CA1 guide cannulae. After confirming that intrahippocampal microinfusion of muscimol impaired hippocampal function, demonstrated by impaired performance in the Morris water maze, the influence of intrahippocampal muscimol was tested in the Novel Object Recognition paradigm. During a test session 24 h after the last habituation/sample session, mice were presented with one familiar object and one novel object. Successful retention of object memory was inferred if mice spent more time exploring the novel object than the familiar object. Results demonstrate that muscimol infused into dorsal CA1 region prior to the test session eliminates novel object preference, indicating that the hippocampus is necessary for the retrieval of this non-spatial memory - a topic that has garnered much debate. Understanding the similarities between rodent and human hippocampal function could enable future animal studies to effectively answer questions about diseases and disorders affecting human learning and memory. / by Lisa Rios. / Thesis (M.A.)--Florida Atlantic University, 2011. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2011. Mode of access: World Wide Web.

The rodent hippocampus is critical for processing spatial memory but its contribution to non-spatial, specifically object memory is debated. The cognitive map theory of hippocampal function states that the hippocampus stores relationships of goal locations (places) to discrete items (objects) encountered within environments. Dorsal CA1 place cells were recorded in male C57BL/6J mice performing three variations of the novel object recognition paradigm to define "object-in-context" representation of hippocampal neuronal activity that may support object memory. Results indicate, (i) that place field stability is higher when polarizing environmental cues are provided during object recognition; (ii) hippocampal place fields remain stable throughout the novel object recognition testing without a polarizing cue; and (iii) time dependent effects on stability when objects were dissociated from the context. These data indirectly support that the rodent hippocampus processes object memory, and challenge the view that "object-in-context" representations are formed when mice perform novel object recognition task. / by Herborg Nanna âAsgeirsdâottir. / Thesis (M.A.)--Florida Atlantic University, 2013. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.

SK channels are small conductance Ca2+-activated K+ channels expressed throughout the CNS. SK channels modulate the excitability of hippocampal CA1 neurons by affecting afterhyperpolarization and shaping excitatory postsynaptic responses. Such SK-mediated effects on activity-dependent neuronal excitability and synaptic strength are thought to underlie the modulatory influence of SK channels on memory encoding. Here,the effect of a new SK1 selective activator, GW542573X, on hippocampal-dependent object memory, contextual and cued conditioning, and trace fear conditioning was examined. The results demonstrated that pre- but not post-training systemic administration of GW542573X impaired object memory and trace fear memory in mice 24 h after training. Contextual and cued fear memory were not disrupted. These current data suggest that activation of SK1 subtype-containing SK channels impairs long-term memory. These results are consistent with converging evidence that SK channel activation suppressed behaviorally triggered synaptic plasticity necessary for encoding hippocampal-dependent memory. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2015. / FAU Electronic Theses and Dissertations Collection

Adolescence is a time filled with opportunities for making choices that have not been encountered before. How do adolescents learn to make these decisions? Maturation of learning processes coupled with dynamic changes in brain systems for learning must be studied in order to determine the mechanisms that underlie adolescent decision making. Research in adults has found contributions from multiple learning systems for decision making. One such system learns incrementally from feedback and reinforcement, and depends in part on the striatum. Another system, in the hippocampus, encodes episodes and allows for flexible use of learned information when required by novel contexts. Recent research in adults explores how these systems can cooperate and compete to facilitate decision making. Ongoing research into learning and decision making processes over the course of adolescence has also implicated the striatum in learning and decision making, but how the hippocampus and striatum interact for decision making remains unknown. In this dissertation I investigate contributions of multiple learning systems for learning and decision making in adolescence. I leverage what is known about underlying brain systems for learning and decision making in adults, and consider how changes in these same systems over adolescence might contribute to behavioral shifts in adolescence. Specifically, in the studies included here, I show how developmental trajectories for learning can enhance performance in adolescents for some types of learning and not others. In the first study I ask how do the striatal and hippocampal systems contribute to feedback based learning in adolescence? I show that in adolescents, both the hippocampus and the striatum contribute to probabilistic feedback learning, and that this type of learning is better in adolescents than in adults. This response to feedback in the hippocampus was found to relate to memory accuracy for features of feedback events only in adolescents. Pushing the finding of hippocampal activation in adolescents, in the second study I ask how does learned value influence flexible decision making in adolescence? Adolescents did not show reliable transfer of value, but there were individual differences in this tendency. Thus, in the third study, I ask which brain regions account for individual differences in learning and value transfer? I show that variability in connectivity at rest between the hippocampus and the vmPFC related to the tendency to transfer value in adults. Taken together, these results contribute to a growing body of research in adolescent decision making, and extend upon our understanding of the mechanisms for learning and decision making systems, and how they change over development.

The ventral hippocampus (vHPC), medial prefrontal cortex (mPFC), and basolateral amygdala (BLA) are each required for the expression of anxiety-like behavior. Yet the role of each individual element of the circuit is unclear. The projection from the vHPC to the mPFC has been implicated in anxiety-related neural synchrony and spatial representations of aversion. The role of this projection was examined using multi-site neural recordings combined with optogenetic terminal inhibition. Inhibition of vHPC input to the mPFC disrupted anxiety and mPFC representations of aversion, and reduced theta synchrony in a pathway-, frequency- and task-specific manner. Moreover, bilateral, but not unilateral, inhibition altered physiological correlates of anxiety in the BLA, mimicking a safety-like state. These results reveal a specific role for the vHPC-mPFC projection in anxiety-related behavior and the spatial representation of aversive information within the mPFC. Moreover, these data suggested that theta-frequency input from the vHPC plays a causal role in anxiety-like behavior. Next, it was investigated whether optogenetic stimulation of the vHPC-mPFC at a theta frequency was sufficient to increase anxiety. Stimulating the vHPC input to the mPFC with a sinusoidal light pattern at 8 Hz significantly increased anxiety behavior. The anxiogenic effect of vHPC terminal stimulation was frequency- (8 Hz but not 20 Hz) and pattern- (sinusoids but not pulses) specific. To understand how pulses and sinusoidal light modulate mPFC neurons differentially, mPFC pyramidal neurons were recorded both in vitro and in vivo while stimulating vHPC terminals with the same sinusoidal or pulsatile patterns. In vitro, sinusoidal stimulation increased the rate of spontaneous EPSCs, while pulses evoked strong, stimulus-locked EPSCs. In vivo, sinusoidal stimulation of vHPC terminals increased the phase-locking of mPFC single unit spiking to the optical stimulation pattern without changing overall firing rates. Together, these results suggest that sinusoidal stimulation at 8 Hz enhances theta-frequency activity in mPFC neurons as well as anxiety-related behavior. Moreover, they suggest that theta-frequency components of neural activity play a privileged role in vHPC-mPFC communication and hippocampal-dependent forms of anxiety.

Traumatic brain injury (TBI) is the signature injury of the ongoing military conflicts in the Middle East and Afghanistan, largely due to the use of improvised explosive devices (IEDs), which have affected soldiers and civilians alike. Blast-induced TBI (bTBI) biomechanics are complex and multiphasic. While research has clearly demonstrated the negative effects of penetrative (secondary blast) and inertia-driven (tertiary blast) injury, the effect of shock wave loading (primary blast) on the brain remains unclear. Combined primary-tertiary blast exposure in vivo has been reported previously to alter brain function, specifically hippocampal function; however, it is extremely difficult to deliver primary blast exposure in isolation with an in vivo injury model. The research presented in this thesis utilized a custom-designed in vitro blast injury model to deliver military-relevant shock wave exposures, in isolation, to organotypic hippocampal slice cultures (OHSCs). To contextualize blast-induced pathobiology with previous TBI studies, the first goal of this thesis was to experimentally characterize the deformation profile induced in OHSCs with our blast injury model. Using stereoscopic, high-speed cameras and digital image correlation to calculate strain, we found that our blast model induced low strain magnitudes (<9%) but at high strain rates (25-86s-1), which aligned closely with associated computational simulations of our model. The second aim was to determine if primary blast was capable of altering hippocampal electrophysiological function. We exposed OHSCs to a range of shock intensities and found, using a micro-electrode array system, that long-term potentiation (LTP), a measure of synaptic plasticity, was very sensitive to primary blast exposure; a threshold for disruption of LTP was found between 9 and 39 kPa•ms impulse. Alternative measures of basal electrophysiology were less sensitive than LTP. Blast exposure significantly reduced LTP between 1 and 24 hours post-injury, and this deficit persisted through 6 days post-injury. Depending on shock intensity, LTP spontaneously recovered 10 days post-injury. The third aim was to explore the cellular mechanisms for blast-induced LTP deficits. Using a chemical LTP induction protocol, blast exposure altered key proteins necessary for the induction of LTP by 24 hours post-injury including, postsynaptic density protein-95 (PSD-95), a major scaffolding protein that organizes the postsynaptic density (PSD), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor 1 (AMPA-GluR1), and stargazin, an auxiliary GluR1 protein that binds AMPA-GluR1 to PSD-95. Modulation of the cyclic adenosine monophosphate (cAMP) pathway reversed the observed effects of blast on LTP. We theorized that blast-induced disruption of PSD-95 prevented translocation, and subsequent phosphorylation, of GluR1-containing AMPARs to the postsynaptic membrane, which, in turn, prevented potentiation. The final aim was to investigate the efficacy of phosphodiesterase-4 (PDE4) inhibitors, which block degradation of cAMP, as a therapeutic strategy. When delivered immediately following primary blast injury, multiple PDE4 inhibitors proved efficacious in restoring LTP measured 24 hours post-injury. Roflumilast, a Food and Drug Administration-approved PDE4 inhibitor, was effective when delivered at a clinically relevant concentration (1nM) and at a delayed time point (up to 6 hours). Roflumilast reversed blast-induced changes in expression/phosphorylation of the key LTP protein targets. We hypothesized that maintenance of PSD-95 drove the observed therapeutic effect. Greater work is necessary to determine how blast exposure degrades PSD-95 and how roflumilast prevented these detrimental effects. This thesis has shown that primary blast exposure can negatively alter neurological function, as well as protein expression and phosphorylation. These studies expand the understanding of primary blast injury mechanisms, provide computational models with important tissue-level tolerance criteria, inform protective equipment design, inform clinical care guidelines for bTBI, and present a promising therapeutic candidate for further clinical investigation.