The present study examined social status and adult neurogenesis in the naked mole rat. These animals live in large colonies with a strict reproductive dominance hierarchy; one female and 1-3 males breed, while other members are subordinate and reproductively suppressed. We examined whether social status affects doublecortin (DCX; a marker for immature neurons) immunoreactivity in the dentate gyrus, piriform cortex (PCx), and basolateral amygdala (BLA) by comparing breeders to subordinates. We also examined subordinates removed from their colony and paired with opposite- or same-sex conspecifics for 6 months. Breeders had reduced DCX immunoreactivity in all areas, with BLA effects confined to females. Effects of housing condition were region-specific, with higher PCx DCX immunoreactivity observed in opposite- than same-sex paired subordinates regardless of gonadal status. The opposite pattern was observed in the BLA. Future work will clarify whether findings are attributable to status differences in stress, behavioural plasticity, or life stage.

The lateral septum is heavily implicated in anxiety regulation, with lesions or pharmacological inhibition of this region suppressing rats' defensive responses in various rat models of anxiety. My first objective was to explore the functional relationship between the lateral septum and its major afferent structure, the ventral hippocampus. Although these structures are extensively connected, it was not clear if they work in concert to regulate anxiety-like behaviours. This idea was tested using a pharmacological disconnection technique, whereby communication between these two structures was disabled by infusing the GABAA agonist muscimol into one side of the lateral septum and the contralateral side of the ventral hippocampus. Increases in open-arm exploration were evident when muscimol was co-infused into one side of the lateral septum and the contralateral ventral hippocampus. By contrast, open arm exploration was not altered when muscimol was co-infused into one side of the lateral septum and the ipsilateral ventral hippocampus. These results support the contention that the ventral hippocampus and the lateral septum regulate rats' open arm exploration in a serial fashion, and that this involves ipsilateral projections from the former to the latter site. My second objective was to further characterize the neuropharmacological aspects of lateral septal regulation of behavioural defence. The lateral septum contains high levels of NPY Y1 and Y2 receptor binding sites in the brain, yet little is known about their contribution in anxiety regulation at this site. Therefore, the second aim of my thesis was to characterize the contribution of NPY and its Y1 and Y2 receptor subtypes in the lateral septal regulation of anxiety in the elevated plus maze, novelty-induced suppression of feeding, and shock-probe burying tests. I determined that distinct NPY receptors differentially contribute to NPY-mediated anxiolysis in a test specific manner, with the Y1 receptor mediating NPY-induced anxiolysis in the novelty-induced suppression of feeding test, and the Y2 receptor mediating NPY13-36-induced anxiolysis in the plus-maze test. Taken together, the results from these studies reinforce the view that the regulation of anxiety involves a variety of different, yet overlapping neural processes. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2012-09-25 18:02:11.172

No description available.

No description available.

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.

At the author’s request, the abstract has been removed due to the confidential nature of the thesis. It will be added once the embargo period has passed.

This study assessed the in vivo effects of various serotonin (5-HT) receptor modulators on 5-HT neurotransmission in the rat hippocampus. Vortioxetine, humanized-vortioxetine, and escitalopram blocked the 5-HT transporter, but similar to ipsapirone did not dampen the sensitivity of postsynaptic 5-HT1A receptors. Long-term administration of all treatments increased the tonic activation of postsynaptic 5-HT1A heteroreceptors, an effect common to all antidepressants. Vortioxetine decreased the function of the terminal 5-HT1B autoreceptor under high but not a low degree of activation, thus showing that its partial agonism led to increased 5-HT release and that long-term administration results in the desensitization of terminal 5-HT1B autoreceptors. Vortioxetine overcame the effects of 5-HT1B and 5-HT3 receptor agonists. This study was unable to determine the involvement of 5-HT7 receptor antagonism exerted by vortioxetine affects 5-HT neurotransmission. Therefore, vortioxetine would appear to exert different actions, via transporter and receptor activity, on the serotonergic system in the hippocampus, consistent with its unique pharmacological profile.

<p>Understanding the mechanisms of limbic epileptogenesis in cellular and molecular terms may provide novel therapeutic targets for its prevention. The neurotrophin receptor tropomyosin-related kinase B (TrkB) is thought to be critical for limbic epileptogenesis. Enhanced activation of TrkB, revealed by immunodetection of enhanced phosphorylated TrkB (pTrkB), a surrogate measure of its activation, has been identified within the hippocampus in multiple animal models. Knowledge of the cellular locale of activated TrkB is necessary to elucidate its functional consequences. Using an antibody selective to pTrkB in conjunction with confocal microscopy and cellular markers, we determined the cellular and subcellular locale of enhanced pTrkB induced by status epilepticus (SE) evoked by infusion of kainic acid into the amygdala of adult mice. SE induced enhanced pTrkB immunoreactivity in two distinct populations of principal neurons within the hippocampus--the dentate granule cells and CA1 pyramidal cells. Enhanced immunoreactivity within granule cells was found within mossy fiber axons and giant synaptic boutons. By contrast, enhanced immunoreactivity was found within apical dendritic shafts and spines of CA1 pyramidal cells. A common feature of this enhanced pTrkB at these cellular locales is its localization to excitatory synapses between excitatory neurons, presynaptically in the granule cells and postsynaptically in CA1 pyramidal cells. Long-term potentiation (LTP) is one cellular consequence of TrkB activation at these excitatory synapses that may promote epileptogenesis.</p><p>The importance of TrkB in diverse neuronal processes, as well as its involvement in various disorders of the nervous system, underscores the importance of understanding how it is activated. The canonical neurotrophin ligand which activates TrkB is brain derived neurotrophic factor (BDNF). Zinc, however, has also been demonstrated to activate this receptor through a mechanism whereby it does not directly interact with it, known as transactivation. Presynaptic vesicles of mossy fiber boutons of stratum lucidum are particularly enriched in zinc, where it is co-released with glutamate in an activity dependent fashion, and incorporated into these vesicles by the zinc transporter, ZnT3. Given the presence of large quantities of zinc within stratum lucidum, we hypothesized that this metal may contribute to TrkB transactivation at this locale. To this end, we examined the contributions of both BDNF and synaptic vesicular zinc to TrkB activation in stratum lucidum of mouse hippocampus under physiological conditions. Utilization of mice which are genetic knockouts for BDNF and/or ZnT3 allowed us to examine TrkB activation in the absence of one or both of these ligands. This was done using an antibody for pTrkB in conjunction with confocal microscopy, assaying immunoreactivity at the cellular and synaptic locales within stratum lucidum where pTrkB was previously found to be enriched. Our results suggest that BDNF contributes to TrkB activation within stratum lucidum. Interestingly, ZnT3 mice displayed an increase in BDNF protein and TrkB activation, demonstrating that synaptic zinc regulates BDNF and TrkB signaling at this locale.</p> / Dissertation

Traumatic brain injury (TBI) damages many regions of the brain but damage to the hippocampus has been particularly linked to functional deficits in memory and wayfinding (i.e., finding one's way in familiar and unfamiliar environments). The current study investigated the nature of these wayfinding problems using a virtual simulation of a Morris water maze, a standard test of hippocampal function in laboratory animals. Eleven TBI survivors and 12 comparison participants, matched for gender, age and education were tested to see if they could find a location in a virtual room marked by a) a visible platform, b) a single object, c) one object of 8 different ones, or d) distal room cues (which requires cognitive mapping). TBI survivors were impaired at finding the location based on room cues but not when the other cues were present. These results indicate that TBI impairs cognitive mapping but not associative processes in wayfinding.

The current dogma states that the medial perforant path (MPP) and lateral perforant path (LPP) inputs to the hippocampal dentate gyrus can be differentiated electrophysiologically using the response to paired-pulse stimuli. Stimulation at 50 ms intervals produces paired-pulse depression (PPD) in the MPP, whereas these same stimuli produce paired-pulse facilitation (PPF) in the LPP (McNaughton 1980). Several years of practical experience in our laboratory has led us to question the utility of paired-pulse administration as a reliable means to differentiate the perforant path subdivisions in vitro. Using field recordings in male Sprague Dawley rats, we demonstrate both subdivisions of the perforant pathway show predominantly PPF at low stimulus intensities. Activation of the LPP registered significantly greater net PPF (24.97±4.08%) relative to the MPP (13.76±3.86%) at the 50 ms interpulse interval. These results were independent of the position in the dorsoventral axis from which the hippocampal slice was obtained but elevating the calcium concentration (2mM to 4mM) or decreasing the temperature (300C to 230C) reduced the paired-pulse ratio. Increasing the magnitude of the applied stimulus could result in PPD in both paths in a manner that was correlated with the emergence of population spikes (r> -0.90). Partial blockade of AMPA receptors reduced the ability of high stimulus intensities to induce PPD and restored PPF in most cases. A comparison of field excitatory postsynaptic potential (fEPSP) characteristics demonstrated MPP waveforms could be differentiated by their significantly shorter peak latency and half-width times, greater total decay time, and the presence of a more reliable bi-exponential decay phase function relative to LPP waveforms. This research helps to refine our view of functional differences between the MPP and LPP, revealing more subtle differences in paired-pulse plasticity and distinct fEPSP waveform parameters as reliable features to distinguish these pathways.