Graduate Theses & Dissertations

Retrograde Amnesia of Fear Memories Following Pentylenetetrazol Kindling
Memories pertaining to fearful events are some of the most salient and long-lasting memories, as they are critical to the survival of an organism. Seizures induce aberrant changes within temporal lobe and limbic brain structures that are critical for supporting fear memories. Seizures can occur at any time; therefore, it is imperative that research address how seizures impact previously learned information. The present series of experiments demonstrate that pentylenetetrazol-kindling induces retention deficits of previously acquired context fear memories in male rats. Kindling induced subsequent fear learning deficits but did not impact spatial learning. Additionally, following kindling, volumetric increase was observed within the hippocampal subfield CA3, as well as increased neural activation within the hippocampal subfield CA1. The results of this work suggests that chronic seizures can alter the function of neural networks important for supporting and retrieving previously acquired memories. Author Keywords: amygdala, anterograde amnesia, context fear conditioning, hippocampus, retrograde amnesia, seizures
Evidence of an Interaction Between Memory Stores for Long-Term Context Fear Memory in the Rat
Memories which typically require the hippocampus (HPC) can become represented in structures outside of the HPC, and therefore resistant to HPC damage, but, the properties of these memories are poorly understood. Some research has suggested that the HPC continually contributes to memories that are resistant to hippocampal damage, and without this support, they are weaker and more susceptible to loss. However, this hypothesis has yet to be tested experimentally. We examined this possibility in rats by assessing decay and extinction of a context fear memory that had become independent of the HPC via repeated learning episodes. We found that HPC-independent context fear memories decay and extinguish faster without continued HPC support, suggesting that the HPC plays a continued role in long-term memory. We also provide new evidence of a persistent interaction between the HPC and other memory systems, which strengthens non-HPC representations so that they withstand HPC damage at longer intervals. Author Keywords: consolidation, context fear, hippocampus, memory, retrograde amnesia
Endocannabinoid Treatment for the Behavioural and Histopathological Alterations of Epilepsy
Epilepsy is associated with a variety of cognitive, emotional, and pain-related symptoms, such as impaired memory and learning, increased risk of anxiety and depression, and increased pain sensitivity. Unfortunately, these symptoms are generally untreated with typical pharmacological interventions, which tend to target seizure activity (i.e., ictogenesis) and not the subsequent histopathological and behavioural alterations resulting from epilepsy (i.e., epileptogenesis). Evidence has demonstrated that targeting the endocannabinoid system can alleviate seizure symptoms as well as cognitive, emotional, and pain-related impairments independent of epilepsy. However, research examining the use of endocannabinoid-based treatment for these behavioural symptoms when they are associated with epilepsy is sparse. In the following thesis, two animal models of epilepsy, several behavioural assessments, and immunohistochemical techniques are utilized to assess the effectiveness of endocannabinoid-based treatment for epilepsy’s interictal symptoms. The findings expand our knowledge and offer encouraging evidence for the usefulness of endocannabinoid-based treatment as an epileptogenesis-targeting pharmacological intervention. Author Keywords: animal models, endocannabinoid system, histopathological alterations, interictal symptoms, temporal lobe epilepsy, treatment
Impaired contextual fear discrimination learning after long-term amygdala kindling
Cognitive impairments, such as memory loss, are a frequent and devastating co-morbidity associated with epilepsy. The neurobiological mechanisms through which recurrent seizures induce cognitive impairments are not well understood. New neurons born after seizures develop abnormal morphological and functional characteristics that promote network hyperexcitability and hippocampal dysfunction. Previously, we found that kindling dramatically increases the rate of neurogenesis at early stages of seizure development, followed by a long-term suppression at later stages. These changes in the rate of cell proliferation coincides with aberrant modifications in the migration, excitability, and functional integration of these new neurons. It has been suggested that the long-term consequences of seizure-induced neurogenesis contributes to the development of cognitive impairment seen in chronic epilepsy. However, direct experimental evidence has been limited. The present series of experiments sough to determine if blocking aberrant seizure-induced neurogenesis can reduce cognitive deficits associated with chronic epilepsy. Our findings suggest that chronic seizures impair the ability of rats to differentiate between similar contexts. In addition, blocking aberrant seizure-induced neurogenesis through treatment with the cytotoxic agent temozolomide was capable of preventing some of the deficits in context discrimination learning when neurogenesis levels were reduced to non-epileptic control levels. This research provides further support of targeting aberrant neurogenesis as a novel treatment to restore cognitive functioning in individuals living with epilepsy. Author Keywords: Amygdala kindling, Dentate gyrus, Hippocampus, Neurogenesis, Pattern separation, Seizures
Assessing the Clinical Usefulness of Three Tablet-Based Visuomotor Tasks to Evaluate Closed Head Injury
Evidence suggests that visuomotor system behaviour may be more sensitive to the prolonged effects of mild brain injuries than neuropsychological tests. We evaluated whether participants with a mild closed head injury (CHI) would show lingering visuomotor deficits, but not cognitive deficits, up to three years post-injury compared to participants with an orthopaedic injury and healthy controls. All three groups completed a tablet-based visuomotor assessment tool and a brief neuropsychological test battery. The CHI participants scored comparable to the control groups on the neuropsychological tests, but when assessed for visuomotor function requiring adjustment to a changing stimulus, CHI participants showed poorer performance than the control groups. Combined, these findings add to the evidence that CHI can lead to persistent visuomotor deficits that extend beyond those of neuropsychological tests. Therefore, visuomotor assessment should be included in brain injury and recovery evaluation, and this can be accomplished easily using tablet-based tasks. Author Keywords: closed head injury, neuropsychological assessment, recovery, tablet, traumatic brain injury, visuomotor
Altered Hippocampal Regulation of Immediate Early Genes after Pentylenetetrazol-Induced Seizures
Seizures induce long-term changes in gene expression in the hippocampus. Experimental evidence has demonstrated a significant effect of epileptic activity on the activity of neurons that participate in complex cognitive and behavioural processes. The present series of experiments involving kindling with subconvulsive doses of PTZ demonstrates a link between seizures and altered immediate early gene expression within the hippocampus and dentate gyrus. In addition, newborn hippocampal neurons were shown to have decreased induction of plasticity-related genes, suggesting deficits in activity-dependent recruitment. These findings may shed light on the mechanisms underlying epileptogenesis and epilepsy-related hippocampal dysfunction in human patients. Author Keywords: hippocampus, IEGs, kindling, neurogenesis, seizures
Practicing and Rewarding Task-Relevant Motor Variability to Optimize Motor Performance
It is universally accepted that human motor performance is variable in both its timing and spatial qualities. However, it is unclear to what extent motor variability impedes performance when learning a new skill and to what extent it enables our ability to learn. The first experiment examined whether performance during a test task depended on whether participants practiced to constrain or vary the task-relevant parameter. Participants used their right hand to make simple point-to-point movements. Results demonstrated the importance of paying attention to test task demands to evaluate which form of practice is most beneficial. The second experiment examined whether levels of variability could be manipulated using a reward-based paradigm to enhance learning when adapting to a perturbation of a simple visually-guided reaching movement. A reward-based feedback task was designed to encourage exploration along the task-relevant dimension, specifically movement direction variability. Overall, I did not find any significant results. Author Keywords: Adaptation, Motor Control, Motor Learning, Reaching
Non-Hippocampal Memory Systems Contributing to Reinstated Context Memory
Damage to the hippocampus (HPC) typically causes retrograde amnesia for contextual fear conditioning. Reinstating the conditioning over several sessions, however, can mitigate the retrograde amnesic effects. Reinstatements, thus, establish a sufficiently strong memory in non-HPC systems to no longer require the HPC for expression, meaning that it has become HPC independent. This thesis aimed to determine the structures comprising the non-HPC system supporting reinstated context fear memory. The contribution of the perirhinal cortex (PRH) and the anterior cingulate cortex (ACC) were examined because of their established role in context memory. Initially, it was demonstrated that HPC damage indeed causes retrograde amnesia for single session, but not reinstated, contextual fear conditioning. Then, it was demonstrated that combined HPC and PRH damage causes retrograde amnesia for reinstated contextual fear conditioning, whereas combined HPC and ACC damage had lesser effects. Therefore, the PRH is a key structure within the non-HPC memory system for reinstated context fear memory. Author Keywords: anterior cingulate cortex, contextual fear conditioning, hippocampus, memory, perirhinal cortex, retrograde amnesia
Role of Multiple Nights of Sleep in the Consolidation of an Engaging and Complex Motor Learning Task
The present study examined the role of multiple nights of sleep in the consolidation of a complex motor learning task. Participants were 24 Trent undergraduates, 12 in the learning group (Mage = 20.33, SD = 1.87, 10 female) and 12 in the control group (Mage = 21.92, SD = 3.42, 7 female). Participants underwent 5 consecutive nights of polysomnographic recordings, with a Rock Band learning session on the third night. A series of 2(group)x4(night) ANOVAs were performed on the sleep variables. Interactions were found in the number of spindles detected at Pz, F(333) = 9.19, p <.01, and in the density of spindles detected at Pz, F(3,33) = 4.06, p <.05. The pattern of changes from baseline was significantly different between the two groups; spindles increased in the learning group and decreased in the control group. The novel finding was that spindle number/density remained elevated at the third post-learning night of sleep. Author Keywords: Motor Learning, Procedural Memory, Sleep, Sleep Spindles
TESTING THE ROLE OF BIMODAL CELLS IN NEAR-HAND EFFECTS
We investigated whether hand-proximity effects arise from the recruitment of visual-tactile bimodal cells. In Experiment 1, we executed right-hand open-loop reaching movements to targets, presented either near or far from the resting left-hand, and after applying repetitive transcranial magnetic stimulation (rTMS) to suppress neuronal activity in the PMd and AIP, in Experiment 2. Results from Experiment 1, indicated that near-hand targets improved accuracy and reduced variability. In Experiment 2, suppressing PMd showed similar near-hand effects as above. In contrast, applying rTMS to AIP disrupted the representation of target location, indicating less accuracy and greater error. Near-hand proximity effects possibly arise from the recruitment of visual-tactile bimodal cells within the human AIP. Author Keywords: anterior intraparietal sulcus, peripersonal space, repetitive transcranial magnetic stimulation (rTMS), , rTMS, anterior intraparietal sulcus, AIP., visual-tactile bimodal neurons

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