Fournier, Neil M

ABSTRACT Patients who undergo chemotherapy often complain of a persistent 'brain fog' that can be present up to years after treatment ends. This fog is expressed as marked impairments in areas of learning, memory and mental health. As it stands, researchers have yet to determine the mechanism at fault for these impairments. The present experiment investigates if the neurogenesis that takes place in the subgranular zone of the hippocampus is suppressed as a result of chemotherapy treatment, and results in these impairments. In the following thesis, two models of chemotherapy are used to explore the treatment effects on Long-Evans rats. From here, three behavioural assessments and three measures of immunohistochemical techniques are used to explore the effects of Temozolomide on memory and anxious behaviour. Our findings support the current literature that suggests that Temozolomide suppresses adult hippocampal neurogenesis and results in cognitive and emotional impairments.

Author Keywords: adult hippocampal neurogenesis, Chemotherapy, Chemotherapy-Induced Cognitive Impairment, CICI, Long-Evans rats, Temozolomide

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

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

Temporal lobe epilepsy increases risk for developing major depression, and conversely, depression increases risk for development of epilepsy. The mechanisms responsible for the widely observed bi-directional relationship between epilepsy and depression are currently poorly understood. One reason why our understanding of shared etiology has had little improvement is due to the lack of availability of a reliable animal model for inducing depression in epileptic animals. The development of a reliable model of epilepsy-depression comorbidity would greatly improve the ability to mechanistically evaluate shared pathophysiology between the conditions. Recently there has been evidence that rapid kindling of the basolateral amygdala can evoke a behavioural phenotype that is comparable to the symptoms of anxiety and depression observed in depressed epileptic patients. However, this work has yet to be replicated, leaving question as to whether or not the behavioural phenotype can be reliably evoked. In the following series of experiments we assessed rapid amygdala kindling as a potential model of epilepsy-depression comorbidity and sought to improve the model with inclusion of the glucocorticoid corticosterone. Our findings may improve our understanding of the unique relationships between epilepsy and depression.

Author Keywords: animal models, depression, hippocampus, kindling, stress, temporal lobe epilepsy

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

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