Lehmann, Hugo

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

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

After active tool-use visual stimuli near a tool are processed more quickly and accurately than those farther away from a tool. Can these near-tool effects be modulated by training demands? To investigate this we asked the participants to complete a tool training task followed by a cross-modal interference task. During the training task the participants performed quick and accurate pointing movements to reach a strict or moderate criterion. The results indicated that the strict group made faster movements than the moderate group. During the cross-modal interference task visual distractors were presented along handheld tools in conjunction with vibrotactile stimuli on the hand. No significant compatibility effects were found for visual distractors near the hand or tool tip, and no consistent group differences were found. Our findings demonstrate the importance of using a novel tool during training, and that virtual stimuli may not be effective to elicit near-tool effects.

Author Keywords: bimodal neurons, cross-modal interference, near-tool effects, tool training, training demands

The assessment of visuomotor function can provide important information about neurological status. Several visuomotor tasks exist for testing in the laboratory, although attempts to make these tests portable to allow quick and reliable assessment have been limited. We developed an assessment tool using two laboratory visuomotor tests as a tablet application: the double-step task, and an interception task. Performance was assessed by measuring the participants' ability to reach toward unpredictably moving targets in each task. Response patterns were compared across equipment types to determine if participants were responding similarly to the moving targets in the standard laboratory and the tablet version of the tasks. On the double-step task, participants adjusted to the displaced target adequately in both the lab and tablet versions. On the interception task, participants intercepted non-accelerating targets, and performed worse on accelerating targets in both versions of the task. These findings suggest that the tablet version of these tasks assesses similar visuomotor processing as the respective laboratory version.

Author Keywords: concussion assessment, double-step task, interception task, visuomotor processing, visuomotor system

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

Current literature on concussion management focuses primarily on the return to physical activity, while the return to learn process is less clearly understood. This knowledge gap is particularly problematic for adolescents, whose primary responsibility is academics. The present study sought to develop a more in-depth understanding of the return to learn process through the perspectives of adolescents who had sustained a concussion and their parents in in-person, semi-structured interviews. A substantive grounded theory of the return to learn process for adolescents that emerged from the data is provided. The basic model is consistent with many speculative, non-empirically based concussion management protocols, but extends these models by emphasizing the central role of parents in managing their child's recovery process, highlighting the importance of role fulfillment within the concussion management network, and identifying the impact of the adolescent's capacity and readiness for help-seeking. The results also highlight the vulnerability of concussed adolescents to losing their support structure as they move through key school transitions. Implications for educators, medical professionals, parents, and adolescents in the return to learn process are also discussed.

Author Keywords: Adolescent, Concussion, Concussion Management, Multidisciplinary Management, Return to Learn, Return to School

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

Distributing contextual fear episodes makes the memory become HPC-independent, meaning increasingly reliant on non-HPC memory structures. It is unclear, however, whether distribution of the conditioning episodes alone is sufficient or whether a combination of distribution and high conditioning saliency is necessary to make the memory become HPC-independent. To resolve this issue, rats were trained using a distributed contextual fear conditioning protocol in which foot-shocks were manipulated to create a low (0.4mA), intermediate (0.7 mA) and high (1.0 mA) saliency condition. This thesis also aimed to determine brain structures supporting the HPC-independent memory by assessing retention-induced c-fos expression in the basolateral- amygdala, perirhinal and anterior cingulate cortices. The results suggest that HPC lesion rats in the high saliency condition displayed similar level of freezing as control rats, indicating "strongly salient" and distributed episodes creates a HPC independent memory. c-fos expression suggests together, an increased context representation in the perirhinal and anterior cingulate cortices and a strengthened fear representation in the basolateral-amygdala supports the HPC-independent memory.

Author Keywords: context fear memory, distributed reinstatements, hippocampus, IEG, rat, saliency