Human adolescents exhibit higher levels of sensation seeking behaviour than younger or older individuals, and sensation seeking is higher in males than females from adolescence onwards. Data suggest that changes in gonadal hormone levels during adolescence and differences in the dopamine neurotransmitter system are the bases for why some people exhibit sensation seeking behaviour while others do not. However, causal relationships between physiology and behaviour have been difficult to establish in humans. In order to explore the physiological influences on novelty-seeking behaviour, we looked at response to novelty in a laboratory rodent. This research examined responses to novelty in the conditioned place preference (CPP) task and the novel object recognition (NOR) task in Lister-hooded rats, and assessed the benefits and limitations of each methodology. While the CPP task was not found to provide a reliable measure of response to novelty, the NOR task was more successful. In order to understand the ontogeny of sex differences in novelty responses, both males and females were tested from adolescence through to adulthood. While no sex difference was found in adults in the NOR test, mid-adolescent males exhibited higher novelty preference behaviour than either younger or older males, or females at each stage of development. Since gonadal hormones levels rise during adolescence, a pharmacological agent (a gonadotrophin-releasing hormone antagonist) was used to suppress gonadal hormone levels from early adolescence before again examining responses on the NOR test at mid-adolescence. Gonadal hormone suppression from early adolescence onwards eliminated the sex difference in the NOR test at mid-adolescence by reducing the male response to novelty, while no difference was measured in the female animals. These findings suggest that gonadal hormones play a significant role in the development of response to novelty, especially in males, and the implications for our understanding of human sensation-seeking behaviour are discussed.

Cognitive impairment, “Chemofog”, has been well established as a negative outcome of otherwise successful medical radiation treatments. Mitigation of this negative feature would dramatically increase quality of life for those recovering from cancer treatment. There is currently no known intervention to protect or restore cognitive function of patients undergoing radiation treatments. Development of a multiple ingredient dietary supplement (MDS) is meant to offer a non-invasive therapy to help mitigate risk and decrease damage to individuals. The MDS was originally designed to off-set 5 key mechanisms associated with aging including oxidative damage, inflammation, impaired glucose metabolism, mitochondrial dysfunction and membrane deterioration. Radiation damage shares many of the same deficiencies that develop with age and supplementation with MDS would impact many of the same pathways. Changes in cytokine profile (inflammation markers), and biomarkers of behavioural functions, sensory functions, and oxidative damage provide preliminary evidence of MDS impacts. / Thesis / Bachelor of Science (BSc) / Cognitive impairment, “Chemofog”, has been well established as a negative outcome of otherwise successful medical radiation treatments. Mitigation of this negative feature would dramatically increase quality of life for those recovering from cancer treatment. There is currently no known intervention to protect or restore cognitive function of patients undergoing radiation treatments. Development of a multiple ingredient dietary supplement (MDS) is meant to offer a non-invasive therapy to help mitigate risk and decrease damage to individuals. The MDS was originally designed to off-set 5 key mechanisms associated with aging including oxidative damage, inflammation, impaired glucose metabolism, mitochondrial dysfunction and membrane deterioration. Radiation damage shares many of the same deficiencies that develop with age and supplementation with MDS would impact many of the same pathways.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / In Alzheimer s disease (AD), β-amyloid peptide (Aβ) has been linked with synaptic loss and cognitive dysfunction, albeit the precise mechanism remains unknown. An involvement of N-Methyl-D-Aspartate receptors (NMDAR) in AD is proposed, since its inhibition attenuates some aspects of AD s neuropathology. In this regard, polyamines, like spermidine and spermine, positive modulators of NMDARs, have been shown to have both concentration and synthesis increased by Aβ. Using the novel object recognition task we showed that negative modulation of polyamine system, been trough blockade of its binding site at NMDAR by arcaine (0.02 nmol/site), traxoprodil (0.002 nmol/site), or inhibition of polyamine synthesis by DFMO (2.7 nmol/site), reverses Aβ25-35-induced memory impairment in mice. The activation of polyamine binding site at NMDAR located at extrasynaptic sites might underlie the cognitive deficits of Aβ25-35-treated mice, since incubation of hippocampal neuron cultures with spermidine (400 μM) or Aβ25-35 (10 μM) significantly increased nuclear accumulation of jacob protein, a marker of extrasynaptic NMDAR activation. Moreover, traxoprodil (4nM), arcaine (4 μM) or DFMO (5 μM) blocked the Aβ-induced jacob nuclear translocation. Activation of extrasynaptic NMDAR in neurons leads to striping of synaptic contacts and simplification of neuronal cytoarchitecture. Incubation of hippocampal neuron cultures with traxoprodil (4 Nm), arcaine (4 μM) or DFMO (5 μM) reversed the deleterious effects of Aβ25-35 on dendritic spine number and spine morphology. We also evaluated the involvement of A-type K+ currents on the Aβ25-35-induced memory impairment. Administration of Tx3-1 (3 100 pmol/site), a selective IA blocker, restored memory of mice injected with Aβ25-35 and tested on the novel object recognition task The reversal of memory impairment and the protective effect on dendritic spine alterations exerted by the modulators of the polyamine system suggest the polyamine binding site at extrasynaptic NMDAR a potential player in Aβ-induced cognitive deficit. / O peptídeo β-amiloide (Aβ), reconhecido como agente tóxico na Doença de Alzheimer (DA) é implicado como causador de danos cognitivos e sinápticos, apesar de os mecanismos não serem completamente compreendidos. O envolvimento do receptor N-metil-D-aspartato (NMDA) na DA é sugerido, visto que o seu bloqueio atenua alguns aspectos neuropatológicos da DA. Nesse contexto, tem sido demonstrado que as poliaminas, como espermidina e espermina, moduladores positivos do receptor NMDA, possuem níveis e síntese elevada tanto no cérebro de pacientes com DA como em preparações in vitro utilizando o peptídeo Aβ. Neste estudo demonstrou-se que a modulação do sistema das poliaminas, através do bloqueio do seu sítio de ligação no receptor NMDA por arcaína (0,02 nmol/sítio), traxoprodil (0,002 nmol/sítio) ou da inibição de sua síntese por DFMO (2,7 nmol/sítio), reverte o déficit cognitivo induzido pela injeção de Aβ25-35 em camundongos testados na tarefa de reconhecimento de objetos. A ativação do sítio de ligação das poliaminas em receptores NMDA extrassinápticos pode subjazer o déficit cognitivo de camundongos injetados com Aβ25-35, visto que a incubação de culturas primárias de neurônios hipocampais com espermidina (400 μM), NMDA (200 μM) ou Aβ25-35 (10 μM) aumenta o acúmulo nuclear de jacob, um marcador de ativação de receptores NMDA extrassinápticos, de maneira significante. Ademais, traxoprodil (4 nM), arcaína (4 μM) ou DFMO (5 μM) bloquearam o acúmulo nuclear de jacob induzido por Aβ. A ativação de receptores NMDA extrassinápticos em neurônios leva a simplificação da citoarquitetura neuronal e a diminuição de contatos sinápticos. Aqui demonstrou-se que a incubação de culturas de neurônios hipocampais com traxoprodil (4 nM), arcaína (4 μM) ou DFMO (5 μM) reverte as alterações na a densidade e morfologia de espinhas dendríticas induzido pela incubação com Aβ25-35. Ainda, também avaliou-se o envolvimento de correntes de K+ do tipo A no déficit cognitivo induzido pela injeção i.c.v. de Aβ25-35. A administração de Tx3-1 (3 100 pmol/sítio), um bloqueador seletivo de correntes IA, reverteu o prejuízo de memória de camundongos injetados com Aβ25-35 e testados na tarefa de reconhecimento de objetos. A reversão dos danos cognitivos e sinápticos induzidos por Aβ25-35 através da modulação do sistema das poliaminas sugere a estimulação do sítio de ligação das poliaminas no receptor NMDA, possivelmente extrassínaptico, como um dos mecanimos por trás do déficit cognitivo induzido pelo peptídeo Aβ.

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