Peripheral alterations underlying the negative effects of a cafeteria diet on brain and behaviour: exercise as a mitigating strategy

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Nota, Minke H. C.
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University College Cork
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A Western lifestyle, characterised by inactivity and overconsumption of saturated fats and sugar, increases risk of depression, anxiety, and cognitive impairment. Obesity, metabolic dysfunction, (neuro)inflammation, and gut microbiota alterations, which can result from a Western lifestyle, are associated with mood disorders and cognitive impairment, thus constituting potential mechanisms by which Western lifestyle impacts the brain. Adult hippocampal neurogenesis (AHN), i.e., the birth of new neurons in the dentate gyrus of the hippocampus, is involved in certain forms of memory, including spatial memory and pattern separation, and in regulating emotion through anxiety behaviours and antidepressant action. A cafeteria (CAF) diet, mimicking human Western-style diets, has been shown to decrease AHN, impair memory, and increase anxiety-like behaviour in rodents, whereas exercise has antidepressant effects and has been shown to improve AHN and cognition. However, interactions between these lifestyle factors remain unclear. Furthermore, effects of Western-style diets and exercise on AHN and associated behaviours have primarily been researched in males, whereas depression, certain anxiety disorders, and dementia disproportionally affect women. The aims of this thesis were to investigate whether voluntary running exercise could alter the effects of a CAF diet on AHN and hippocampus-associated behaviour, and the intake of and preference for a CAF diet in adult male and female rats, and to determine if a CAF diet and exercise could impact metabolic markers, inflammation, and gut-derived metabolites in males. Exercise had anxiolytic effects in males and females, induced modest improvements in spatial learning in males, and decreased spatial memory in females. Additionally, exercise mitigated a CAF diet-induced increase in depression-like behaviour, and a CAF diet blunted an exercise-induced increase in AHN, in males but not females. In exercising males and females with access to CAF diet, intake of energy from CAF foods and saturated fat was decreased, and fibre and protein intake was increased compared to sedentary rats with access to a CAF diet. Moreover, compared to sedentary rats, exercising rats had reduced preference for CAF foods over standard chow, which was maintained for 2 and 5 weeks in females and males, respectively. Increased hypothalamic Drd1 gene expression, which has been shown to promote overeating, in exercising males with access to a CAF diet possibly explained reduced preference for CAF foods in exercising rats not being maintained past 5 weeks. Alterations in metabolic hormones and caecal metabolites offer potential explanations for behavioural and neurogenic effects observed in males. Exercise-induced increased PYY potentially contributed to anxiolytic effects of exercise, and a CAF diet attenuating exercise-induced increased GLP-1 possibly explained the blunting of neurogenic effects of exercise. Attenuation of CAF diet-induced increased leptin and insulin and decreased caecal indole-3-carboxylate and deoxyinosine by exercise potentially contributed to exercise mitigating CAF diet-induced increased depression-like behaviour. Furthermore, exercise attenuated a CAF diet-induced decrease in abundance of caecal anserine, a metabolite previously associated with improved cognitive function. No definitive pro- or anti-inflammatory pattern of a CAF diet and exercise emerged that might have contributed to changes observed in behaviour and AHN. However, ventral hippocampal Il-6r gene expression was decreased in exercising males with access to a CAF diet, possibly explaining the finding that in males, exercise attenuated a CAF diet-induced increase in depression-like behaviour, as reduced general IL-6 activity has been associated with antidepressant effects. Ultimately, these data highlight the importance of exercise combined with a healthy diet for hippocampal health, along with sex differences in lifestyle influences on brain and behaviour. Moreover, these data indicate potential mechanisms, including metabolic hormones and gut microbial metabolites, underlying interactions between a CAF diet and exercise on brain and behaviour, thereby aiding advancement of preventative measures for depression and cognitive impairment.
Western diet , Exercise , Behaviour , Hippocampal neurogenesis , Metabolism , Microbiota-gut-brain axis , Animal study , (Neuro)inflammation , Cognition , Depression , Anxiety
Nota, M. H. C. 2024. Peripheral alterations underlying the negative effects of a cafeteria diet on brain and behaviour: exercise as a mitigating strategy. PhD Thesis, University College Cork.
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