Adolescence as a vulnerable period for the effects of intrinsic and extrinsic regulators of neurogenesis on cognitive behaviour

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O'Leary, James Daniel
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University College Cork
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Postnatal hippocampal neurogenesis is the birth of new neurons within the dentate gyrus that occurs throughout the lifespan. In adulthood, these new neurons have been shown to be necessary for cognitive tasks such as spatial and contextual memory. It is well established that adult hippocampal neurogenesis can be modulated by a number of intrinsic and extrinsic factors, such as intracellular signalling molecules, exercise, inflammation and stress. Moreover, levels of adult hippocampal neurogenesis do not remain constant throughout life. Indeed, levels of hippocampal neurogenesis and integration of new neurons within the dentate gyrus are up to four times higher during adolescence than during adulthood. The first aim of this thesis (addressed in Chapter 2) was to explore the extent and involvement of Tlx in motor, cognitive and anxietyrelated behaviour. A spontaneous deletion of Tlx, a key intrinsic regulator of neurogenesis, was demonstrated to impair motor, cognitive and anxiety-related behaviours during adolescence and adulthood. The second aim of this thesis (addressed in Chapters 3 and 4) was to investigate the impact of adolescent-initiated exercise on hippocampal plasticity and contextual and cued fear conditioning as well as pattern separation in adulthood. It was demonstrated that adult-initiated exercise enhanced both contextual and cued fear conditioning, while conversely, exercise that began in adolescence did not affect performance in these tasks and these differential effects were accompanied by differential expression of plasticity-related genes in the hippocampus in adulthood. Moreover, adult and adolescent-initiated exercise enhanced cognitive flexibility and dendritic complexity of immature neurons in the dentate gyrus. The third aim of this thesis (addressed in Chapter 5) was to examine the impact of chronically elevated IL-1β on adult hippocampal neurogenesis and pattern separation. It was shown that chronic lentiviral-mediated overexpression of IL-1β within the dorsal hippocampus impaired neurogenesis and performance in its associated cognition, while sparing neurogenesis independent cognition. Finally, the fourth aim of this thesis (addressed in Chapter 6) was to explore the impact of chronic IL-1β, chronic unpredictable stress exposure, or a combination of an initial chronic IL-1β insult was examined following exposure to chronic unpredictable stress on learning and memory and depressive-like behaviours. It was shown that exposure to chronically elevated IL1β and chronic stress independently impair certain types of learning and memory and increased depressive-like behaviour. However, exposure to a sequential ‘two-hit’ of chronically elevated hippocampal IL-1β and chronic stress did not produce an exacerbated phenotype. In summary (Chapter 7), disruption of intrinsic regulators of neurogenesis, such as Tlx, or exposure to extrinsic factors, such as exercise or adverse stimuli, like inflammation and stress, and the consequent effect on cognition may provide insight into why adolescence is a vital period for correct conditioning of hippocampal function in later life.
Cognition , Hippocampus , Touchscreen operant behaviour , Learning and memory
O'Leary, J. D. 2017. Adolescence as a vulnerable period for the effects of intrinsic and extrinsic regulators of neurogenesis on cognitive behaviour. PhD Thesis, University College Cork.