Novel insights into the role of hippocampal TLX in neurogenesis, neuroinflammation and behaviour in adolescence and adulthood

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Kozareva, Danka A.
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University College Cork
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The orphan nuclear receptor TLX is a key regulator of embryonic and adult neurogenesis and is primarily expressed in the neurogenic niches of the brain. Adult hippocampal neurogenesis is characterized by the generation of new granule cells that become integrated into the circuitry and contribute to cognitive function. Impaired hippocampal neurogenesis has been reported in neurodegenerative and psychiatric conditions and efforts to develop therapeutic strategies that employ the hippocampal NSCs are ongoing. TLX is one of an array of intrinsic factors regulating NSC proliferation and differentiation, in combination with extrinsic regulators such as stress, exercise and neuroinflammation. Adolescence is a sensitive period of neurodevelopment, during which the environment can have profound effects. Little has been reported on TLX function during adolescence. TLX performs its role by transcriptional activation and repression of a number of genes in order to promote NPC proliferation and to maintain the neurogenic pool of NSCs in the DG. In its absence neurogenesis is dramatically decreased, positioning it as the master modulator of the neurogenic process. The aims of this thesis were to investigate the role of the immune cells of the brain, microglia, on hippocampal neurogenesis in the presence/absence of TLX, and to determine whether TLX plays a role in microglia-neuronal crosstalk; to investigate the role of TLX in hippocampal neurogenesis during adolescence, and the impact thereupon of exercise and stress; and to understand the role of TLX in behavioural and cognitive function during adolescence and adulthood, through evaluating two deletion models of TLX – a spontaneous deletion mouse model, and a rat model using lentiviral knockdown of TLX. We have shown that a lack of TLX is implicated in the deregulation of microglial phenotype, resulting in activated microglia and elevated levels of the pro-inflammatory cytokine IL-1β, and that consequently the survival and function of newborn cells in the hippocampus is impaired. Furthermore, we showed that when neuronal-microglial signalling is impaired in the absence of the chemokine receptor CX3CR1, the expression of TLX and some of its downstream targets is altered. We also have shown that TLX is necessary for the pro-neurogenic effects of exercise during adolescence, and that deletion of TLX modulates motor, cognitive and anxiety-related behaviours during adolescence and adulthood in both male and female mice. Lastly, we demonstrated that silencing of TLX expression in the dDG during adolescence resulted in impairments in hippocampal-independent behaviours, which either did not persist or were reversed during adulthood. In summary, we confirm the importance of TLX in the regulation of neurogenesis and neuronal-microglial cross-talk as well as the temporal importance and function of TLX during adolescent development. Disentangling the complex interactions between TLX, the immune system and other extrinsic regulators of hippocampal neurogenesis would thus provide valuable insights into the development of therapeutics for neurodegenerative disorders using stem-cell-stimulation based approaches.
TLX , Neurogenesis , Neuroinflammation , Hippocampus , Adolescence
Kozareva, D. A. 2018. Novel insights into the role of hippocampal TLX in neurogenesis, neuroinflammation and behaviour in adolescence and adulthood. PhD Thesis, University College Cork.