Investigating the regulatory role of the nuclear receptor TLX in IL-1β-induced changes in hippocampal neurogenesis

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Ó Léime, Ciarán S.
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University College Cork
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Hippocampal neurogenesis is the process by which new neurons are born within the dentate gyrus (DG). This process begins during embryonic development and persists throughout life. Neurogenesis encompasses proliferation, differentiation and integration of neural progenitor cells (NPCs) into the surrounding neural network. Each stage is regulated by a host of intrinsic and extrinsic factor such as intracellular signalling molecules, exercise, environmental enrichment, diet and learning. TLX is an orphan nuclear receptor and transcription factor, which promotes the proliferation of NPCs, maintains the neurogenic pool of cells within the DG, and has been shown to promote hippocampal neurogenesis-associated cognition. Conversely, the proinflammatory cytokine IL-1β is a major mediator of the anti-neurogenic effects of hippocampal neuroinflammation, and previous work from the group has shown that IL-1β can suppress the expression of TLX within proliferating NPCs. The aims of this thesis were to investigate the interactions between TLX and IL-1β both in vitro and in vivo, and to determine the behavioural outcome of enhancing TLX and IL-1β, as well as well as in response to dietary intervention in vivo. We demonstrate that IL-1β suppresses TLX expression and neurogenesis (neurosphere expansion) in vitro, and that these effects are mediated by the NF-κB pathway. Restoration of TLX expression is sufficient to attenuate the negative effects of IL-1β on neurogenesis. We have shown using an RNA sequencing approach that TLX expression maintains a reduced inflammatory transcriptional profile in the hippocampus at baseline, and regulates the transcriptional response to IL-1β in vivo. We demonstrate that lentiviral-mediated overexpression of TLX does not enhance hippocampal neurogenesis-associated cognitive processes in vivo but that it impairs object recognition memory in rats. This suggests that enhancing cell proliferation is not sufficient to promote certain hippocampal-associated cognitive processes, and may even have a detrimental effect on cognitive behaviour. Finally, we show that an adolescent cafeteria diet which induces negative effects on hippocampal-associated memory, does not induce lasting cognitive defects when rats are switched to standard chow diet in adulthood. Lentiviral-mediated overexpression of IL-1β does not impact upon cognitive behaviours in rats fed a cafeteria diet throughout adolescence. However, we show that this chronic low-grade hippocampal IL-1β-mediated inflammation promotes fear memory in adulthood. In summary, TLX and IL-1β can enhance and repress hippocampal neurogenesis respectively. Determining the role that TLX has on neurogenesis-associated cognition and how it can interact with IL-1β may position TLX as a novel therapeutic target for the treatment of neuroinflammatory-associated disorders where hippocampal neurogenesis is impaired.
Ó Léime, C. S. 2017. Investigating the regulatory role of the nuclear receptor TLX in IL-1β-induced changes in hippocampal neurogenesis. PhD Thesis, University College Cork.