An Investigation into Neuroimmune, Cognitive and Affective Behaviour after Chemotherapy Exposure in a Rat Model: Implications for Chemotherapy-induced Gut Toxicity and ‘Chemobrain’
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(Thesis)
Date
2021
Authors
George, Rebecca Peta
Editors
Advisors
Howarth, Gordon
Whittaker, Alexandra
Whittaker, Alexandra
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Thesis
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Abstract
Patients receiving chemotherapy frequently experience debilitating side-effects. Side-effects such as chemotherapy-induced gut toxicity (CIGT) are acute, however chemotherapy-induced cognitive impairment (CICI) can persist for years following treatment. CIGT and CICI can significantly impact patient quality of life, thus understanding the aetiology and developing therapeutic strategies is critical. Animal models are commonly used in these investigations and are excellent for determining cellular and molecular mechanisms. However, translational validity may be poor if they do not consider actual impacts on the animal’s cognitive and affective domains. Although there are a range of well-validated behavioural tests utilised in other research areas, these tests may be insensitive to subtle cognitive impairments observed in CICI and neglect to measure animal emotional experience. Whilst the underlying mechanisms that contribute to CICI remain unclear, neuroinflammation has been postulated as a key contributor. It is hypothesised that chemotherapy agents can cause direct or indirect CNS damage, negatively impacting cognition. Therefore, peripheral inflammatory events such as CIGT may also play a role in CICI pathogenesis. Our understanding of the effects of chemotherapy agents on gut inflammation in CIGT have been well characterised, however the underlying mechanisms that contribute to CICI and resulting neuroimmune changes occurring in the CNS at acute and chronic time-points remain relatively unclear, as do the effects of palliative treatments such as opioids. Pain mitigation strategies typically involve administration of opioid agents and play a crucial therapeutic role for pain management, yet are largely understudied for their effects on neuroimmune responses and behaviour. Subsequently, this thesis examined the effects of chemotherapy on neuroimmune outcomes and cognitive and affective behaviour in a rat model of CIGT and CICI. In chapter 2, the judgement bias task was utilised to investigate and validate a reliable test to measure the effect of chemotherapy on affective state in a rat model of 5-FU. Furthermore, the utility of the Rat Grimace Scale (RGS) was investigated for pain assessment in a tumour-bearing rat model of CIGT (chapter 3). A systematic review was undertaken to assess compliance of scientific publications evaluating CICI in rodent models with the ‘Animals in Research: Reporting in vivo Experiments’ guidelines (chapter 4). Additionally, a systematic scoping review (chapter 5) was conducted to identify and map available literature on neuroimmune reactivity marker expression changes and resulting cognitive changes, in preclinical rodent models of CICI. Chapter 6 comprised an experimental study assessing the effect of opioid co-administration with 5-FU on gut inflammation and architectural changes associated with CIGT, cellular changes in the CNS and associated cognitive changes utilising a tumour-bearing rat model. Additionally, neuroimmune reactivity marker expression changes and resulting cognitive changes were explored in a subacute and chronic rat model of MTX and 5-FU-induced CICI (chapter 7). Importantly, this was achieved through the use of cognitive behavioural tests to assess hippocampal and pre-frontal cortex functioning. In summary, this thesis describes establishment of a validated and reliable judgement bias task and 5CSRTT as promising cognitive behavioural methods in preclinical models of CIGT and CICI. Furthermore, it identifies neuroimmune reactivity marker changes occurring in tandem with cognitive impairments. This has implications for future study design using animal models in CICI and CIGT to improve translational validity. Furthermore, it paves the way for further investigations of actions at the neuroinflammatory response as a potential therapeutic strategy in CICI.
School/Discipline
School of Animal and Veterinary Sciences
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, School of Animal and Veterinary Sciences, 2021
Provenance
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