Submission note: A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Clinical Neuropsychology [to the] School of Psychological Science, Faculty of Science, Technology and Engineering, La Trobe University, Bundoora.
Calorie restriction (CR) increases longevity and elicits many health-enhancing benefits. Although the underlying mechanisms of these effects are unknown, a likely contributor is altered immunity. We recently demonstrated that CR suppresses lipopolysaccharide (LPS)-induced fever and promotes an anti-inflammatory signalling bias in the hypothalamus. The current thesis extended this work by investigating regional changes in LPS-induced microglial activation in mice exposed to 50 percent CR or ad libitum feeding for 28 days. A set of brain sections were immunolabelled for ionized calcium-binding adapter molecule-1 (Iba1), a marker of microglial activation. We found that CR suppressed LPS-induced fever and microglial activation in the arcuate nucleus (ARC) and ventromedial nucleus of the hypothalamus and the subfornical organ. The ARC contains neurons that synthesise neuropeptide Y (NPY), an anti-inflammatory neuropeptide that is upregulated following CR. To investigate whether NPY expression in the ARC was associated with microglial activation, a set of hypothalamic sections were immunolabelled for NPY and the density was assessed in the ARC and the hypothalamic paraventricular nucleus (PVN). We also investigated microglial morphology by digitally constructing Iba1-positive cells in the ARC. We demonstrated that CR enhanced NPY-immunoreactivity in the ARC but not the PVN. CR also blunted the LPS-induced increase in Iba1 intensity and reduced microglia cell area in the ARC of LPS-treated mice. We found that the relationship between NPY and mean Iba1 intensity was statistically mediated by body temperature. Body temperature was also found to be strongly associated with both NPY and microglial cell area. Together, these data suggest that changes in NPY may be involved in the blunting of LPS-induced microglial activation following CR, specifically through its effects on LPS-induced fever.
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