Post-septic encephalopathy is a poorly understood condition in survivors of sepsis that is characterised by cognitive and affective impairments. This thesis sought to understand this condition by undertaking a comprehensive behavioural and cognitive assessment of mice who had previously survived sepsis. Mice were treated with a septic dose of lipopolysaccharide and one month after this assessed on a battery of tests. Post-septic animals were found to display significant levels of depressive-like and anxiety-like behaviour but no cognitive impairments were found. The hippocampus and amygdala, two key brain areas for affective and cognitive functioning, were also examined in post-septic animals. Significant microglial activation was found in the hippocampus 24 hours post-sepsis and this remained upregulated at two months post-treatment. Other neuroimmune factors were also affected in the post-septic hippocampus and amygdala such as neural precursor cell production and the production of proteins important to long-term potentiation. In order to investigate whether pharmacological intervention could ameliorate these post-septic changes NF-κB inhibitor pyrrolidine dithiocarbamate was administered prior to sepsis induction which significantly improved outcomes in post-septic mice. To examine whether any intervention after sepsis onset could improve outcomes another experiment was conducted investigating the effects of chronic fluoxetine administration to post-septic mice. This treatment significantly improved affective behaviours and had anti-inflammatory effects in post-septic mice. In order to further examine what may be leading to the behavioural and neuroimmune changes in post-septic mice it was also examined whether these mice were “primed” for excessive inflammatory responses to secondary insults and whether aspects of hippocampal circadian rhythmicity were altered in these mice. Mice were not found to be primed, although circadian parameters were disrupted post-sepsis. In summary it is demonstrated that LPS-induced sepsis produces long-lasting, but ameliorable, affective changes in mice, accompanied by significant inflammation in the hippocampus. These findings contribute new knowledge which may aid the comprehension of this poorly understood condition.