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The present study was undertaken to explore the possible mechanisms of the behavioral alterations that develop in response to cancer and to cancer therapy. For this purpose we used a syngeneic heterotopic mouse model of human papilloma virus (HPV)-related head and neck cancer in which cancer therapy is curative. Mice implanted or not with HPV+ tumor cells were exposed to sham treatment or a regimen of cisplatin and radiotherapy (chemoradiation). Sickness was measured by body weight loss and reduced food intake. Motivation was measured by burrowing, a highly prevalent species specific behavior. Tumor-bearing mice showed a gradual decrease in burrowing over time and increased brain and liver inflammatory cytokine mRNA expression by 28 days post tumor implantation. Chemoradiation administered to healthy mice resulted in a mild decrease in burrowing, body weight, and food intake. Chemoradiation in tumor-bearing mice decreased tumor growth and abrogated liver and brain inflammation, but failed to attenuate burrowing deficits. PCR array analysis of selected hypoxia and mitochondrial genes revealed that both the tumor and chemoradiation altered the expression of genes involved in mitochondrial energy metabolism within the liver and brain and increased expression of genes related to HIF-1α signaling within the brain. The most prominent changes in brain mitochondrial genes were noted in tumor-bearing mice treated with chemoradiation. These findings indicate that targeting mitochondrial dysfunction following cancer and cancer therapy may be a strategy for prevention of cancer-related symptoms.

Neonatal lipopolysaccharide (LPS) exposure increases anxiety-like behaviour in adulthood. Our current aim was to examine whether neonatal LPS exposure is associated with changes in microglial activation, and whether these alterations correspond with alterations in behaviour. In adulthood, LPS-treated animals exhibited significantly increased anxiety-like behaviour and hippocampal microglial activation. The efficacy of the LPS challenge was confirmed by increased neonatal plasma corticosterone and tyrosine hydroxylase (TH) phosphorylation in the adrenal medulla. These findings suggest a neuroimmune pathway which may underpin the long-term behavioural and neuroendocrine changes following neonatal infection.