Hippocampal dysfunctions in tumor-bearing mice

Highlight•Peripheral tumor per se is sufficient to cause hippocampal dysfunctions, possibly through changes in the immune and endocrine systems.

Individuals with cancer are particularly susceptible to depression and cognitive impairment. However, the precise mechanisms underlying cancer-induced hippocampal dysfunction are poorly understood. We investigated the effects of a peripheral tumor on emotional behavior, hippocampus-dependent memory and associated molecular and cellular features using an experimental animal model. Behavioral alterations were examined; stress-related parameters measured; hippocampal neurogenesis evaluated; and the levels of pro-inflammatory cytokines, brain-derived neurotrophic factor (BDNF) and cyclooxygenase-2 (COX-2) assayed, 2 weeks after inoculation of adult BALB/c mice with cells of a colon carcinoma cell line (CT26). As the tumors developed, CT26-inoculated mice showed significant increases in the depression-like behavior (measured using the tail suspension test) and memory impairment (in terms of object recognition) compared with vehicle-inoculated controls. The presence of a peripheral tumor significantly elevated the hippocampal levels of mRNAs encoding interleukin-6 (IL-6) and tumor necrosis factor-α, as well as plasma IL-6 and corticosterone levels. Additionally, the adrenal glands became enlarged, and the numbers of Ki-67-positive proliferating hippocampal cells and doublecortin-positive immature progenitor neurons, as well as the constitutive levels of mRNAs encoding BDNF and COX-2 were significantly reduced. Therefore, a peripheral tumor alone may be sufficient to induce hippocampal dysfunction, possibly by reducing the rate of neurogenesis and the levels of BDNF and COX-2 in that tissue and also by increasing stress-related parameters and the circulating levels of pro-inflammatory cytokines.