Minocycline ameliorates persistent social deficits and hippocampal microglial dysfunction in mice following tumor...

Cancer patients often experience psychiatric dysfunctions, such as depressive symptoms, which have been shown to persist long after treatment. However, the underlying mechanisms remain elusive. In the present study, we evaluated tumor bearing-associated biological effects on behavior and brain function after cancer remission, using mice that underwent surgical resection of tumors formed following inoculation with colon 26, a murine colorectal cancer cell line. In tumor-resected mice, hippocampal Iba1-positive cells exhibited shortened process length until 14 days post-resection, consistent with the persistent social deficits. Furthermore, in the hippocampus of tumor-resected mice, the area ratio of CD68/Iba1 double-positive cells and the expression level of the Tnf gene were significantly increased. Antidepressant fluoxetine or the microglial modulator minocycline improved both the social deficits and the shortened process length of hippocampal Iba1-positive cells in tumor-resected mice. To clarify the relationship between microglia and neurons, their interactions with synapses were assessed. In the hippocampus of tumor-resected mice, an increased number of PSD-95-positive particles colocalized with Iba1-positive cells was observed, along with a decrease in the density of dendritic spines of hippocampal neurons; these changes were ameliorated by minocycline. These findings demonstrate that functional changes in hippocampal microglia and neuronal structural alterations are associated with social deficits persisting after tumor resection.