MICROGLIAL CONTRIBUTION TO DOXORUBICIN-INDUCED ‘CHEMOFOG’

​Cancer survivors treated with chemotherapy experience persistent memory deficits, commonly known as ‘chemofog’. Currently there are no effective treatments for chemotherapy-induced cognitive impairment, and the underlying molecular mechanisms are poorly understood. Recent evidence suggests that chemotherapy induces chronic microglia reactivity, the brain’s resident immune cells. In this study we investigated the role of microglia in doxorubicin (Dox)-induced cognitive and behavioral alterations by a loss-of-function strategy via pharmacological microglia depletion (PLX5622).
Female mice treated with Dox exhibited increased freezing during neutral and fear-associated tones in auditory fear conditioning, suggesting fear sensitization. Moreover, Dox-treated females showed a trend toward impaired spatial recognition (NOL). These alterations were abolished by microglia depletion, indicating a microglia-dependent effect. Dox did not affect basal anxiety-like behavior or nociceptive sensitivity, and object recognition memory (NOR) was preserved. Acute stress impaired NOR performance across all groups, independently of treatment. Morphological and cytometric analyses revealed that Dox induced microglial changes in females, particularly increased soma size and partial resistance to pharmacological depletion with PLX5622. A better understanding of the cellular and molecular underpinnings of ‘chemofog’ will facilitate the development of new therapeutic strategies aimed at ameliorating these long-lasting impairments.