Advances in the early detection and treatment of
breast cancer has greatly improved survival, but chemotherapy is often
associated with lingering neurological side-effects commonly referred to as
“chemo-fog”. Despite the high incidence and significant impact of
chemotherapy-induced neurological symptoms on the quality of life of breast
cancer survivors, little is known about the physiological mechanisms underlying
the development of cognitive and affective deficits. Our hypothesis is that
chemotherapy-induced hypothalamic-pituitary-adrenal (HPA) axis activation and
neuroinflammation contribute to the observed behavioral changes. Within hours of
administering doxorubicin + cyclophosphamide to mice, there is a significant
increase in serum corticosterone and proinflammatory cytokine concentrations,
as well as increased proinflammatory cytokine expression in various brain
regions, including the hippocampus, cortex and hypothalamus. Cognitive and
affective deficits, as measured using the Barnes maze, novel object recognition
task, elevated plus maze, and forced swim test, emerge within three days of the
first chemotherapy treatment. In addition, chemotherapy treatment is associated
with a significant decrease in dendritic spine density within the CA1 and CA3
regions of the hippocampus. The administration of minocycline prevents the chemotherapy-induced
neuroinflammation and behavioral deficits without altering circulating corticosteroid
concentrations. In contrast, exposure to stress prior to chemotherapy administration
significantly increases the neuroinflammatory and depressive-like effects. In
sum, these data suggest that the administration of doxorubicin and cyclophosphamide
in doses that approximate the typical dose used for women being treated for
breast cancer, results in HPA axis activation, neuroinflammation, alterations
in dendritic spine density, and concomitant affective and cognitive deficits in
female mice. The effects of chemotherapy on neuroinflammation and behavior are
further amplified by prior exposure to stress. Together, these data suggest
that stress exposure could be an important factor in determining an
individual’s susceptibility to the neurobehavioral side-effects of
chemotherapy. Supported by a Pelotonia Idea Award to ACD and
MBL.