The chemotherapy agent doxorubicin induces CNS expression of Ascl1, a regulator of adult neurogenesis and differentiation.

Cancer-related cognitive impairment (CRCI) is a common side effect of cancer and its treatments. Cancer chemotherapy has been associated with hippocampal dysfunction and memory impairment. We investigated the effects of one chemotherapy agent, doxorubicin, on the transcription factor Ascl1 and proliferation of stem cells in the brain. We used an inducible mouse model designed to express TdTomato in Ascl1-lineage cells. Five to six-month-old Ascl1-CreERT2:ROSA mice were treated peripherally with a single dose of either doxorubicin (10 mg/kg) or DMSO control (n = 9 per group, n = 4-5 per sex). We analyzed brains of mice that had been exposed to doxorubicin for 2 weeks and had induced Ascl1 expression after the first week. We used immunostaining of neurogenesis stage specific markers to evaluate the doxorubicin effects on neuronal differentiation in the dentate gyrus of the hippocampus. Overall, doxorubicin significantly increased Ascl1 expression by 81% at this time point. As measured by Ascl1 double stains with Sox2, GFAP, and NeuroD1, doxorubicin-treated mice experienced an increase in Ascl1-mediated neural proliferation compared to control. A similar significant increase in the number of Ascl1-expressing cells (by 146%) after doxorubicin treatment was observed in the gray matter of the cerebral cortex. Thus, rather than leading to the loss of developing neurons, we found that a single dose of doxorubicin increased their appearance and progression, suggesting that hippocampal losses from chemotherapies may require greater and more sustained damage.