Fig. 1

Treatment with CSF1R inhibitor reverses Adriamycin-induced cognitive impairments. a, Schematic presentation of the study design: Six-month old wild type (C57BL/6 J) male mice were injected with vehicle or Adriamycin (ADR, 2 mg/kg, i.p.), once weekly for 4 weeks. 72 h after the last ADR injection, mice began treatment with the CSF1R inhibitor PLX5622 in rodent chow and continued on diet till the end of the study. ADR-treated animals that received control chow served as vehicle group. One month after initiation of PLX5622 treatment, mice were administered spatial and episodic memory retention testing using the novel object recognition (NOR) and object in place (OIP) tasks followed by fear conditioning (FC) task. After completion of cognitive testing brains were collected for immunohistochemistry, RNA sequencing and cytokine analyses. b, c The tendency to explore novel spatial locations or objects was derived from the Discrimination Index, calculated as ([Novel object exploration time/Total exploration time] – [Familiar object exploration time/Total exploration time]) × 100. Chronic treatment with ADR significantly impaired cognitive function. Preference towards the novel object (NOR task, *, P’s < 0.01 compared to ADR group, b, c) was significantly reduced in the ADR-treated group receiving control diet. In contrast, ADR-treated mice receiving the PLX5622 diet showed significant improvements on the performance on both NOR and OIP tasks (**, P’s < 0.006 compared to ADR group, b, c). d Treatment with CSF1R inhibitor improves cognitive function on the hippocampal-dependent contextual fear-conditioning task. The baseline freezing levels were comparable among groups, and all groups (Control, ADR and ADR + PLX5622) showed elevated freezing behavior following a series of 5 tone-shock pairings (post-training). 24 h after fear conditioning training, the context test was administered where the ADR-treated mice receiving control diet showed significantly decreased freezing compared to Controls (**, P < 0.006). ADR-treated mice receiving PLX5622 diet (ADR + PLX5622) showed a significant elevation in freezing behavior compared to ADR treated mice receiving the control diet (*, P < 0 .01), and the level of freezing was indistinguishable from the control group. After the initial training phase (48 h), the context (spatial environment) and the odor was changed that resulted in a considerable reduction in freezing behavior (Pre-Cue bars) that was restored when tone was played (Post-Cue test bars), indicating intact amygdala function in all groups. Data are presented as mean ± SEM (N = 10 mice per group). P values were derived from ANOVA and Bonferroni’s post hoc test