A) Schematic of study design: 6 month old wild type male mice were irradiated (0 or 9 Gy, head only) and administered CSF1R inhibitor PLX5622 in rodent chow after irradiation (IRR) and continued on diet till the end of study. Animals that received control chow served as vehicle group. A small cohort of mice was euthanized at 3 days and 2 weeks of PLX5622 treatments for assessment of microglial elimination. One month post-IRR and PLX5622 treatment (week 5 to 6), mice were tested on spatial and episodic memory retention using the novel object recognition (NOR) and object in place (OIP) tasks followed by fear conditioning (FC) task. (B– D) The tendency to explore novel location(s) was derived from the Discrimination Index (DI), calculated as ([Novel location exploration time/Total exploration time] − [Familiar location exploration time/Total exploration time]) × 100. Cranial irradiation (9 Gy) show significant behavioral deficits on the NOR and OIP tasks compared to controls (0 Gy) as indicated by impaired preference to novel object ( B) or place ( C). Irradiated animals receiving CSF1R inhibitor (9 Gy + PLX5622) show significant preference for the novelty when compared with irradiated (9 Gy) animals receiving vehicle. (D) CSF1R inhibitor improves behavior on the hippocampal-dependent contextual fear-conditioning task. The baseline freezing levels were comparable among groups, and all groups showed elevated freezing behavior following a series of 5 tone-shock pairings (post-training bars). The context test was administered 24 hour later, and irradiated mice (9 Gy) showed significantly decreased freezing compared to controls (0 Gy). Irradiated animals receiving PLX5622 diet (9 Gy + PLX5622) showed a significant elevation in freezing behavior that was indistinguishable from the 0 Gy group. After the initial training phase (48 hours), the context was changed that resulted in a considerable reduction in freezing behavior (Pre-Cue bar s) that was restored following the tone sound (Post-Cue test bars), indicating intact amygdala function in all groups. Data are presented as mean ± SEM ( N = 8–10 mice/group). P values are derived from ANOVA and Bonferroni’s multiple comparisons test. *** P < 0.001; ** P < 0.01, * P < 0.05 compared with the 9 Gy group.