Fig. 1

Treatment with riluzole reverses cranial radiation-induced cognitive impairments. A Research design: 12–13 weeks old wild type (C57BL/6) male mice received cranial radiation therapy (RT, 0 or 9 Gy) with protection of eyes and cerebellum. 48 h after cranial RT, mice were treated with riluzole (RZ) in the drinking water (13 mg/kg) and continued on RZ till the end of the study (6–7 weeks). 0 Gy irradiated animals that received drinking water served as the vehicle group. For the assessment of dentate neurogenesis, 2 weeks post-RT, mice received BrdU injections (5-Bromo-2′-deoxyuridine, 50 mg/kg, IP, once daily for 6 days). One month after initiation of RZ treatment, mice were administered a hippocampal-dependent spatial memory retention test (Object Location Memory, OLM), anxiety-related tasks (Open Field Activity, OFT; and Elevated Plus Maze, EPM), and in the end, a fear extinction memory consolidation task (FE). After completion of cognitive testing, mice were euthanized, and brains were collected for the tissue analyses. B Representative heat maps depicting animals exploring novel or familiar placement of objects in each experimental group during the OLM task. C Cranially irradiated mice receiving vehicle spent significantly less time exploring the novel placement of the object. Percentage time spent exploring the novel placements of objects during the test phase of the OLM task show that Control + Vehicle, Control + RZ and RT + RZ mice spent significantly more time exploring novel versus familiar location whereas RT + Vehicle group spent comparable time exploring both locations indicating a novel place location memory deficit. D For the OLM task, the tendency to explore a novel placement of the object was derived from the Memory Index (MI), calculated as ([Novel location exploration time/Total exploration time]—[Familiar location exploration time/Total exploration time]) × 100. Cranial RT significantly impaired spatial location memory as indicated by significantly reduced MI in the RT + Vehicle group compared to the Control + Vehicle, and RT + RZ group. Importantly, irradiated mice treated with RZ did not show a decline in spatial location memory and the MI was significantly higher compared to the RT + Vehicle group. E During the conditioning phase fear extinction memory task, cranial RT or RZ treatment did not impair the acquisition of conditioned fear response as indicated by the elevated freezing following a series of three-tone and shock pairings (80 dB, 0.6 mA, T1–T3). 24 h later, fear extinction training was administered every 24 h (20 tones) for the subsequent 3 days. Each data point for the extinction training Days 1–3 is presented as average of percentage time freezing for 5 tones (4 data points per day). All group of mice showed a gradual decrease in freezing behavior (Days 1–3), however, RT + Vehicle group spent a significantly higher time freezing compared with Control + Vehicle group. F Twenty-four hours after the extinction training phase, on the extinction test, Control + Vehicle and Control + RZ mice showed abolished fear memory (reduced freezing) compared with the RT + Vehicle mice. Importantly, cranial RT-exposed mice receiving RZ (RT + RZ) were able to successfully abolish fear memory (reduced freezing) compared with the RT + Vehicle group. Data is presented as mean ± SEM (N = 10–26 mice per group). P values were derived from two-way ANOVA and Bonferroni's multiple comparisons test. *P < 0.01, versus Control + Vehicle. **P < 0.0001, T1 versus T3 for all experimental groups