Behavioral Correlates in Mouse Model of CNS radiation-induced hypersomnia

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Radiation therapy is the standard of care for both primary and secondary central nervous system tumors tumors. A majority of patients experience radiation induced hypersomnia (RIH) which may impact life quality and treatment tolerance. Currently, there is no mouse model of RIH that measures behavioral sleep and activity. Previously, we demonstrated that Ethovison software can be used to effectively monitor differences in the sleep behavior of mice. Here we test the dose effect of radiation in mice using our system prior to introducing tumor. Aims: Establish the optimal radiation dose to recapitulate symptoms experienced by patients who receive cranial irradiation, such as heightened daytime sleep and reduced activity. Experimental Procedure: Animals: Male young (6wk) C57BL/6 mice were individually housed in Phenotyper cages Monitored for 10 days pre-irradiation and 11 days post irradiation under 12:12 light dark conditions. 24 non-tumor bearing C57BL/6 mice received whole brain radiation at one of 4 doses (sham, 2Gy, 5Gy, and 15Gy) using a single fraction Ethovision XT Software automatically generate general activity data as total distance travelled over time. Mouse Behavior recognition module scored Sleep/Rest, Walking, Grooming and Eating. Data Analysis: General activity was examined for total activity across 24 hours for 11 days between doses.Behaviors were compared between doses for three days (Day 8-10). Groups were analyzed between high (5&15Gy) and low (0&2Gy) doses. Baseline Analysis: Baseline activity was not significantly different between groups (F(3.23) = 0.649, p=0.593). As expected, activity levels are higher during the dark period (active period), while sleep is higher during the light period (inactive period). Post-Irradiation Activity Analysis: Activity levels were unchanged, less than 5% difference, for sham and 2Gy, however high doses 5Gy and 15Gy were suppressed by 10% Suppression of activity started after 2 days in 15Gy and 5 days in 5Gy mice. Data was corrected to baseline, which is represented by zero in the graph Post-Irradiation Behavioral Analysis: Across three days (8-10), 5Gy and 15Gy (19,87sec) had more sleep during their active phase (t=2.27, p=0.03) than sham or 2Gy (17,618 sec). Grooming was significantly higher (t=2.588, p=0.017) for low radiation dose during the active phase. There are no effects on amount of time spent eating or the amount of time spent walking Animals had no significant difference in baseline activity or sleep between groups. Shams and 2Gy had activity levels similar to baseline, while 5 and 15Gy had decreased activity levels post-radiation. Mice exposed to 15Gy radiation had an earlier onset of radiation induced hypersomnolence, with decreases starting three days before 5Gy mice. Significant effects for sleep and grooming were observed during the active phase with animals exposed to high radiation doses having more sleep and less grooming. No changes were observed for eating or total walking time between groups. Our study demonstrates that cranial irradiation causes a clear increase in sleep during the active period and decrease in activity, both factors that recapitulate the human RIH experience. Activity and sleep are impacted by irradiation in patients. A good behavioral model to observe these changes has not yet been developed in rodents. Here we demonstrate a reliable system to collect and analyze activity and sleep parameters in mice exposed to irradiation that will serve as the foundation for ongoing experiments.