0054 Effects of Sik3 Sleepy Mutation on Hypothalamic Function in Mice

Abstract Introduction The hypothalamus is a small brain region involved in diverse functions such as the sleep/wake cycle, metabolic control, thermoregulation, and innate behaviors such as aggression and sex. The Sik3Slp/+ mouse model was identified by a forward-genetics screen for sleep duration. While Sik3Slp/+ mice exhibit decreased total wake time and increased NREM time with elevated delta wave density during the dark phase, sleep microarchitecture and other aspects of hypothalamic function have not previously been assessed. Methods Sleep architecture was recorded and analyzed in Sik3Slp/+ mice and non-transgenic littermates via 24hr EEG/EMG between 2 and 8 months of age. Weight, glucose and insulin tolerance tests (GTT and ITT) were recorded across the life span. Core body temperature was recorded for 3 weeks using intraperitoneal temperature sensor. Finally, aggressive behavior of male Sik3Slp/+ and non-transgenic mice was assessed in the light and dark cycle using the resident intruder test (RI). Results Sleep architecture analyses revealed that total sleep time (TST) and total NREM sleep time (p< 0.001) were increased in Sik3Slp/+ mice as expected, with increased slow oscillation density (p < 0.0001), but mean NREM bout length was significantly shorter (p< 0.0001) with increased arousal index (p< 0.001). Spindle duration (p = 0.001) and power (p = 0.005) were also significantly decreased in Sik3Slp/+ mice. Sik3Slp/+ mice gain excessive weight with age, and manifest significantly increased glucose levels during GTT but not ITT. Core body temperature mesor (p = 0.05) and amplitude (p< 0.0001) were lower in Sik3Slp/+ compared to non-transgenic mice, and there was a significant inverse relationship between weight and core body temperature in Sik3Slp/+ mice. Evaluation of aggression levels using RI test in Sik3Slp/+ and non-transgenic male mice, revealed a trend towards lower total aggression time in Sik3Slp/+ males in the dark phase. Conclusion Sik3Slp/+ sleep architecture suggests an increased sleep drive coupled with a less stabile sleep architecture, which we speculate may stem from altered neuronal calcium dynamics. The lower core body temperature, obesity, and tendency to lower levels of aggression in males, also support the hypothesis of hypothalamic dysfunction of this mouse model. Support (if any)