International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

H14 Genetics of Circadian Behavior and Sleep in the Mouse

Veasey, S. C., Kapfhamer, D., Valladares, O., Leach, G., Nolan, P.*, and Bucan, M. University of Pennsylvania, Philadelphia, PA; *MRC Institute of Hearing Research, Nottingham NG7 2RD, UK

In an effort to identify molecular components of the mammalian sleep and circadian systems, our laboratory is developing and validating phenotypical asssays to screen for anomalies in circadian and sleep control, as part of a large scale random mutagenesis effort to identify genes involved in various behaviors. This approach involves: 1) establishing baseline data in the inbred strains of mice used in mutagenesis protocols for various activity parameters relevant to circadian rhythm (entrainment to light:dark schedule, period of activity in constant dark (t), length of active (a) and rest (r) phases , and diurnal ratio of activity), and sleep parameters (baseline amounts of Wake, NREM and REM, sleep efficiency, diurnal ratio of waking, duration of sleep bouts, arousal index, and recovery patterns following sleep deprivation) and 2) prescreening progeny of ENU mutagenized mice for abnormal activity patterns, with potential mutant lines subsequently analyzed for abnormal sleep parameters.

Baseline wheel running data was collected for C57BL/6J, C3H/HeJ, Balb/cJ, DBA/2J, FVB/NJ, 129/SvImJ, and 129/SvevJ mice. Little effect of strain was observed for the following measures: t, a, r, diurnal ratio of activity, and phase angle of entrainment, with the exception of the Balb/cJ strain, which exhibited a shorter t and increased diurnal ratio of activity.

To obtain baseline sleep data, C57BL/6J, C3H/HeJ, [C57BL/6J X C3H/HeJ] F1, and 129/SvevJ mice were surgically implanted with electrodes for recording EEG and EMG signals. Data was collected and analysed using a modified version of the Benington and Heller sleep scoring system, which we have validated as 95.9% accurate for waking, 94.9% for NREMS, and 81.7% for REMS in mice. Among the inbred strains analysed, sleep bout length, arousal index, and sleep efficiency did not vary significantly. Total sleep time (NREM+REM) was significantly greater in C57BL/6J than C3H/HeJ and 129/SvevJ (p<0.05), and 129/SvevJ displayed a greater diurnal ratio of waking than the other strains tested (p<0.01).

To date, approximately 2000 progeny of ENU mutagenized C57BL/6J mice have been prescreened for anomalies in wheel running activity. Rest:activity mutants identified in this screen and confirmed by progeny testing include: 3 short period mutants, 3 mutants with altered diurnal activity, and one short a mutant. Earlybird, a short period mutation, has been localized to the proximal portion of mouse chromosome 8. Preliminary sleep analysis in Earlybird mice suggests that the mutation does not effect amounts of the three sleep stages, however, the period of Waking, NREM and REM is shortened, in parallel with activity, by the mutation. Esterline, another mutation confirmed by progeny testing, is characterized by a shortened period of activity in heterozygotes and arrhythmicity in homozygotes. Genetic mapping of Esterline and sleep analysis are currently underway.


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