Circadian pacemakers drive innumerable physiological and behavioral 24 h rhythms in almost all organisms - including humans. These pacemakers can be used to synchronize internal physiological processes and to anticipate or predict periodic environmental events. To be useful for organisms, however, endogenous circadian pacemakers must be synchronized or entrained to environmental time. The principal entraining agent for many pacemakers is the environmental light cycle and the process of photic entrainment has been well studied in mammals. Abnormalities in human circadian entrainment have been implicated in specific sleep disorders including advanced sleep phase syndrome, non-24h sleep-wake syndrome, as well as """"""""jet lag"""""""" and disorders related to shift-work. Recently, significant components of the mammalian circadian pacemaker have been uncovered using the mouse as a model system. Several circadian genes have been identified and the interactions of these """"""""clock"""""""" genes and their products appear to operate as a molecular feedback loop within neurons of the hypothalamic suprachiasmatic nucleus - the site of a mammalian circadian pacemaker. Among these genes mPer1 and mPer2 appear to play a crucial dual-role within the circadian mechanism -- acting as both integral clock genes as well as important components of the photic entrainment path-way -- the neural pathway that carries light information to reset and synchronize the molecular circadian mechanism. My long-term objectives include characterizing the functional operation of the photic pathway that mediates circadian entrainment in mPer2 mutant mice. Functional behavioral analyses provide an invaluable link between molecular analyses of the circadian clock and the operation of the pacemaker within intact animals. Experiments in this application focus upon 4 specific aims: 1) We will characterize the responsiveness of the photic entrainment pathway for the mPer2 and wild type mice at several phases of the circadian cycle. 2) We will directly compare two commonly used assays of circadian photic responsiveness (measured on circadian cycles 1 and 7 of constant darkness). Importantly this comparison will include both wild type as well as mPer2 mutant mice. 3) We will quantify the sensitivity of the photic entrainment pathway to the irradiance and duration of light pulses in mice carrying the mPer2(brdm1) mutation, comparing the characteristics of photic sensitivity measured for wild-type mice. 4) We will characterize entrainment of mPer2-mutant mice to complete LD cycles to determine how changes in photic sensitivity in mPer2(brdm1) mutant mice may influence the entrainment of the circadian pacemaker. Together these experiments will provide a comprehensive functional analysis of circadian photic responses in the mPer2 and wild type mice -- and furnish critical experimental tools for future dissections [of] the mammalian circadian mechanism and photic entrainment pathway at the cellular and molecular levels.
| Khammanivong, A; Nelson, D E (2000) Light pulses suppress responsiveness within the mouse photic entrainment pathway. J Biol Rhythms 15:393-405 |
