Circadian Rhythms in Mammals

The Albrecht lab investigates circadian clocks in mammals. Circadian clocks organize an organism's daily behavior and physiology on a 24-hour time scale. These 24-hour rhythms are pervasive at all levels of organization, from complex behavior to organ specific function down to the scale of autonomous cellular oscillations. The timing in mammals is organized hierarchically, with a master pacemaker in the suprachiasmatic nuclei (SCN) controlling subordinate central and peripheral clocks making up the circadian system. This system is tuned to the environment via light and food. Drugs like alcohol and cocain can interfere with these environmental stimuli leading to misalignement of the circadian clock with the day/night cycle. We are interested in the question how clocks in different tissues adjust to environmental cues and how the brain integrates this information to produce coherent systemic circadian rhythms as observed in food anticipation, drug seeking and metabolic rhythms. This is of central interest, because loss of a stable clock-phase relationship between organs is one of the characteristics found to be altered in many human diseases including depression, obesity and cancer. 

• Molecular function of Per1 and Per2

  Exploring the differences between PER1 and PER2, we found that PER2 rather than PER1 acts as a co-regulator of various nuclear receptors. The physical interaction of PER2 with PPARa and REV-ERBa allows for a modulation of Bmal1 gene regulation and a precise coupling of the core and the stabilizing loop. Additionally, PER2 and nuclear receptors affect rhythmic transcription of output genes, allowing the fine-tuning and optimization of cellular responses to environmental signals. Future investigations are aimed at the study of modulatory properties of PER2 on various nuclear receptors and what the role of the different phosphorylation sites on PER2 are important for its function.

• Clock and brain function

  Evidence is accumulating that a relationship between circadian clock function and central nervous system disorders exists. Aside from generating robust rhythms, the circadian system is sensitive to environmental cues in order to synchronize its phase to the prevailing day/night cycle, a process termed entrainment. The environmental signals reach the SCN clock via neurotransmitter/neuromodulator and hormonal pathways and can reset the phase of clock gene expression in the SCN. Although there are extra-SCN oscillators that can receive environmental phase-resetting information, they also experience strong entrainment signals from the SCN. Hence, it is a process of bidirectional communication and feedback that establishes the phasing and entrainment of all clocks in the brain and body, which we are studying.

• Per2 and food uptake

  Per2 plays a role in the anticipation of intermittent feeding, most likely through the regulation of ketone body signaling. We are interested in how the different organs as well as how astrocytes and neurons contribute in the regulation of this process.

• Clock synchronization and sleep

  Sleep is mainly controlled by two mechanisms: A homeostatic component regulates need and intensity of sleep according to the time spent awake or asleep, whereas a circadian component schedules sleep and wakefulness to the appropriate times within one day. We are studying signaling pathways common to the circadian and homeostatic components of sleep. In addition we are interested in metabolic mechanism that may contribute or regulate the sleep homeostat.