Figure 1.
The Mammalian Molecular Circadian Oscillator.
The molecular circadian oscillator incorporates numerous transcriptional and posttranslational elements. Disruptions in many of the individual circadian elements in mice can lead to behavioural disturbances that mirror endophenotypes in human neurological and psychiatric disorders. Moreover, some studies have established circadian gene polymorphisms in psychiatric conditions and mutations in behavioural syndromes (see text for details). The central component of the figure depicts the core mammalian circadian feedback loop. CLOCK(or NPAS2):BMAL1 heterodimers drive the transcription of multiple genes (Cry1/2, Per1-3, Rev-Erba/b, Rora/b/c, multiple CCGs) through E-box elements. Nuclear accumulation of CRY and PER proteins can inhibit CLOCK:BMAL1-mediated transcription by directly interacting with the complex (black bar–ended arrow). As PER and CRY levels fall, the negative repression is lifted and CLOCK:BMAL1-driven transcription re-occurs. In an additional stabilising loop, REV-ERB and ROR proteins co-regulate the transcription of Bmal1 by competing for RREs in its promoter sequence. Rhythmic output of the clock is achieved through E-box elements in CCG which can impact a range of cell processes and physiology. The stability and subcellular localisation of circadian proteins is highly regulated by kinases and phosphatases (inset box). Although not entirely understood, the phosphorylation state of circadian proteins can affect their cellular localisation and/or stability. Mutations affecting the stability of Per proteins can accelerate the molecular clock in humans, leading to the inherited syndrome familial advanced sleep phase syndrome (FASPS).
Figure 2.
The Circadian System and the Mammalian Brain.
The SCN acts as a “master” clock, sending neuronal and humoral output to a number of regions in the CNS. The SCN can passively drive rhythmicity in these regions, or nuclei may themselves have their own automomous clocks. Within the SCN, every cell is a potentially independent oscillator unit. Extensive intra-SCN signalling is used to synchronise the rhythms of multiple cells. Entrainment is a process whereby environmental stimuli can alter the timing or phase of central rhythms so that they are coincidental with the prevailing daily cycle (far left). Time cues reach the SCN via several pathways involving intermediate brain areas. Some of these relay nuclei may contain their own oscillators and/or have rhythms in their function (blue and orange arrows and oscillators). Others may not have rhythmic function (green arrow). Extra-SCN oscillators may directly utilise time cues (blue and orange oscillators) or may rely solely on the SCN to synchronise/entrain rhythms (lilac arrows to grey oscillators). These oscillators may also provide feedback which impacts on the operation of the SCN (grey return arrows). In addition, extra-SCN oscillators may drive/influence rhythmicity in other brain areas (smaller grey oscillator) and communicate with each other independently from the SCN (reciprocal grey arrows). Within the CNS, some neurotransmitters/neuromodulators involved in signalling are indicated. The overall output of this complex system (large red arrow) creates the daily rhythmicity seen in a range of neurological functions and behaviours (far right). There is a wider communication with clock/oscillator units throughout the entire body. However, these so-called “peripheral” oscillators and their actions are not shown here.
Table 1.
Rhythm/Sleep Endophenotypes in Human CNS Disease and in Mouse Models.