Various brain functions, such as sleep, wake, foraging, food intake, alertness, emotion, motivation, and cognitive performance, controlled by different brain regions, show circadian rhythms. Moreover, any information is processed in a temporal context. Consistently, many brain regions harbour circadian oscillators, which are governed by the SCN
[32]. At the cellular level, these oscillators are composed of single cells each harbouring a molecular clockwork composed of transcriptional/translational feedback loops of clock genes. The clock genes encode for activators of transcription, such as CLOCK and its forebrain-specific analog NPAS2
[33], BMAL1, and ROR, as well as the repressors of transcription PER1 and PER2, CRY1, CRY2, and REV-ERBα
[3].
The molecular clockwork drives the rhythmic expression of clock controlled gene (see below) and posttranscriptional processes (reviewed in
[34]) and modulates the chromatin landscape
[35], thus regulating rhythmic cell function at multiple levels. The molecular clockwork in the SCN and subordinate extra-SCN brain circadian oscillators drives various rhythms in neuron and glia function including ATP concentration
[36], neuronal electrical activity (reviewed in
[37]), metabolism
[38], redox homeostasis (reviewed in
[39]), tyrosine hydroxylase expression in dopaminergic neurons
[40], dopamine receptor signalling in the hippocampus
[41], and extracellular glutamate homeostasis
[42]. In addition, some rhythms in the SCN are time-of day-dependent and do not persist in constant darkness, such as rhythmic expression of connexion 30
[43], which contribute to astrocyte gap junctions and hemichannels (reviewed in
[44]), as well as the stability of circadian rhythms and re-entrainment under challenging conditions
[43]. Circadian clock gene expression in the SCN and the hippocampus persists with high robustness in vitro, indicating a strong coupling of single cell oscillators, while it damps rapidly in other brain regions, indicating a weak coupling
[45][46][47]. Mice with a targeted deletion of the essential clock gene
Bmal1 are arrhythmic under constant environmental conditions
[48], so a loss of function in a single gene strongly affects circadian rhythmicity. In mouse models for compromised molecular clockwork function, such as Bmal1-deficient mice,
Per1/2 double mutants, and
Cry1/Cry2 double mutants, circadian rhythms are abolished, while various parameters of physiology and behaviour are rhythmic under the LD 12:12 conditions due to masking
[48][49][50]. This emphasizes the strong impact of the environmental light/dark conditions on rhythmic brain function. In this context, it is important to note that
Cry1/Cry2 double mutants and Bmal1-deficient mice show deficits in retinal visual physiology
[51] and, consequently, impaired visual input into the circadian system
[52][53]. Nevertheless, even under LD 12:12 conditions, many brain functions, such as spatial memory consolidation and contextual fear
[54][55], adult neurogenesis
[56], and sleep architecture
[57] are affected in Bmal1-deficient mice, indicating the importance of this clock gene/transcription factor for general brain function.