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 [
34]. 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 [
35], BMAL1, and ROR, as well as the repressors of transcription PER1 and PER2, CRY1, CRY2, and REV-ERBα [
5].
The molecular clockwork drives the rhythmic expression of clock controlled gene (see below) and posttranscriptional processes (reviewed in [
36]) and modulates the chromatin landscape [
37], 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 [
38], neuronal electrical activity (reviewed in [
39]), metabolism [
40], redox homeostasis (reviewed in [
41]), tyrosine hydroxylase expression in dopaminergic neurons [
42], dopamine receptor signalling in the hippocampus [
43], and extracellular glutamate homeostasis [
44]. 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 [
45], which contribute to astrocyte gap junctions and hemichannels (reviewed in [
46]), as well as the stability of circadian rhythms and re-entrainment under challenging conditions [
45]. 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 [
47,
48,
49]. Mice with a targeted deletion of the essential clock gene
Bmal1 are arrhythmic under constant environmental conditions [
50], 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 [
50,
51,
52]. 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 [
53] and, consequently, impaired visual input into the circadian system [
54,
55]. Nevertheless, even under LD 12:12 conditions, many brain functions, such as spatial memory consolidation and contextual fear [
56,
57], adult neurogenesis [
58], and sleep architecture [
59] are affected in Bmal1-deficient mice, indicating the importance of this clock gene/transcription factor for general brain function.