Linking neural activity and molecular oscillations in the SCN

• Published in: Nature reviews. Neuroscience Vol. 12; no. 10; pp. 553 - 569
• Main Author: Colwell, Christopher S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2011; Nature Publishing Group
• Subjects: 631/136/7; 631/378/1385; 631/378/1697; 692/699/375/365; Action Potentials - physiology; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological and medical sciences; Biological Clocks - physiology; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Chronobiology; Circadian rhythm; Circadian Rhythm - physiology; Feedback; Fundamental and applied biological sciences. Psychology; Gene expression; General aspects. Models. Methods; Genes; Genetic aspects; Humans; Kinases; Membrane Potentials - physiology; Neurobiology; Neurons; Neurons - physiology; Neurosciences; Pacemakers; Peptides; Physiological aspects; review-article; Suprachiasmatic Nucleus - physiology; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: nervous system and sense organs; United States; United States > US; California; Suprachiasmatic nucleus; Calcium; Electrical activity; Central nervous system; Electrophysiology; Action potential; Slow potential; Biological rhythm; Hypothalamus; Ionic current; Circadian rhythm; Encephalon; Neuron; Oscillation; Physiology; Timing; Hyperpolarization
• ISSN: 1471-003X; 1471-0048; 1471-0048; 1469-3178
• DOI: 10.1038/nrn3086

Key Points Neurons in the suprachiasmatic nucleus (SCN) function as part of a central timing circuit that drives daily changes in our behaviour and underlying physiology. We have a good conceptual understanding of the cell-autonomous molecular clockwork that regulates the generation of circadian rhythms in gene expression, but there is a lack of a mechanistic understanding of how this molecular feedback loop interacts with the membrane to produce physiological circadian rhythms. A hallmark feature of the SCN population is that these neurons are mostly electrically silent during the night, start to fire action potentials near dawn and then continue to generate action potentials with a slow and steady pace all day long. Individual SCN neurons exhibit variability in their firing patterns and are best thought of as weakly coupled oscillators. Sets of currents are responsible for this daily rhythm in spontaneous activity. During the day, SCN neurons are much more depolarized than neurons that do not show spontaneous activity. A set of currents (persistent sodium, hyperpolarization-activated, cyclic nucleotide-gated (HCN) and T- and L-type calcium currents) provide the excitatory drive that is necessary for any spontaneously active neurons. The excitatory drive in SCN neurons seems to be relatively constant throughout the daily cycle. Another set of currents translate this excitatory drive into a regular pattern of action potentials. In the SCN, the fast delayed rectifier (FDR) current, subthreshold-operating A-type K + current (I A current) and BK potassium current all seem to play a part in the regulation of spontaneous action potential firing in SCN neurons during the day. The biophysical properties of these currents suggest that these three currents will also be critically involved in determining how SCN neurons respond to synaptic stimulation from other regions. These currents are mostly active during the day. There are currents that hyperpolarize the membrane and thereby underlie the nightly silencing of firing. We know the least about these night-active currents but two-pore domain potassium channels (K2P, TASK and TREK) are the most likely candidates. There is evidence that membrane excitability and/or synaptic transmission may be required for the generation of molecular oscillations in SCN neurons. The hypothesis that dysregulated neural activity and synaptic transmission weakens basal Ca 2+ and cyclic AMP-responsive element (CRE) activity to a level that is insufficient to drive the expression of period ( PER ) or cryptochrome ( CRY ) genes. This evidence is discussed but it is premature to form a conclusion. Certainly, many cell types without electrical activity can generate circadian oscillations. There is strong evidence that membrane excitability can alter clock gene expression. The cellular and molecular mechanisms by which light regulates the expression of PER1 in the SCN have been the subject of much analysis and provide a clear example of how electrical activity can adaptively alter gene expression in this system. Several studies that have explored the impact of mutations in the core clockwork on electrical activity rhythms that are recorded in the SCN have provided strong evidence that the molecular clockwork in the SCN can drive the rhythms in electrical activity. Unfortunately, we can only speculate about the likely mechanisms (rhythmic transcription and translation, ion channel trafficking, and post-translational modifications) by which the molecular clockwork alters membrane properties of SCN neurons. Lastly, evidence is presented that raises the possibility that a decline in neural activity in the SCN may be a crucial mechanism by which ageing and disease may weaken the circadian output and contribute to a set of symptoms that impacts human health. Neurons in the suprachiasmatic nucleus (SCN) show circadian patterns, not only in gene transcription and protein translation but also in neural activity. Christopher Colwell describes the mechanisms that drive the rhythmic firing patterns of SCN neurons, including the contribution of ion channels, and discusses the mutual regulation of neural activity and the molecular clock. Neurons in the suprachiasmatic nucleus (SCN) function as part of a central timing circuit that drives daily changes in our behaviour and underlying physiology. A hallmark feature of SCN neuronal populations is that they are mostly electrically silent during the night, start to fire action potentials near dawn and then continue to generate action potentials with a slow and steady pace all day long. Sets of currents are responsible for this daily rhythm, with the strongest evidence for persistent Na + currents, L-type Ca 2+ currents, hyperpolarization-activated currents (I H ), large-conductance Ca 2+ activated K + (BK) currents and fast delayed rectifier (FDR) K + currents. These rhythms in electrical activity are crucial for the function of the circadian timing system, including the expression of clock genes, and decline with ageing and disease. This article reviews our current understanding of the ionic and molecular mechanisms that drive the rhythmic firing patterns in the SCN.