Neurobiology of Circadian and Interval Timing

Abstract

Temporal processing in the brain is fundamental to environmental adaptation in humans and other animals. Biological timing ranges from the microsecond scale (e.g. sound localisation) to seasonal frequencies (such as reproductive cycles). Two of the main scales of biological timing ubiquitous in most organisms are interval timing (seconds‐to‐minutes range) and circadian timing (24 h range). Interval timing is crucial to learning, memory, decision‐making and other cognitive tasks, whereas circadian timing is essential for the regulation of several physiological and behavioural functions. Several brain areas, circuits and neuromodulators that are critical to temporal processing have now been identified. However, with the exception of the circadian system, the genetic and molecular machinery that regulates biological clocks has not been systematically examined. As a consequence, the molecular basis of these two temporal mechanisms is currently the subject of intense research, as well as their possible relationship.

Key Concepts

  • Biological timing (from microseconds to seasonal cycles) is fundamental for survival and optimal goal reaching in humans and other animals.
  • Circadian timing (24 h) and interval timing (hundreds of milliseconds to minutes) are ubiquitous in nature and are required for normal physiology and behaviour.
  • Dopamine metabolism in the striatum is critical for interval timing, and it is also the subject of circadian control.
  • Circadian and interval timing may share some common pathways, including dopamine metabolism.
  • Circadian and interval timing are seriously disrupted in human pathologies with dopamine dysfunction.

Keywords: biological timing; circadian system; interval timing; temporal discrimination; time perception; corticostriatal circuits; dopamine

Figure 1. Different scales of biological timing. Spectrum of biological timing scales, from microsecond to infradian timing. Among these scales, circadian and interval timing are present in almost all living organisms.
Figure 2. (a) Main components of the circadian timing system. Circadian rhythms consists of three main components: (1) an input pathway integrating exogenous signals to synchronise circadian phase and period, (2) a central oscillator that generates the endogenous circadian signal and (3) an output pathway driving circadian periodicity and coupling of biological processes. (b) The molecular circadian clock. Simplified model of the transcriptional/translational feedback loops that constitute the mammalian circadian clock. In the primary feedback loop, the positive elements CLOCK and BMAL1 initiate transcription of target genes containing E‐box sequences, including Period (in mice, Per1, Per2 and Per3) and Cryptochrome (Cry1 and Cry2). Once in the cytoplasm, the resulting PER and CRY proteins heterodimerise and translocate back to the nucleus. Negative feedback is achieved by PER:CRY heterodimers to repress their own transcription by acting on the CLOCK:BMAL1 complex. Another regulatory loop is induced by CLOCK:BMAL1 heterodimers activating transcription of Rev‐erbα and Rorα. REV‐ERBα and RORα subsequently compete to bind RORE elements present in Bmal1 promoter. Thus, the circadian oscillation of Bmal1 is both positively and negatively regulated by RORα and REV‐ERBα. The result of these complex regulatory pathways is that the mRNA and protein levels of most circadian genes and clock‐controlled genes (CCGs) oscillate with a ∼24 h period.
Figure 3. Interval timing. (a) Corticostriatal circuits involved in interval timing. The thalamus projects to cortical areas that are involved in temporal processing. According to the SBF model, the activation patterns of oscillatory neurons in the cortex are monitored by MSNs in the dorsal striatum. Colour lines indicate different neurotransmitter signalling. Solid or dashed lines refer to the direct or indirect pathway, respectively. GABA, γ‐aminobutyric acid; GPe, globus pallidus external capsule; GPi, globus pallidus internal capsule; SNpc, substantia nigra pars compacta; SNpr, substantia nigra pars reticulata; STN, subthalamic nucleus. (b) Scalar property. When timing a specific interval, responses typically distribute normally around this target duration. The width or variability of these responses grows proportional to the target duration (e.g. greater width for timing 30‐s than 15‐s). When the response distributions are plotted on the same relative scale (e.g. 1/T, T being the target duration), they are normally superimposed, thereby demonstrating the scalar property of interval timing (Buhusi and Meck, ). (c) Peak‐interval procedure. In a typical duration reproduction procedure known as the ‘peak‐interval procedure’, participants receive training trials, during which they are presented with specific target durations in order to form temporal criteria, and with test trials in which participants are asked to reproduce these target durations. In animal models, FI trials are primed for reinforcement at the associated target durations, interleaved with unreinforced PI (probe) trials.
Figure 4. Circadian regulation of dopaminergic metabolism. The circadian system is able to regulate daily rhythms in components related to dopaminergic neurotransmission in the basal ganglia. Thus, circadian clock proteins act as transcription factors through binding to E‐boxes and RORE elements from the promoter regions of target genes. Some examples involve rhythmic DA synthesis by TH, rhythmic DA release – under the control of D2 autoreceptors – or rhythmic degradation mediated by MAO. This regulation also affects postsynaptic neurons – such as striatal medium spiny neurons. For example, daily rhythms in striatal DAT expression and DA content have been described. Abbreviations: COMT, catechol‐O‐methyltransferase; D1, dopamine receptor type 1; D2, dopamine receptor type 2; DA, dopamine; DAT, dopamine transporter; DDC, DOPA decarboxylase; DOPAC, 3,4‐dihydroxyphenylacetic acid; E‐box′, noncanonical E‐box; HVA, homovanillic acid; MAO, monoamine oxidase; ROR, retinoid‐related orphan receptor; RORE, ROR response element; SN, substantia nigra; TH, tyrosine hydroxylase; TYR, tyrosine; VTA, ventral tegmental area.
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Further Reading

Gu B‐M, Jurkowski AJ, Lake JI, et al (2015) Bayesian models of interval timing and distortions in temporal memory as a function of Parkinson's disease and dopamine‐related error processing. In: Vatakis A and Allman MJ (eds) Time Distortions in Mind: Temporal Processing in Clinical Populations, pp. 284–329. Boston, MA: Brill Academic Publishers.

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Hinton SC and Meck WH (1997b) The “internal clocks” of circadian and interval timing. Endeavour 21: 82–87.

Kononowicz TW, van Rijn H and Meck WH (2017) Timing and time perception: a critical review of neural timing signatures before, during, and after the to‐be‐timed interval. In: Wixted J (Editor‐in‐Chief) and Serences J (Editor, Vol. II) Sensation, Perception and Attention, Volume II – Stevens' Handbook of Experimental Psychology and Cognitive Neuroscience, 4th edn, pp. 1–35. New York, NY: Wiley, in press.

Meck WH (ed.) (2003) Functional and Neural Mechanisms of Interval Timing. Boca Raton, FL: CRC Press.

Meck WH and Ivry RB (2016) Editorial overview: time in perception and action. Current Opinion in Behavioral Sciences 8: vi–x.

Merchant H and de Lafuente V (eds) (2014) Neurobiology of Interval Timing. New York, NY: Springer‐Verlag.

van Rijn H, Gu B‐M and Meck WH (2014) Dedicated clock/timing‐circuit theories of time perception and timed performance. Advances in Experimental Medicine and Biology 829: 75–99.

Vatakis A, Balcı F, Correa A and Di Luca M (eds) (2017) Timing and Time Perception: Procedures, Measures, and Applications. Leiden: Brill, in press.

Yin B, Lusk NA and Meck WH (2017) Interval‐timing protocols and their relevancy to the study of temporal cognition and neurobehavioral genetics. In: Tucci V (ed.) Handbook of Neurobehavioral Genetics and Phenotyping, pp. 179–227. New York, NY: Wiley‐Blackwell.

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Agostino, Patricia V, Acosta, Julieta, and Meck, Warren H(Nov 2017) Neurobiology of Circadian and Interval Timing. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027161]