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Towards an integrated understanding
of the biology of timing
Valter Tucci1, Catalin V. Buhusi2, Randy Gallistel3 and Warren H. Meck4
Cite this article: Tucci V, Buhusi CV, Gallistel
R, Meck WH. 2014 Towards an integrated
understanding of the biology of timing. Phil.
Trans. R. Soc. B 369: 20120470.
One contribution of 14 to a Theme Issue
‘Timing in neurobiological processes: from
genes to behaviour’.
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego,
30, 16163 Genova, Italy
Department of Psychology, Utah State University, Logan, UT, USA
Department of Psychology and Center for Cognitive Science, Rutgers University, 152 Frelinghuysen Rd,
Piscataway, NJ 08854-8020, USA
Department of Psychology and Neuroscience, Duke University, Durham, NC 27708, USA
As time passes by, our own understanding of time is close to the truth. The
brain is an efficient machine in orchestrating temporal information across a
wide range of time scales. Remarkably, circadian and interval timing processes
are shared phenomena across many species and behaviours. Moreover, timing
is a pivotal biological function that supports fundamental cognitive (e.g.
memory, attention, decision-making) and physiological (e.g. daily variations
of hormones and sleep –wake cycles) processes. Behavioural, neurobiological
and computational investigation of timing has formed a rich literature on this
theme. However, the study of timing now deserves to enter an era of genetic
and epigenetic exploration in order to reveal how evolution has shaped the
biology of timing. Within the brain, we have now identified specific brain
regions, circuits and neuromodulators that are central to the physical realization
of our perception and storage of timing information [1–4]. Nevertheless, with
only the exception of the circadian clock [5], the genetic and molecular machinery
that regulates biological clocks is far from being fully revealed.
Although many neuroscience investigations seriously take into account
temporal properties, the exact mechanisms by which neural activity in the
brain codes for duration and temporal order are still unknown. In humans,
mice and many other species, conditioned behaviours are subjected to temporal
determinants and a brief (seconds to minutes) duration of a light or tone
may itself embody the critical information to be learned from the signal. The
other most studied example of timing is around the daily 24-h oscillations.
Single-cell organisms have adapted, during evolution, their internal metabolic
processes to the environment by entraining with external stimuli (caused
by the Earth’s rotation around the Sun). Multi-cellular organisms built upon
the temporal regularity of this rest-activity cycle by incorporating it into the
circadian clock that controls sleep–wake rhythms [6].
The success in discovering molecular loops that set and reset the circadian
clock has favoured the diffusion of clock-like research models across many
time scales and, classically, the neural mechanisms underlying timing and time
perception have been theorized to rely on pacemakers. By contrast, different computational models suggest that timing is an intrinsic property of oscillating neural
networks, which are modulated by the same circadian rhythms described above.
Recent advances in molecular and cellular biology, genomics and other
‘–omics’ promote the investigation of new dynamics in the brain. Genetic polymorphic variations at different genomic regions are not only responsible for
stable trait changes across organisms, but also have the potential to affect gene
expression over time [7] and, hypothetically, to modulate the neuronal coding
of timing. The understanding of how genetic sequences translate into complex
phenotypes is a major challenge in current functional genomics. This difficulty
may be due to the fact that modules of genes and gene variations that co-express
[8] must respond to precise temporal dynamics in order to encode a particular
phenotype. In addition, a number of epigenetic regulators are set in time to
modulate gene expression and cell cycle and are intimately associated with the
functioning of neural processes. Indeed, the temporal relationship between, for
& 2014 The Author(s) Published by the Royal Society. All rights reserved.
Downloaded from on September 16, 2016
clock and to develop a common dialect across scientists with
different expertise but with a common goal: the study of
timing [6,10].
World-renowned experts in the fields of genetics/genomics, neurobiology and psychology address the dynamics
among these distinct chronobiological dimensions within
the Theme Issue. In particular, we would like to emphasize
in this issue that the investigation of timing mechanisms
can go further and target specific mechanisms at sub-cellular
level, which we envisage will represent a new perspective in
the field of timing.
Allman MJ, Teki S, Griffiths TD, Meck WH. 2013
Properties of the internal clock: first- and second-order
principles of subjective time. Annu. Rev. Psychol. 65,
743–771. (doi:10.1146/annurev-psych-010213115117)
Merchant H, Harrington DL, Meck WH. 2013 Neural
basis of the perception and estimation of time.
Annu. Rev. Neurosci. 36, 313– 336. (doi:10.1146/
Agostino PV, Golombek DA, Meck WH. 2011
Unwinding the molecular basis of interval and
circadian timing. Front. Integr. Neurosci. 5, 64.
Coull JT, Cheng RK, Meck WH. 2011
Neuroanatomical and neurochemical substrates of
timing. Neuropsychopharmacology 36, 3 –25.
Barnard AR, Nolan PM. 2008 When clocks go
bad: neurobehavioural consequences of
disrupted circadian timing. PLoS Genet.
4, e1000040. (doi:10.1371/journal.pgen.
Tucci V. 2011 Sleep, circadian rhythms, and interval
timing: evolutionary strategies to time information.
Front. Integr. Neurosci. 5, 92. (doi:10.3389/fnint.
Francesconi M, Lehner B. In press. The effects of
genetic variation on gene expression dynamics
during development. Nature. (doi:10.1038/
Litvin O, Causton HC, Chen BJ, Pe’er D. 2009
Modularity and interactions in the genetics of
gene expression. Proc. Natl Acad. Sci.
USA 106, 6441 –6446. (doi:10.1073/pnas.
9. Borrelli E, Nestler EJ, Allis CD, Sassone-Corsi P. 2008
Decoding the epigenetic language of neuronal
plasticity. Neuron 60, 961 –974. (doi:10.1016/j.
10. Lassi G, Ball ST, Maggi S, Colonna G, Nieus T,
Cero C, Bartolomucci A, Peters A, Tucci V. 2012
Loss of Gnas imprinting differentially affects REM/
NREM sleep and cognition in mice. PLoS
Genet. 8, e1002706. (doi:10.1371/journal.pgen.
Phil. Trans. R. Soc. B 369: 20120470
example, chromatin mechanisms and transcription is pivotal in
many circadian processes and sleep [9].
The investigation of the interplay between genetic elements
and neuronal functioning requires a multidisciplinary effort
across molecular genetics and behavioural and computational
neuroscience. Although many mechanisms within the organism rely on well-defined timed processes, there is limited
cross-talk among disciplines that investigate timing at different
levels and on different time scales. For this reason, we provide
in this Theme Issue a series of overviews and original research
papers that aim to broaden the understanding of the biological