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Downloaded from http://rstb.royalsocietypublishing.org/ on September 16, 2016 Towards an integrated understanding of the biology of timing Valter Tucci1, Catalin V. Buhusi2, Randy Gallistel3 and Warren H. Meck4 rstb.royalsocietypublishing.org Preface 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. http://dx.doi.org/10.1098/rstb.2012.0470 One contribution of 14 to a Theme Issue ‘Timing in neurobiological processes: from genes to behaviour’. 1 Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genova, Italy 2 Department of Psychology, Utah State University, Logan, UT, USA 3 Department of Psychology and Center for Cognitive Science, Rutgers University, 152 Frelinghuysen Rd, Piscataway, NJ 08854-8020, USA 4 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 http://rstb.royalsocietypublishing.org/ 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. 1. 2. 3. 4. 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/ annurev-neuro-062012-170349) Agostino PV, Golombek DA, Meck WH. 2011 Unwinding the molecular basis of interval and circadian timing. Front. Integr. Neurosci. 5, 64. (doi:10.3389/fnint.2011.00064) Coull JT, Cheng RK, Meck WH. 2011 Neuroanatomical and neurochemical substrates of 5. 6. 7. timing. Neuropsychopharmacology 36, 3 –25. (doi:10.1038/npp.2010.113) Barnard AR, Nolan PM. 2008 When clocks go bad: neurobehavioural consequences of disrupted circadian timing. PLoS Genet. 4, e1000040. (doi:10.1371/journal.pgen. 1000040) Tucci V. 2011 Sleep, circadian rhythms, and interval timing: evolutionary strategies to time information. Front. Integr. Neurosci. 5, 92. (doi:10.3389/fnint. 2011.00092) Francesconi M, Lehner B. In press. The effects of genetic variation on gene expression dynamics during development. Nature. (doi:10.1038/ nature12772) 8. 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. 0810208106) 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. neuron.2008.10.012) 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. 1002706) Phil. Trans. R. Soc. B 369: 20120470 References 2 rstb.royalsocietypublishing.org 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