Controlling Time Perception using Optogenetics

Imagine you have a device which can help you control your perception of time, so that you can speed up or slow down the subjective time at your will. Sounds like a science fiction but not in the near future. Yes a step has been taken to control time perception in mice using optogenetics. A recent study by Sofia Soares, Bassam Atallah, and Joseph Paton published in Science, not only measured the activity of the Dopaminergic (DA) neurons in substantia nigra pars compacta (SNc) in mice but also manipulated the activity of these neurons using optogentics resulting in altered timing behaviour.

They first trained mice to categorize variable interval between two tones (0.6, 1.05, 1.26, 1.38, 1.62, 1.74, 1.95 and 2.4 sec) as shorter or longer than 1.5 sec by touching the right or left port with their nose. The correct response was rewarded. After around 2 months of training mice were very accurate in performing this task.

Next, to confirm that the activity in SNc-DA neurons is essential for accurate timing, they used pharmacogenetic suppression approach. In this, they injected the SNc of a set of mice with the viral vector carrying the genes (hM4D(Gi)-mCherry). When hM4Di is expressed it does not affect the normal functioning of the neurons, but when an inert molecule like clozapine-N-oxide (CNO) is introduced it activates the hM4Di which then results in silencing of those neurons. They found that the timing behavior become very poor in the set of mice treated with CNO compared to the control set which were treated with saline. They also checked for timing accuracy before and after the CNO treatment showing that mice regained its timing accuracy.

Further, to establish a strong molecular basis for trial-by-trial variation in timing, they used the fiber photometry approach. In this, they measured the activity in the DA neurons while mice were performing the timing task. To accomplish this they injected SNc of a set of mice with the viral vector carrying the genes (GCaMP6f and tdTomato). When neurons are active there is lot of intake of Ca2+, which then binds with GCaMP6f and tdTomato protein leading to conformation changes and fluorescence. The amount of fluorescence is the indicator of activity of the cells. To assess whether trial-by-trial change in the activity within these neurons correlates with the timing behavior of mice, they distributed all the trials based on the measured activity of DA neurons into three categories i.e. low activity, medium activity, and high activity. They found that when the activity in the dopamine neurons was high, mice more often reported shorter response, whereas when the activity was low, mice more often reported longer response. Thus, the activity in the DA neurons of SNc could predict the mice behavioural response.

Finally, to establish a causal link between the activity of the DA neurons in SNc and timing behavior, they used optogenetic approach. They injected neurons in SNc with viral vectors carrying genes (ChR2-EYFP, and ArchT-GFP, or eNpHR3.0.EYFP). ChR2 codes for photo sensitive channel rhodopsin which when stimulated with 473nm (blue light) leads to influx of positive ions (cations) inside the cells thus activating the cell. On the other hand, eNpHR3 codes for halorhodopsin which when stimulated with 596nm (yellow light) leads to influx of chloride ions thus silencing the neurons by hyperpolarization. They found that when these neurons were optogentically activated using blue light, mice responded shorter response more often. Whereas when these neurons were optogentically silenced using yellow light, mice responded longer response more often. These changes in timing behavior were transient as mice timing accuracy was again restored in the absence of light. Thus, the authors were able to manipulate the timing behaviour of the mice using optogenetics.

The study explains the underestimation of time during fun or pleasurable activity where dopamine is supposedly high and overestimation of time during stress and fear where dopamine is low. Although, this study suggests that increased activity in the DA neurons leads to underestimation of time, however there are studies which suggest that increase in dopamine leads to overestimation of time (1,2,3).

Overall, this study happens to be the first to manipulate timing behaviour in mice using optogenetics, giving hope for the future where individuals could one day manipulate their own subjective time.

Source article: Soares, S., Atallah, B. V., & Paton, J. J. (2016). Midbrain dopamine neurons control judgment of time. Science, 354(6317), 1273-1277.

References:

  1. Buhusi, C. V., & Meck, W. H. (2002). Differential effects of methamphetamine and haloperidol on the control of an internal clock. Behavioral neuroscience, 116(2), 291.
  2. Failing, M., & Theeuwes, J. (2016). Reward alters the perception of time. Cognition, 148, 19-26.
  3. Terhune, D. B., Sullivan, J. G., & Simola, J. M. (2016). Time dilates after spontaneous blinking. Current Biology, 26(11), R459-R460.

—-Mukesh Makwana (Doctoral student), mukesh@cbcs.ac.in
Centre of Behavioural and Cognitive Sciences (CBCS), University of Allahabad, India.