Representation of interval timing by temporally scalable firing patterns in rat prefrontal cortex

Abstract

Perception of time interval on the order of seconds is an essential component of cognition, but the underlying neural mechanism remains largely unknown. In rats trained to estimate time intervals, we found that many neurons in the medial prefrontal cortex (PFC) exhibited sustained spiking activity with diverse temporal profiles of firing-rate modulation during the time-estimation period. Interestingly, in tasks involving different intervals, each neuron exhibited firing-rate modulation with the same profile that was temporally scaled by a factor linearly proportional to the instructed intervals. The behavioral variability across trials within each task also correlated with the intertrial variability of the temporal scaling factor. Local cooling of the medial PFC, which affects neural circuit dynamics, significantly delayed behavioral responses. Thus, PFC neuronal activity contributes to time perception, and temporally scalable firing-rate modulation may reflect a general mechanism for neural representation of interval timing. P erception of time on the order of seconds (interval timing) is crucial for a variety of behaviors (1-4). In interval timingrelated tasks, the animal must keep track of the elapsed time from a previous event and decide when to anticipate a future event or to execute motor actions. Whereas timing perception in shorter timescale (e.g., motor timing) is controlled by automatic timing system in the cerebellum (5, 6), interval timing is thought to involve prefrontal and parietal cortices (7), which are associated with attention and working memory (8). However, how timing information is represented in the neural activity in these cortical areas is unclear. To understand how the brain performs time estimation, it would be particularly useful to examine changes in the pattern of neuronal activity when the animal estimates different time intervals. We thus designed a behavioral task in which the rat was required to estimate two time intervals in the same behavioral session, and multiple single-unit recording was performed concurrently to examine how the task timing was represented by activities of medial prefrontal cortex (mPFC) neurons. Finally, local brain cooling was applied to explore whether mPFC neural network dynamics play causal role in the animal's perception of time intervals on the order of seconds. ResultsAdult rats were trained to perform the time-estimation task ( Fig. 1A and Movie S1), with two instructed durations (1.5 and 2.5 s) in alternating blocks of trials. Each trial was initiated when the rat poked the nose into the waiting port. After a random delay (drawn from a uniform distribution within 0.5-1.5 s), a sound stimulus was presented to indicate the instructed duration of either 1.5 s (pure tone) or 2.5 s (white noise). During "instructive trials," the sound was presented for the instructed duration, and the rat was rewarded only if it exited from the waiting port within a ∼1-s window (Materials and Methods) at the sound termination. The "exit time" is defined as the time be...

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“…1C]. The variability of rodent behavior observed in this study was in the range of previous studies of interval timing in rodents (Kim et al 2013;Meck 2006;Narayanan et al 2012;Parker et al 2014;Xu et al 2014). Nonetheless, a repeated-measures ANOVA revealed that, across rodents, there was a main effect of both MFC 6-OHDA and interval, as well as a significant interaction term ( Fig.…”

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“…3). For instance, slow synaptic receptor types such as NMDA can slowly integrate sensory input (Wang, 2002), resulting in population firing rate ramping similar to experimental observations in interval timing tasks (Xu et al, 2014). Were we to incorporate slow recurrent excitatory synapses in this way, the duration of represented events would be determined by the decay timescale of NMDA synapses.…”

Clock Speed as a Window into Dopaminergic Control of Emotion and Time Perception

“…Notably, medial frontal regions in humans and rodents can have similar patterns of neuronal activity (Narayanan, 2016;Narayanan et al, 2013;Parker et al, 2015a), facilitating mechanistic investigation of temporal processing in rodents. Disrupting rodent medial frontal cortex impairs performance of operant tasks requiring temporal control of action (e.g., Kim et al, 2009;Laubach et al, 2015;Narayanan & Laubach 2006;Narayanan et al, 2012;Xu et al, 2014). Single neurons in medial frontal cortex (e.g., Narayanan & Laubach 2009;Niki & Watanabe 1979;Parker et al, 2014) and medial premotor cortex (Merchant et al, 2013b) are strongly modulated during timing tasks.…”