Ruey-Kuang Cheng

Neuroanatomical and Neurochemical Substrates of Timing

We all have a sense of time. Yet, there are no sensory receptors specifically dedicated for perceiving time. It is an almost uniquely intangible sensation: we cannot see time in the way that we see color, shape, or even location. So how is time represented in the brain? We explore the neural substrates of metrical representations of time such as duration estimation (explicit timing) or temporal expectation (implicit timing). Basal ganglia (BG), supplementary motor area, cerebellum, and prefrontal cortex have all been linked to the explicit estimation of duration. However, each region may have a functionally discrete role and will be differentially implicated depending upon task context. Among these, the dorsal striatum of the BG and, more specifically, its ascending nigrostriatal dopaminergic pathway seems to be the most crucial of these regions, as shown by converging functional neuroimaging, neuropsychological, and psychopharmacological investigations in humans, as well as lesion and pharmacological studies in animals. Moreover, neuronal firing rates in both striatal and interconnected frontal areas vary as a function of duration, suggesting a neurophysiological mechanism for the representation of time in the brain, with the excitatory–inhibitory balance of interactions among distinct subtypes of striatal neuron serving to fine-tune temporal accuracy and precision.

Differential effects of cocaine and ketamine on time estimation: Implications for neurobiological models of interval timing

The present experiment examined the effects of cocaine (0.0 and 15 mg/kg, i.p.) and ketamine (0.0, 10.0 and 15 mg/kg, i.p.) on timing behavior using a 12-s differential reinforcement of low rates (DRL) procedure and a 2- vs. 8-s bisection procedure in rats. DRL (time production) and bisection (time perception) procedures are sensitive to effects of dopaminergic drugs and provide an assessment of the accuracy and precision of interval timing as well as the subjects level of impulsivity. When administered to rats trained on either the DRL or the bisection procedure, cocaine shifted the psychophysical functions leftward relative to control conditions. In contrast, ketamine produced no change in the temporal control of behavior on either procedure. These differential effects of cocaine and ketamine are consistent with previous reports suggesting that dopamine levels in the dorsal striatum, but not in prefrontal cortex, ventral striatum or hippocampal regions, are crucial for the regulation of the speed of an internal clock.

Prenatal choline supplementation alters the timing, emotion, and memory performance (TEMP) of adult male and female rats as indexed by differential reinforcement of low-rate schedule behavior

Choline availability in the maternal diet has a lasting effect on brain and behavior of the offspring. To further delineate the impact of early nutritional status, we examined effects of prenatal-choline supplementation on timing, emotion, and memory performance of adult male and female rats. Rats that were given sufficient choline (CON: 1.1 g/kg) or supplemental choline (SUP: 5.0 g/kg) during embryonic days (ED) 12-17 were trained with a differential reinforcement of low-rate (DRL) schedule that was gradually transitioned through 5-, 10-, 18-, 36-, and 72-sec criterion times. We observed that SUP-females emitted more reinforced responses than CON-females, which were more efficient than both groups of males. In addition, SUP-males and SUP-females exhibited a reduction in burst responding (response latencies <2 sec) compared with both groups of CON rats. Furthermore, despite a reduced level of burst responding, the SUP-males made more nonreinforced responses prior to the DRL criterion as a result of maintaining the previous DRL criterion following transition to a new criterion. In summary, long-lasting effects of prenatal-choline supplementation were exhibited by reduced frustrative DRL responding in conjunction with the persistence of temporal memory in SUP-males and enhanced temporal exploration and response efficiency in SUP-females.

Gene-dose dependent effects of methamphetamine on interval timing in dopamine-transporter knockout mice

The dopamine transporter (DAT) is the major regulator of the spatial and temporal resolution of dopaminergic neurotransmission in the brain. Hyperdopaminergic mice with DAT gene deletions were evaluated for their ability to perform duration discriminations in the seconds-to-minutes range. DAT -/- mice were unable to demonstrate temporal control of behavior in either fixed-interval or peak-interval timing procedures, whereas DAT +/- mice were similar to DAT +/+ mice under normal conditions. Low to moderate-dose methamphetamine (MAP) challenges indicated that DAT +/- mice were less sensitive to the clock-speed enhancing effects of MAP compared with DAT +/+ mice. In contrast, DAT +/- mice were more vulnerable than DAT +/+ mice to the disruptive effects of MAP at high doses as revealed by the elevation of response rate in the right hand tail of the Gaussian-shaped timing functions. Moreover, this treatment made DAT +/- mice functionally equivalent to DAT -/- mice in terms of the loss of temporal control. Taken together, these results demonstrate the importance of dopaminergic control of interval timing in cortico-striatal circuits and the potential link of timing dysfunctions to schizophrenia and drug abuse.

Prenatal choline supplementation increases sensitivity to time by reducing non-scalar sources of variance in adult temporal processing

Choline supplementation of the maternal diet has a long-term facilitative effect on timing and temporal memory of the offspring. To further delineate the impact of early nutritional status on interval timing, we examined effects of prenatal choline supplementation on the temporal sensitivity of adult (6 months) male rats. Rats that were given sufficient choline in their chow (CON: 1.1 g/kg) or supplemental choline added to their drinking water (SUP: 3.5 g/kg) during embryonic days (ED) 12-17 were trained with a peak-interval procedure that was shifted among 75%, 50%, and 25% probabilities of reinforcement with transitions from 18 s-->36 s-->72 s temporal criteria. Prenatal choline supplementation systematically sharpened interval timing functions by reducing the associative/non-temporal response enhancing effects of reinforcement probability on the Start response threshold, thereby reducing non-scalar sources of variance in the left-hand portion of the Gaussian-shaped response functions. No effect was observed for the Stop response threshold as a function of any of these manipulations. In addition, independence of peak time and peak rate was demonstrated as a function of reinforcement probability for both prenatal choline-supplemented and control rats. Overall, these results suggest that prenatal choline supplementation facilitates timing by reducing impulsive responding early in the interval, thereby improving the superimposition of peak functions for different temporal criteria.

Acquisition of “Start” and “Stop” response thresholds in peak-interval timing is differentially sensitive to protein synthesis inhibition in the dorsal and ventral striatum

Time-based decision-making in peak-interval timing procedures involves the setting of response thresholds for the initiation (“Start”) and termination (“Stop”) of a response sequence that is centered on a target duration. Using intracerebral infusions of the protein synthesis inhibitor anisomycin, we report that the acquisition of the “Start” response depends on normal functioning (including protein synthesis) in the dorsal striatum (DS), but not the ventral striatum (VS). Conversely, disruption of the VS, but not the DS, impairs the acquisition of the “Stop” response. We hypothesize that the dorsal and ventral regions of the striatum function as a competitive neural network that encodes the temporal boundaries marking the beginning and end of a timed response sequence.

QUINPIROLE-INDUCED SENSITIZATION TO NOISY/SPARSE PERIODIC INPUT: TEMPORAL SYNCHRONIZATION AS A COMPONENT OF OBSESSIVE-COMPULSIVE DISORDER

Quinpirole-sensitized rats were tested on a discrete-trials 40-s peak-interval procedure using lever pressing as the instrumental response. Although there was no evidence of rhythmical activity in lever pressing, periodic output was observed in a secondary response (food-cup entries) during the inter-trial interval following the delivery of reinforcement on fixed-interval trials, but not during unreinforced probe trials. This repetitive pattern of behavior with a 40-s period points to the primacy of reinforcement as a time marker and an increased tendency to synchronize to noisy and sparse periodic input as a result of reduced inhibitory control in cortico-striatal circuits following chronic quinpirole administration. Parallels between quinpirole-induced rhythmical behavior and the repetitive motor habits frequently observed in obsessive-compulsive disorder are discussed.

“Speed” Warps Time: Methamphetamines Interactive Roles in Drug Abuse, Habit Formation, and the Biological Clocks of Circadian and Interval Timing

The indirect dopamine (DA) agonist methamphetamine (MAP) is evaluated in terms of its impact on the speed of temporal processing across multiple time scales involving both interval and circadian timing. Behavioral and neuropharmacological aspects of drug abuse, habit formation, neurotoxicity, and the potential links between interval and circadian timing are reviewed. The view that emerges is one in which the full spectrum of MAP-induced effects on timing and time perception is both complex and dynamic in as much as it involves DA-glutamate interactions and gene expression within cortico-striatal circuitry spanning oscillation periods ranging from milliseconds to multiple hours. The conclusion is that the psychostimulant properties of MAP are very much embedded within the context of temporal prediction and the anticipation of reward.

Prenatal-choline supplementation differentially modulates timing of auditory and visual stimuli in aged rats

Choline supplementation of the maternal diet has a long-term facilitative effect on the interval-timing ability and temporal memory of the offspring. Here, we examined whether prenatal-choline supplementation has modality-specific effects on duration discrimination in aged (20 mo) male rats. Adult offspring of rats that were given sufficient choline in their chow (CON: 1.1 g/kg) or supplemental choline added to their drinking water (SUP: 3.5 g/kg) during embryonic days (ED) 12-17 were trained and tested on a two-modality (auditory and visual signals) duration bisection procedure (2 s vs. 8 s). Intensity (high vs. low) of the auditory and visual timing signals was systematically manipulated across test sessions such that all combinations of signal intensity by modality were tested. Psychometric response functions indicated that prenatal-choline supplementation systematically increased sensitivity to auditory signals relative to visual signals, thereby magnifying the modality effect that sounds are judged to be longer than lights of equivalent duration. In addition, sensitivity to signal duration was greater in rats given prenatal-choline supplementation, particularly at low intensities of both the auditory and visual signals. Overall, these results suggest that prenatal-choline supplementation impacts interval timing by enhancing the differences in temporal integration between auditory and visual stimuli in aged subjects.

Zebrafish forebrain and temporal conditioning

The rise of zebrafish as a neuroscience research model organism, in conjunction with recent progress in single-cell resolution whole-brain imaging of larval zebrafish, opens a new window of opportunity for research on interval timing. In this article, we review zebrafish neuroanatomy and neuromodulatory systems, with particular focus on identifying homologies between the zebrafish forebrain and the mammalian forebrain. The neuroanatomical and neurochemical basis of interval timing is summarized with emphasis on the potential of using zebrafish to reveal the neural circuits for interval timing. The behavioural repertoire of larval zebrafish is reviewed and we demonstrate that larval zebrafish are capable of expecting a stimulus at a precise time point with minimal training. In conclusion, we propose that interval timing research using zebrafish and whole-brain calcium imaging at single-cell resolution will contribute to our understanding of how timing and time perception originate in the vertebrate brain from the level of single cells to circuits.