Christopher J. MacDonald

Systems-level integration of interval timing and reaction time.

Reaction time (RT) procedures are a prominent tool for the study of information processing by humans and other animals. The interpretation of how RT changes after manipulating the appropriate experimental variables has contributed to the contemporary understanding of a variety of cognitive constructs, including attention and memory. With the use of properly designed tasks, evaluating how RT is modified in response to various neural perturbations has become common within the realms of behavioral and cognitive neuroscience. One interesting observation made during both human and animal RT experiments is that the RT to a signal often speeds-up as more time is allotted to prepare for the signals onset-referred to as the preparatory interval (PI) effect. In the human RT literature, the PI effect has been used as evidence for time estimation playing a fundamental role in the determination of RT. On the other hand, our theoretical understanding of time estimation remains largely divorced from the RT findings in the animal cognition literature. In order to bridge these different perspectives, we provide here a review of the behavioral parallels between RT and interval-timing experiments. Moreover, both the PI effect and interval timing are shown to be jointly influenced by neuropathologies such as Parkinsons disease in humans or dopamine-depleting brain lesions in experimental animals. The primary goal of this review is to consider human and animal RT experiments within the broader context of interval timing. This is accomplished by first integrating human RT theory with scalar timing theory-the leading model of interval timing. Following this, both RT and interval timing are discussed at a brain systems level insofar as these two processes share common neural substrates. Our conclusion is that interval timing and RT processes are in fact two sides of the same coin.

Distinct Hippocampal Time Cell Sequences Represent Odor Memories in Immobilized Rats

Previous studies have revealed the existence of hippocampal “time cells,” principal neurons in CA1 that fire at specific moments in temporally organized experiences. However, in all these studies, animals were in motion; and so, temporal modulation might be due, at least in part, to concurrent or planned movement through space or self-generated movement (path integration). Here the activity of hippocampal CA1 neurons was recorded in head-fixed and immobile rats while they remembered odor stimuli across a delay period. Many neurons selectively and reliably activated at brief moments during the delay, as confirmed by several analyses of temporal modulation, during a strong ongoing θ rhythm. Furthermore, each odor memory was represented by a temporally organized ensemble of time cells composed mostly of neurons that were unique to each memory and some that fired at the same or different moments among multiple memories. These results indicate that ongoing or intended movement through space is not necessary for temporal representations in the hippocampus, and highlight the potential role of time cells as a mechanism for representing the flow of time in distinct memories.

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.

Amygdala Inactivation Reverses Fear's Ability to Impair Divided Attention and Make Time Stand Still

The cognitive and emotional effects of amygdala or frontal cortex lesions were compared in rats trained to time both a 50-s visual signal paired with food and an embedded 10- or 20-s auditory signal that was paired with either appetitive (food) or aversive (footshock) outcomes. When both auditory and visual signals were paired with food, control and amygdalar-lesioned rats were able to divide attention and to time both signals simultaneously, whereas when the embedded auditory signal was paired with footshock, control rats were impaired in their ability to divide attention and were able to time only one signal at a time. In contrast, amygdalar inactivation blocked this fear-related impairment and allowed rats to time both signals simultaneously, whereas rats with frontal cortex lesions demonstrated sequential processing under all conditions. These results support the proposal that the frontal cortex exerts executive control over the allocation of attentional resources, but that under stressful conditions the amygdala is crucial for the emergence of fear-evoked increments in selective attention leading to deficits in the ability to time 2 or more signals simultaneously.

A Unified Mathematical Framework for Coding Time, Space, and Sequences in the Hippocampal Region

The medial temporal lobe (MTL) is believed to support episodic memory, vivid recollection of a specific event situated in a particular place at a particular time. There is ample neurophysiological evidence that the MTL computes location in allocentric space and more recent evidence that the MTL also codes for time. Space and time represent a similar computational challenge; both are variables that cannot be simply calculated from the immediately available sensory information. We introduce a simple mathematical framework that computes functions of both spatial location and time as special cases of a more general computation. In this framework, experience unfolding in time is encoded via a set of leaky integrators. These leaky integrators encode the Laplace transform of their input. The information contained in the transform can be recovered using an approximation to the inverse Laplace transform. In the temporal domain, the resulting representation reconstructs the temporal history. By integrating movements, the equations give rise to a representation of the path taken to arrive at the present location. By modulating the transform with information about allocentric velocity, the equations code for position of a landmark. Simulated cells show a close correspondence to neurons observed in various regions for all three cases. In the temporal domain, novel secondary analyses of hippocampal time cells verified several qualitative predictions of the model. An integrated representation of spatiotemporal context can be computed by taking conjunctions of these elemental inputs, leading to a correspondence with conjunctive neural representations observed in dorsal CA1.

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.

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.

Interaction of raclopride and preparatory interval effects on simple reaction time performance.

In a series of three experiments, simple reaction time (RT) was characterized with respect to a variable preparatory interval (PI) in order to investigate the relationship between interval timing and RT. In Experiment 1, it was shown that RT decreases as a function of PI and that this effect varies with amount of training. In Experiment 2, RT was shown to increase during probe trials that used a novel 6.25s PI, suggesting that the specific durations of the PIs encoded during initial training contribute to the PI effect on RT. In Experiment 3, 100 microg/kg i.p. of raclopride proportionally slowed RT as a function of the PI. These results are discussed within the context of neuropsychological models of interval timing and support an underlying role for cortico-striatal dopaminergic function in temporal processing and simple RT measurements.

Retrospective and Prospective Views on the Role of the Hippocampus in Interval Timing and Memory for Elapsed Time

The overlap of neural circuits involved in episodic memory, relational learning, trace conditioning, and interval timing suggests the importance of hippocampal-dependent processes. Identifying the functional and neural mechanisms whereby the hippocampus plays a role in timing and decision-making, however, has been elusive. In this article we describe recent neurobiological findings, including the discovery of hippocampal ‘time cells’, dependency of duration discriminations in the minutes range on hippocampal function, and the correlation of hippocampal theta rhythm with specific features of temporal processing. These results provide novel insights into the ways in which the hippocampus might interact with the striatum in order to support both retrospective and prospective timing. Suggestions are also provided for future research on the role of the hippocampus in memory for elapsed time.