Matthew S. Matell - US grants

Previous work has demonstrated a relationship between the internal clock used for duration perception and reinforcement rate. As such, a full understanding of the changes in perceived event duration due to psychostimulant administration, as well as the mechanisms underlying these changes, are crucial to the formation of successful strategies of prevention and treatment of drug abuse. The current proposal seeks to understand the neural mechanisms underlying psychostimulant-induced perceptual changes in interval timing. This will be accomplished by simultaneous extracellular recording of multiple neurons, in multiple brain nuclei, in a rat on and off and off psychostimulants (e.g., methamphetamine and cocaine) while performing in a temporal-production task. Experiment 1 investigates the spatiotemporal patterns of neural firing during timing behavior within the substantia nigra pars compacta, caudate-putamen, and medial prefrontal cortex (areas believed to underlie duration perception). The changes in neural activity patterns, before and after stimulant administration, will be matched to observed behavioral changes. Experimetn 2 is designed to investigate the dynamic changes in the neural firing patterns during chronic stimulant administration. Previous work has demonstrated a specific pattern of changes in temporal perception during chronic stimulant administration which is qualitatively similar to descriptions of tolerance following withdrawal from chronic stimulants. Utilizing differing routes of chronic methamphetamine and cocaine administration: continuous vs. intermittent, the development of behavioral and pharmacodynamic sensitization an tolerance can be manipulated. Ensemble recording of the hypothesized timing circuit during this development will allow investigation of the underlying mechanisms causing these changes. Finding a specific relationship between changes in time perception and chronic stimulant-induced tolerance will implicate the use of treatment strategies designed to alter duration memory in order to counter the effects of these stimulant-induced changes in perceived time.

DESCRIPTION:(provided by applicant) The role of the basal ganglia in movement related disorders, such as Parkinson's disease, has been well documented. The overall movement deficits of these patients are partly due to difficulties in the sequencing of motor actions, and these deficits can be construed as separate from their elemental motor difficulties. As symptoms of Parkinson's patients include deficits on over-learned movement sequences, the mechanisms underlying these normally "automated" behaviors may be more closely related to innate stereotypical sequences, than to the arbitrary learned sequences typically used in animal models of sequencing. Indeed, experimental results confirm this notion. While similarities between the representation of well-learned and innate sequences are considerable, they are not complete. The goal of the present proposal is to understand the neural mechanisms underlying both types of sequential motor control by recording from ensembles of striatal neurons in rats while they perform natural or learned motor sequences. Neural activity, anatomical area, and neuronal interactions will be compared and contrasted across these two motor sequences. The ability of dopaminergic drugs to alter both types of sequential behavior and the related neuronal activity will also be evaluated, in order to further develop treatment strategies for Parkinson's disease.

DESCRIPTION (provided by applicant): The perception of time in the seconds to minutes range, interval timing, is fundamental to behavior. Alterations in temporal perception result from the acute and chronic administration of a variety of drugs, and such alterations may play a part in the use and abuse of these drugs. Understanding the psychological and neural mechanisms of interval timing, as well as the changes brought on by drug use, may provide important insights into the range of processes that underlie drug use. While previous work has suggested a role for cortico-striatal-thalamic loops in interval timing, the specific computations performed by these brain structures remain unknown. Models of interval timing have proposed that cortical activity serves as the source of a temporal signal that is integrated by the striatum to estimate time. However, the specific pattern of this cortical signal is debated, and may be subserved by oscillatory mechanisms, linear or non-linear increases/decreases in firing rates, temporally specific peak functions, or other, more complex, firing patterns. The present proposal will investigate the role of frontal cortex in interval timing, through the use of ensemble extracellular recording techniques in rats performing an interval timing task. Specifically, rats will be trained to nosepoke at 2 distinct times, 5 and 30 seconds after onset of a tone signal. They will also be trained to nosepoke to receive food at an unpredictable time in response to a different tone. Following training, electrodes will be chronically implanted into dorsal medial frontal cortex and dorsal anterior striatum. Activity from single neurons will be evaluated as a function of time in the trial to determine the overall firing pattern (ramp, peak, oscillation). Firing rates will also be compared across different times of equivalent behavior (i.e., 5 sec vs. 30 sec) or without a temporally-specific expectation (random ratio schedule) to evaluate whether the degree to which frontal cortex represents time, general expectancy, or motor preparation. Changes in firing rates/patterns following methamphetamine administration will be investigated.

[unreadable] DESCRIPTION (provided by applicant): The perception of time in the seconds to minutes range, interval timing, is fundamental to behavior. Alterations in temporal perception result from the acute and chronic administration of a variety of drugs, and such alterations may play a part in the use and abuse of these drugs. For instance, dopaminergic drugs of abuse, such as methamphetamine and cocaine, cause alterations in the perception of time, such that time feels as though it is passing more slowly. This effect has been associated with an increase in the speed of an internal clock used for timing and time perception. Understanding the psychological and neural mechanisms of interval timing, as well as the changes brought on by drug use, may provide important insights into the range of processes that underlie drug use. For instance, understanding where and how dopamine is altering the perception of time may allow development of specific treatment strategies. While previous work has suggested a role for cortico-striatal-thalamic loops in interval timing, the specific computations performed by these brain structures remain unknown. A recent model of interval timing has proposed that cortical activity serves as the source of a temporal signal that is integrated by the striatum in order to estimate time. As dopaminergic drugs can directly alter neural activity in both cortical and striatal regions, it remains unclear where in the brain these drugs are exerting their effects. The current proposal will determine the location(s) in which dopamine modulates the speed of the internal clock. Specifically, we propose to microinject pharmacological agents that will increase or decrease the activity of the primary dopaminergic nuclei of the midbrain, (i.e., the substantia nigra and/or ventral tegmental area), and investigate the effects of these alterations on interval timing. These effects will be evaluated by training subjects to respond at specific times for food reinforcement, and evaluating the change in response times following drug administration into specific brain regions. Following an assessment of the effects of acute administration, the impact of chronic infusion of pharmacological agents into these nuclei will be assessed, as previous work using chronic systemic administration has shown that organisms adapt to a continually altered perception of time. By evaluating where these adaptations to chronic alterations in clock speed occur, we will better understand whether timing processes follow similar adaptation patterns as drug reinforcement and locomotor behaviors. Drugs of abuse have been shown to alter the perception of time in both an acute and chronic fashion. Determining the neural locations of these changes in timing, as well as their adaptation following chronic use will provide important information regarding the array of neural changes involved in the use, abuse, and dependence of drugs. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The perception of time allows individuals to adapt to the temporal regularities of environmental events. It also plays a direct role in the choices we make. Delay discounting refers to the decrease in subjective value of a potential commodity (e.g., money, drugs, food) as a function of the expected delay until acquisition of that commodity, and numerous experiments have demonstrated "irrational" preference for the receipt of a small reward at a shorter delay over a larger reward at a longer delay. The rate of discounting has been shown to differ in individuals with substance abuse problems, and is thought to contribute to the short-sighted choice to take drugs. Importantly, changes in discounting rate can be understood as resulting from changes in temporal expectation, as a consequence of drug-induced alterations in temporal perception and temporal memory. Specifically, it has been shown that a number of abused drugs, including both psychostimulants and hallucinogenics, alter the perception of time. The global hypothesis underlying the proposed project is that memories associated with drug-present states are combined with drug-free memories when generating temporal expectations. These synthesized temporal expectations would then lead to alterations in anticipated value of possible choices (due to their impact on discounting), and may contribute to "impulsive" behaviors such as drug use. We have recently reported that rats trained with two component cues that each indicate food availability after a different interval has elapsed (e.g., tone = 10 sec and light = 20 sec) will demonstrate that they expect food at the average of these times (15s) when presented with the simultaneous compound cue (tone + light). We refer to this phenomenon as the synthesis of incongruent temporal information (SITI). Of particular relevance to the present project, we have also recently demonstrated that temporal memory synthesis can occur across drug states. Specifically, rats trained to expect food availability at 10s following saline adminstration, but 20s following amphetamine administration (0.5 mg/kg) will demonstrate temporal expectancy at 15s when tested, without feedback, following an intermediate dose of amphetamine (0.25 mg/kg). These data indicate that the memories associated with different drug states can be combined at retrieval to generate temporal expectancies that are maladaptive. Numerous questions remain about the nature of temporal memory synthesis across drug-states, as well as the conditions that promote SITI in drug naove subjects. The present application seeks to investigate the synthesis of drug state-associated temporal memories (Aim 1), investigate conditions related to incentive value that appear to moderate the incidence of SITI (Aim 2), develop procedures allowing an investigation of SITI in preference/choice (Aim 3), and investigate a novel hypothesis related to altered expectation due to drug-induced bias in temporal memory sampling. The work proposed here has significant potential to increase our understanding of the temporal expectations resulting from drug use that may influencing choice. PUBLIC HEALTH RELEVANCE: Temporal expectations are at the heart of delay discounting (the decrease in anticipated value of a commodity as a function of the expected delay until its receipt), and both temporal perception and the rate of delay discounting have been shown to be altered following acute and chronic drug use. We have shown that temporal memories formed during drug use can be averaged with temporal memories formed in drug-free states, and hypothesize that these combinatorial, maladaptive expectations will impact choice via their influence on anticipated value. The current project examines temporal memory synthesis across drug states, and the involvement of memory synthesis in choice behavior.

Instead of asking ?How is perceived time altered by drug administration??, in order to better understand drug addiction, this proposal addresses the question in reverse, asking ?How do temporal expectations directly influence the processes underlying addiction??. A number of drug addiction models have identified different underlying processes that contribute to drug dependence, including magnified incentive motivation processes (?wanting?, Robinson and Berridge,1993) dampened hedonic responsiveness ('liking', Koob and Le Moal 2001), and habitual drug seeking (Everitt, Dickinson et al. 2001). These models concur that drug-associated cues promote drug seeking. While it has been well established that the time between a conditioned cue and its predicted outcome moderates the magnitude and timing of conditioned behavior, addiction models essentially ignore the contribution of these implicit temporal expectations. The guiding hypothesis of the proposed project is that the time between drug cues and drug intake influences the magnitude and timing of the psychological and physiological processes that underlie addiction. Understanding the temporal dynamics of these addiction-related processes may be of critical importance to applied treatment options for substance addicted patients, for example, by optimizing ?schedule reduction? treatment schedules to the temporal fluctuations in drug craving (Cinciripini, Lapitsky et al. 1995). Specifically, we hypothesize that drug ?wanting? induced by conditioned drug-associated stimuli will be maximal at the time that drug administration usually occurs, whereas drug ?liking? will be minimal at the time that drug administration usually occurs. We propose three aims to examine the temporal dynamics of motivation and hedonic evaluation in rodents trained to expect temporally predictable reinforcement (US) in response to Pavlovian conditioned cues (CS). In Aim 1, we will investigate whether hedonic evaluation is modulated by time, by using a negative anticipatory contrast paradigm which provides an assessment of changes in hedonic palatability as a function of expectation. We hypothesize that ?liking? will be diminished in a dynamic manner that reflects the expected time of a future reward. Such results would support our hypothesis that temporal expectations shape hedonic experience. In Aim 2, we will examine cue-induced ?wanting? using the Pavlovian-Instrumental Transfer paradigm. We predict that the temporally specific relations learned during the Pavlovian phase will be reflected in the strength of instrumental responding when the CS is presented (i.e., temporal transfer), thereby supporting the hypothesis that conditioned motivation can be temporally dynamic, rather than static. In Aim 3, we examine the role of temporal expectations on ?wanting? and ?liking? when an abused drug is the expected outcome (i.e., nicotine or ethanol). In addition, we will concurrently record heart rate and body temperature to evaluate whether compensatory opponent processes of physiological systems are impacted by the expected time of drug availability.