Neuroanatomical localization of an internal clock: A functional link between mesolimbic, nigrostriatal, and mesocortical dopaminergic systems

Abstract

The effects of selective dopamine (DA) depleting lesions with 6-hydroxydopamine microinjection into the SN, CPu, and NAS, as well as radiofrequency lesions of the CPu on the performance characteristics of rats trained on a single-valued 20-s peak-interval (PI) timing procedure or a double-valued 10-s and 60-s PI procedure were evaluated. A double dissociation in the performance of duration discriminations was found. Rats with CPu lesions were unable to exhibit temporal control of their behavior suggesting complete insensitivity to signal duration but were able to show discrimination of the relative reward value of a signal by differentially modifying their response rates appropriately. In contrast, rats with NAS lesions were able to exhibit temporal control of their behavior by differentially modifying their response rates as a function of signal duration(s), suggesting no impairment of sensitivity to signal duration, but were unable to show discrimination of the relative reward value of a signal.

Introduction

The neural pathways essential for the behavioral effects mediated by the neurotransmitter dopamine (DA) can be divided into three major categories based on the locations of the DA cells bodies in the ventral tegmental area (VTA) and substantia nigra (SN) and their sites of projection. These target sites are primarily composed of the nucleus accumbens (NAS), the prefrontal cortex (PFC), and the caudate–putamen (CPu)—which have been termed the mesolimbic, mesocortical, and nigrostriatal DA systems, respectively. Historically, the nigrostriatal DA system has been considered to play a major role in motor function (Marsden, 1982), whereas the mesocortical and mesolimbic DA systems have been associated with working memory and the quantification of reward, respectively (e.g., Abi-Dargham et al., 2002, Au-Young et al., 1999, Kelley and Berridge, 2002, Nicola et al., 2000, Phillips et al., 2004, Schultz et al., 1997, Smith-Roe and Kelley, 2000). The view that the nigrostriatal DA system is exclusively involved in motor function, however, has evolved over time and it is now generally accepted that it also contributes to attentional set switching, error prediction regarding the occurrence of rewards, and timing and time perception (e.g., Dreher and Grafman, 2002, Gibbon et al., 1997, Meck and Benson, 2002, Middleton and Strick, 2000, Pastor et al., 1992).

Of particular interest is the observation that the CPu and NAS receive dense dopaminergic innervation from mesencephalic A9 and A10 neurons (e.g., Moore et al., 1998, Ungerstedt, 1971), and pharmacologically distinct DA receptor subtypes (e.g., D1 and D2) have been identified that mediate different behaviors (e.g., Bunney, 1979, Cox and Waszczak, 1990, Dawson et al., 1985, Fowler et al., 1984, Kebabian and Calne, 1979, LaHoste and Marshall, 1990, Robertson and Robertson, 1987, Walters et al., 1987, White, 1987). In rats, discrete stimulation or blockade of telencephalic DA receptors by intracerebral administration of DA agonists or antagonists mimics the effects of these agents when given peripherally. For example, apomorphine induces stereotyped motor behavior whether it is injected systemically or placed directly into the CPu (e.g., Giménez-Llort et al., 2005, Ungerstedt et al., 1969) and rats will self-administer amphetamine either systemically or directly into the NAS (e.g., Hoebel et al., 1983, Ikemoto et al., 2005).

The large-scale inactivation of DA function with DA receptor antagonists and midbrain neurotoxin lesions results in a behavioral syndrome that is very similar to Parkinson's disease in man. Rats show akinesia, catalepsy, and are impaired in performance in a variety of behavioral situations that may involve the timing of stimulus events (Fibiger et al., 1974, Gibbon et al., 1997, Koob et al., 1984). More specific impairments of DA systems induced by microinjection of DA receptor antagonists or by neurotoxin terminal lesions have resulted in differential effects on behavior depending on the locus of the DA system and the type of behavior studied. For example, depletion of DA in the CPu, but not in the NAS, impairs reaction-time performance in a simple reaction-time task (e.g., Amalric and Koob, 1987, MacDonald and Meck, 2004), impairs a conditional discrimination of temporal frequency (Robbins et al., 1990), and impairs simple stimulus–response (S-R) associations in a variety of tasks, including the conditioned emotional response paradigm (White, 1989a). In contrast, neurotoxin-induced lesions of DA neurons in the NAS, but not the CPu, attenuates amphetamine self-administration and the enhanced responding to reward-related stimuli produced by intra-accumbens amphetamine injections (Lyness et al., 1979, Taylor and Robbins, 1986) as well as the motor stimulation induced by this drug (Kelly and Iversen, 1976). Furthermore, the differential behavioral effects of amphetamine microinjections into striatal sub-regions have been extensively mapped, suggesting that the NAS, but not the CPu, is the primary site underlying the registration of reward (Kelley and Delfs, 1991). It has also been demonstrated that NMDA glutamate receptors and dopamine D1 and D2 receptors interact in the regulation of signal transduction and induction of transcription factors in the basal ganglia for the expression of behavior (e.g., Radulovic et al., 2000).

One hypothesis that has been suggested to explain this overall pattern of results is that the ventral striatum (subsuming the NAS) is implicated in the processes of incentive motivation and the determination of the rewarding (approach-eliciting) properties of a stimulus, both of which contribute to associative measures of response strength (e.g., Robbins et al., 1990, White, 1989b); whereas the dorsal striatum (subsuming the CPu) is implicated in processes of sensorimotor integration, as exemplified by simple S-R associations that are necessary for planning, initiating, and coordinating a conditioned movement (real or imaginary) to a sensory cue (Amalric and Koob, 1987, Graybiel, 1990, Robbins and Everitt, 1992, Robbins et al., 1990, White, 1989a).

In order to investigate the contributions of these interacting DA systems to interval-timing behavior, a set of experimental procedures have been developed that can be used to separate the different psychological processes involved in timing and time perception (Church, 1984, Church, 1989, Meck and Church, 1982, Meck et al., 1987, Paule et al., 1999, Penney et al., 1996, Penney et al., 2000). For example, in the basic discrete-trial fixed-interval (FI) procedure, each trial begins with a signal onset. The animal is free to respond at any time during the trial, but only the first response after a trained temporal criterion (e.g., 20 s) is reinforced. The peak-interval (PI) procedure, a variation of the FI procedure, provides independent measures of several processes involved in duration discriminations (e.g., Church et al., 1991, Church et al., 1994, Miller et al., 2006, Rakitin et al., 1998, Roberts, 1981). Reinforced trials are identical to those of the FI procedure. For other probe trials, however, the signal continues much longer than the trained temporal criterion, and no reinforcement is made available. During these non-reinforced probe trials, the animal's response rate increases as a function of the signal duration until a point near the time that reinforcement is available in the FI procedure, when it decreases in a fairly symmetrical manner when plotted on a linear time scale. The mode of the Gaussian-shaped response rate function is called the peak time and it represents the time during the signal presentation that animals maximally expect reinforcement to be made available. The response rate at that time is called the peak rate and it represents the subject's level of motivation and/or the incentive value of a particular signal. Peak time and peak rate are considered to be independent measures to the extent that treatments may affect one of these measures without affecting the other (Roberts, 1981). A discrimination index (DI) can also be calculated by dividing the peak or maximal response rate by the mean response rate. This measure provides a measure of the animal's sensitivity to signal duration, values near 1.0 would indicate that the subject was highly insensitive to the temporal properties of the signal, perhaps indicating that the mechanism(s) responsible for timing had been damaged.

Although there exists considerable information on the function of the central dopaminergic projections in motor and motivational processes, only recently has research been directed to the exploration of the specific roles of DA and glutamate in timing and time perception (e.g., Abner et al., 2001, Buhusi, 2003, Buhusi and Meck, 2002, Cevik, 2003a, Cheng et al., in press, Cevik, 2003b, Drew et al., 2003, Gibbon et al., 1997, Maricq and Church, 1983, Matell et al., 2003, Matell et al., 2006, Matell et al., in press, Meck, 1983, Meck, 1986, Meck, 1988a, Meck, 1988b, Meck, 1996, Meck, 2003, Meck and Benson, 2002, Miller et al., 2006, Neil and Herndon, 1978, Ohyama et al., 2000, Rammsayer, 2006, Lustig and Meck, 2005, MacDonald and Meck, 2005). These questions, apart from their intrinsic importance, are currently of considerable interest, given the growing evidence of cognitive deficits in Huntington's disease and Parkinson's disease (e.g., Canavan et al., 1989, Harrington and Haaland, 1999, Lawrence et al., 1998), which are closely related to neuronal damage in the striatum and substantia nigra, respectively. Of particular interest are the observations that when Parkinson's disease patients are trained to perform in PI timing procedures developed for human participants (e.g., Rakitin et al., 1998), they show evidence of temporal memory dysfunctions and a slowing of time perception when tested off of their levodopa (l-DOPA) medication. In contrast, the same PD patients exhibit relatively normal temporal cognition when tested on their l-DOPA medication suggesting an important role of SNc DA neurons in timing and time perception in the seconds to minutes range (e.g., Malapani et al., 1998, Malapani et al., 2002).

In order to investigate the role of DA pathways in timing behavior, the present study examined the behavioral effects of DA depletion in rats produced by radiofrequency or 6-hydroxydopamine (6-OHDA) neurotoxin lesions of the CPu, NAS, or SN on duration discriminations trained using the PI timing procedure. In addition, we examined whether l-DOPA administration would selectively restore interval-timing behavior to rats with CPu or SN lesions.