Dopamine Modulates Striato-Frontal Functioning during Temporal Processing

With genesis in the ventral tegmental area and the substantia nigra pars compacta (SNc), the neurotransmitter dopamine influences brain function through three distinct pathways: the nigrostriatal, mesolimbic, and mesocortical. Dopamine plays a crucial role in a range of functions, for example: reward-related processing (Schultz et al., 1997) and reinforcement learning (Montague et al., 1996; Frank and Claus, 2006; Frank et al., 2007), working memory (Brozoski et al., 1979; Kimberg et al., 1997; Lustig et al., 2005; Cools et al., 2008), and motor function, including determining the vigor of actions (e.g., Niv et al., 2007; Smith and Villalba, 2008). Here our focus is on the role of dopamine in temporal processing, a less commonly recognized function (Meck, 1996; Buhusi and Meck, 2005; Meck et al., 2008; Jones and Jahanshahi, 2009; Allman and Meck, 2011; Coull et al., 2011 – but see Hata, 2011). A growing body of research has sought to characterize the role of dopamine in interval timing, which can be broadly thought of as motor and perceptual timing in the millisecondsand seconds-range. The influence of dopamine on interval timing has been demonstrated in pharmacological studies both with animals (Drew et al., 2003; Matell et al., 2006; Cheng et al., 2007; Meck et al., 2011) and humans (Rammsayer, 1993, 1997, for reviews see Meck et al., 2008; Jones and Jahanshahi, 2009; Coull et al., 2011). Using the peak-interval procedure, in which a learnt temporal interval is reproduced, animal research has established that dopamine agonists lead to the interval being underestimated, whereas dopamine antagonists lead to overestimation (e.g., Drew et al., 2003; Matell et al., 2004, 2006; MacDonald and Meck, 2005). These results have been interpreted as the effect of dopamine agonists and antagonists on speeding and slowing an “internal clock,” respectively. Lesions to the SNc and the caudate–putamen (CPu) both impair temporal control on the task, while rats with lesions to the nucleus accumbens show no evidence of disrupted temporal performance (Meck, 2006a). This pattern implicates the nigrostriatal (substantia nigra–dorsal striatum) dopamine pathway in interval timing. Further, levodopa, a precursor to dopamine that is commonly used to treat Parkinson’s disease (PD), restores timing performance in rats with lesions to the SNc but not in those with lesions to the CPu, which may reflect the distinct roles of these structures in temporal calculation (Meck, 2006a). Work on healthy humans has established that haloperidol, a nonspecific D2 receptor antagonist, attenuates both millisecondsand seconds-range perceptual timing (comparing the length of two stimuli), whereas remoxipride, which blocks D2 receptors in the mesolimbic and mesocortical tracts, only impairs secondsrange timing (Rammsayer, 1997). These results were considered to support the role of the nigrostriatal system in millisecondsrange timing. More recently, Wiener et al. (2011) were able to apply a more targeted investigation by studying the effect of different single-nucleotide genetic polymorphisms on perceptual timing. Participants with a polymorphism affecting the density of striatal D2 receptors showed increased variability for millisecondsbut not seconds-range perceptual timing. Conversely, participants with a polymorphism that affects an enzyme (COMT) influencing prefrontal dopamine showed greater variability only in the seconds-range. Thus, these data suggest a double dissociation, with the nigrostriatal pathway being important for milliseconds-range perceptual timing and the mesocortical pathway being important for seconds-range perceptual timing. Parkinson’s disease is a movement disorder associated with degeneration of dopaminergic neurons in the SNc. There is now a body of evidence that motor and perceptual timing within the millisecondsand seconds-range are impaired in PD (see Jones and Jahanshahi, 2009; Allman and Meck, 2011; Coull et al., 2011). Dopaminergic medication often improves performance on perceptual (e.g., Pastor et al., 1992a; Malapani et al., 1998) and motor timing tasks (e.g., Pastor et al., 1992b; O’Boyle et al., 1996) in patients with PD; although the pattern of effects (e.g., whether accuracy or variability is affected) is variable and significant effects are not always found (e.g., Pastor et al., 1992b; O’Boyle et al., 1996; Jones et al., 2008; Harrington et al., 2011b). The variable findings might relate to the insufficiency of dopaminergic medication for fully restoring striato-frontal function (Harrington et al., 2011b), or to the inadequacy of medication withdrawal and the lingering effects of long-acting medication in patients tested “off” medication. Difficulties with interval timing have also been observed in other disorders that are associated with dopaminergic dysfunction, including schizophrenia and attentiondeficit/hyperactivity disorder (ADHD; see Jones and Jahanshahi, 2009; Allman and Meck, 2011). There is consensus from imaging studies that the basal ganglia, particularly the dorsal striatum, are engaged during interval timing (e.g., Rao et al., 2001; Harrington et al., 2004, 2010, 2011a,b; Jahanshahi et al., 2006, 2010; Coull et al., 2008, for reviews see Meck et al., 2008; Jones and Jahanshahi, 2009; Coull et al., 2011). The basal ganglia are closely connected to the cortex through a series of striato-cortical loops (Alexander et al., 1986). Recording from neural ensembles in animal studies supports the role of both striatal and cortical regions in encoding temporal intervals (e.g., Matell et al., 2003, 2011; Lebedev et al., 2008; Höhn et al., 2011), whilst cortical lesions in rats attenuate temporal performance (Meck, 2006b). Further, patients with cortical lesions and healthy individuals with short-lasting TMS-induced disruption to cortical function demonstrate difficulties on temporal