Prefrontal D1 dopamine signaling is required for temporal control

Abstract

Temporal control, or how organisms guide movements in time to achieve behavioral goals, depends on dopamine signaling. The medial prefrontal cortex controls many goal-directed behaviors and receives dopaminergic input primarily from the midbrain ventral tegmental area. However, this system has never been linked with temporal control. Here, we test the hypothesis that dopaminergic projections from the ventral tegmental area to the prefrontal cortex influence temporal control. Rodents were trained to perform a fixed-interval timing task with an interval of 20 s. We report several results: first, that decreasing dopaminergic neurotransmission using virally mediated RNA interference of tyrosine hydroxylase impaired temporal control, and second that pharmacological disruption of prefrontal D1 dopamine receptors, but not D2 dopamine receptors, impaired temporal control. We then used optogenetics to specifically and selectively manipulate prefrontal neurons expressing D1 dopamine receptors during fixed-interval timing performance. Selective inhibition of D1-expressing prefrontal neurons impaired fixed-interval timing, whereas stimulation made animals more efficient during task performance. These data provide evidence that ventral tegmental dopaminergic projections to the prefrontal cortex influence temporal control via D1 receptors. The results identify a critical circuit for temporal control of behavior that could serve as a target for the treatment of dopaminergic diseases.T emporal control, or guiding movements in time to achieve behavioral goals, is a crucial function of mammalian nervous systems. This process depends on the integrated activity of corticostriatal systems (1-3) and requires intact dopaminergic signaling (4). Patients with Parkinson disease with depleted dopamine have dramatically impaired temporal control (5). Despite these data, the neural circuitry influenced by dopamine during temporal computations is not understood.Temporal control can be carefully studied using an intervaltiming task (Fig. 1) (6), in which participants estimate a discrete interval of time. In rodents, disrupting nigrostriatal dopamine (7) in the dorsal, but not the ventral, striatum (8) impairs temporal control. Overexpression of D2 receptors in the striatum also diminished temporal control of behavior (9). A brain region that organizes goal-directed behavior is the medial prefrontal cortex (10, 11). In metabolic imaging studies, hypoactivity in this area is correlated with impaired executive function in Parkinson disease (12). Medial prefrontal regions are activated during human brain imaging of fixed-interval timing tasks (13). In rodents, the medial prefrontal cortex has single neurons that encode the passage of time (14) and exerts topdown control over other brain areas to control movements in time (11). Medial prefrontal regions receive prominent dopaminergic input from the midbrain ventral tegmental region (8), which loses dopamine neurons in Parkinson disease (15)(16)(17). Dysfunction of this system may contribute to cog...

Cannabinoid Receptor Activation Shifts Temporally Engendered Patterns of Dopamine Release

“…Previous accounts of interval timing proposed that the brain contains a neural timer that resets to zero by the occurrence of reinforcement (Gallistel and Gibbon, 2000;Gibbon, 1977) and that dopamine is critically involved in second-to-second estimation Buhusi and Meck, 2005;Coull et al, 2010;Coull et al, 2012;Matell and Meck, 2000;Meck et al, 2008;Narayanan et al, 2012;Wittmann, 2013). Consistent with this theory, we observed a decrease in subsecond dopamine concentrations throughout the interval of an FI task that resets after each reinforcement-evoked dopamine event.…”

“…To assess quantitatively the extent and direction of the cannabinoid-induced change in the temporal response pattern, we applied a previously characterized mathematical analysis known as the index of curvature (Fry et al, 1960;Narayanan et al, 2012). In the index of curvature analysis, a premature acceleration of responding will produce a negative index, while a slower acceleration of responding will produce a positive index.…”

“…Now dopaminergic modulation of the converging input into the accumbens is lost, and an unchecked high response pattern of reinforcement-directed behavior predominates. We would like to acknowledge that our speculative model only describes rapid dopamine concentration changes observed in the nucleus accumbens core, and it is likely that divergent patterns of dopamine concentration may be observed along different timescales in distinct neural substrates and that dopamine levels below our limit of detection may also have a role (Narayanan et al, 2012). According to our model, if dopamine concentrations were enhanced at interval onset, yet still sufficiently decreased at the interval terminus, competing forces over reinforcement-directed behavior would be minimized and a behavioral repertoire that is dominated by obtaining primary reinforcement through the interval would emerge.…”

“…Cannabinoids act on the brain's mesocorticolimbic dopamine system (Cheer et al, 2004), a neural pathway recently implicated in the temporal control of behavior (Narayanan et al, 2012). Such control can be assessed using fixed-interval (FI) schedules (Narayanan et al, 2012), which reinforce behavior on the basis of time (Dews, 1970).…”

“…Such control can be assessed using fixed-interval (FI) schedules (Narayanan et al, 2012), which reinforce behavior on the basis of time (Dews, 1970). FI procedures produce a characteristic pattern of behavior known as a scallop.…”