Phasic dopamine release in the medial prefrontal cortex enhances stimulus discrimination

Abstract

Phasic dopamine (DA) release is believed to guide associative learning. Most studies have focused on projections from the ventral tegmental area (VTA) to the striatum, and the action of DA in other VTA target regions remains unclear. Using optogenetic activation of VTA projections, we examined DA function in the medial prefrontal cortex (mPFC). We found that mice perceived optogenetically induced DA release in mPFC as neither rewarding nor aversive, and did not change their previously learned behavior in response to DA transients. However, repetitive temporal pairing of an auditory conditioned stimulus (CS) with mPFC DA release resulted in faster learning of a subsequent task involving discrimination of the same CS against unpaired stimuli. Similar results were obtained using both appetitive and aversive unconditioned stimuli, supporting the notion that DA transients in mPFC do not represent valence. Using extracellular recordings, we found that CS-DA pairings increased firing of mPFC neurons in response to CSs, and administration of D 1 or D 2 DAreceptor antagonists in mPFC during learning impaired stimulus discrimination. We conclude that DA transients tune mPFC neurons for the recognition of behaviorally relevant events during learning.learning | attention | dopamine T he firing activity of dopamine (DA) neurons in the ventral tegmental area (VTA) is consistent with a role of reward prediction error signal, which is believed to guide behavioral adaptation through DA release in target brain regions (1-7). Experiments using optogenetic manipulations have established a causal link between the activity of DA neurons in VTA and the reinforcing signal that mediates learning and conditioning (8-10). Stimulation of VTA, however, results in transient DA release in many target areas, and it is unclear how each of these regions contributes to learning. For example, compared with the striatum, the medial prefrontal cortex (mPFC) receives fewer DA projections (11), expresses fewer DA reuptake transporters (12), and exhibits an overall lower level of DA (13,14). Nevertheless, pharmacological studies have implicated DA as a powerful neuromodulator of mPFC, able to influence many cognitive functions that support learning (15-21). Furthermore, DA neurons in VTA projecting to either the striatum or mPFC have distinct intrinsic neuronal properties and receive distinct inputs (22-24); thus, they are likely to serve different roles. It remains unclear what function phasic DA release might have in mPFC, whether it carries any valence, or how it affects stimulus-specific learning.In this study, we addressed specifically the role of phasic DA release in stimulus-response association. Using optogenetically timed release of DA from VTA neuronal projections in mPFC, we found that DA transients enhance the firing of mPFC neurons in response to the paired conditioned stimuli (CSs), whereas blocking DA receptors in mPFC during learning impairs stimulus discrimination. Furthermore, pairing a CS with optogenetic stimulation of DA fibers in ...

Nicotinic and Cholinergic Modulation of Reward Prediction Error Computations in the Ventral Tegmental Area: a Minimal Circuit Model

“…Furthermore, this activity has been shown to increase in the early stage of a classical-conditioning learning task (Schoenbaum et al, 1998; Le Merre et al, 2018). Especially, the PFC participates in the association of temporally separated events in trace-conditioning task through working-memory mechanisms (Connor and Gould, 2016), maintaining a representation of the CS accross the the CS-US interval, and this timing-association is dependent on dopamine modulation in the PFC (Puig et al, 2014; Popescu et al, 2016).…”

“…For the last two decades, a great amount of experimental studies depicted which brain areas send this information to the VTA. Notably, a subpopulation of pedunculopontine tegmental nucleus (PPTg) has been found to send the actual reward signal to dopamine neurons (Kobayashi and Okada, 2007; Okada et al, 2009; Keiflin and Janak, 2015), while other studies showed that the prefrontal cortex (PFC) and the nucleus accumbens (NAc) respond to the predictive cue (Keiflin and Janak, 2015; Oyama et al, 2015; Funahashi, 2006; Connor and Gould, 2016; Le Merre et al, 2018), highly depending on VTA DA feedback projections in the PFC (Puig et al, 2014; Popescu et al, 2016) and the NAc (Yagishita et al, 2014; Keiflin and Janak, 2015; Fisher et al, 2017). However, how each of these signals are integrated by VTA DA neurons during classical-conditioning remains elusive.…”

Lateral Hypothalamic Control of the Ventral Tegmental Area: Reward Evaluation and the Driving of Motivated Behavior

“…The VTA dopaminergic system in particular has been implicated in brain-stimulation reward and food reward, psychomotor stimulation, learning and memory formation (Yokel and Wise, 1975; De Wit and Wise, 1977; Berridge, 2007; Friedman et al, 2014; Popescu et al, 2016), and it has been shown that goal-directed behavior is promoted by dopamine release from VTA DA neurons (Gallistel et al, 1985; Phillips et al, 2003; Grace et al, 2007). Studies have shown that both the synaptic connections and intrinsic excitability of DA neurons are highly plastic dependent on the experiences of the animals (Stuber et al, 2008; Mao et al, 2011; Collo et al, 2014; Friedman et al, 2014; Gore et al, 2014).…”

Dopamine transients delivered in learning contexts do not act as model-free prediction errors

“…The proposal linking transient changes in the firing of dopamine neurons to value learning is supported mainly by correlative studies, too numerous to mention fully (see 5 for full review) . However support also comes from a growing number of causal reports, showing that artificially induced dopamine transients, with a brevity and timing similar to the physiological prediction-error correlates, are able to drive enduring changes in behavior to antecedent cues, contexts, or events [6][7][8][9][10][11][12] . These changes are assumed to reflect value learning, however almost none of these studies investigate the informational content of the learning to confirm or refute this assumption.…”

“…, top left) revealed a main effect of cue (i.e. AX-A vs. B-BX; F(1,10)=7.567, p=0.020), a main of session (F(6,60)=7.574, p=0.000), and a session × group interaction (F(6,60)=2.442, p=0.035). The source of this interaction was due to rats in the ChR2 group showing faster acquisition of both configural discriminations (i.e.…”