Tonic or Phasic Stimulation of Dopaminergic Projections to Prefrontal Cortex Causes Mice to Maintain or Deviate from Previously Learned Behavioral Strategies

Abstract

Dopamine neurons in the ventral tegmental area (VTA) encode reward prediction errors and can drive reinforcement learning through their projections to striatum, but much less is known about their projections to prefrontal cortex (PFC). Here, we studied these projections and observed phasic VTA-PFC fiber photometry signals after the delivery of rewards. Next, we studied how optogenetic stimulation of these projections affects behavior using conditioned place preference and a task in which mice learn associations between cues and food rewards and then use those associations to make choices. Neither phasic nor tonic stimulation of dopaminergic VTA-PFC projections elicited place preference. Furthermore, substituting phasic VTA-PFC stimulation for food rewards was not sufficient to reinforce new cue-reward associations nor maintain previously learned ones. However, the same patterns of stimulation that failed to reinforce place preference or cue-reward associations were able to modify behavior in other ways. First, continuous tonic stimulation maintained previously learned cue-reward associations even after they ceased being valid. Second, delivering phasic stimulation either continuously or after choices not previously associated with reward induced mice to make choices that deviated from previously learned associations. In summary, despite the fact that dopaminergic VTA-PFC projections exhibit phasic increases in activity that are time locked to the delivery of rewards, phasic activation of these projections does not necessarily reinforce specific actions. Rather, dopaminergic VTA-PFC activity can control whether mice maintain or deviate from previously learned cue-reward associations. Dopaminergic inputs from ventral tegmental area (VTA) to striatum encode reward prediction errors and reinforce specific actions; however, it is currently unknown whether dopaminergic inputs to prefrontal cortex (PFC) play similar or distinct roles. Here, we used bulk Ca imaging to show that unexpected rewards or reward-predicting cues elicit phasic increases in the activity of dopaminergic VTA-PFC fibers. However, in multiple behavioral paradigms, we failed to observe reinforcing effects after stimulation of these fibers. In these same experiments, we did find that tonic or phasic patterns of stimulation caused mice to maintain or deviate from previously learned cue-reward associations, respectively. Therefore, although they may exhibit similar patterns of activity, dopaminergic inputs to striatum and PFC can elicit divergent behavioral effects.

Interhemispheric gamma synchrony between parvalbumin interneurons supports behavioral adaptation

“…2f-i). Notably, this error-related increase in synchrony was frequency-specific: for both lower (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) and higher (50-70 Hz) frequency bands, interhemispheric PV interneuron synchronization was similar across the baseline period, after correct decisions, and after errors.…”

“…To address these issues, we explored the role of gamma-frequency synchronization between prefrontal PV interneurons as mice perform a task involving the type of behavioral adaptation outlined above. Variants of this task have previously been characterized by our laboratory and others 14,15,[19][20][21][22] . On each trial, mice choose between two bowls to find a hidden food reward ( Fig.…”

Direct Glutamatergic Signaling From Midbrain Dopaminergic Neurons Onto Pyramidal Prefrontal Cortex Neurons

“…Optogenetic manipulations of the dopaminergic VTA→PFC fibers (that release dopamine and glutamate) caused mice to maintain or deviate from previously learned cue–reward associations (Ellwood et al, 2017). The loss of mesocortical dopaminergic neurons that release glutamate in the PFC increases the perseverative behaviors and present alterations in impulsivity and attention (Kabanova et al, 2015).…”

Amphetamine disrupts haemodynamic correlates of prediction errors in nucleus accumbens and orbitofrontal cortex

“…Prediction errors related to receipt of reward have been strongly associated with dopaminergic neurons and their projections to frontostriatal circuits [1][2][3][4]. In rodents and humans, presentation of reward-predicting cues cause an increase in dopaminergic neuron activity and dopamine release in terminal regions, not only in proportion to the expected value of the upcoming reward but also to the deviation from that expectation when the reward is actually delivered [5][6][7][8][9][10][11][12].…”