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Differential contributions of striatal dopamine D1 and D2 receptors to component processes of value-based decision making.

ABSTRACT: Dopamine has been implicated in value-based learning and decision making by signaling reward prediction errors and facilitating cognitive flexibility, incentive motivation, and voluntary movement. Dopamine receptors can roughly be divided into the D1 and D2 subtypes, and it has been hypothesized that these two types of receptors have an opposite function in facilitating reward-related and aversion-related behaviors, respectively. Here, we tested the contribution of striatal dopamine D1 and D2 receptors to processes underlying value-based learning and decision making in rats, employing a probabilistic reversal learning paradigm. Using computational trial-by-trial analysis of task behavior after systemic or intracranial treatment with dopamine D1 and D2 receptor agonists and antagonists, we show that negative feedback learning can be modulated through D2 receptor signaling and positive feedback learning through D1 receptor signaling in the ventral striatum. Furthermore, stimulation of D2 receptors in the ventral or dorsolateral (but not dorsomedial) striatum promoted explorative choice behavior, suggesting an additional function of dopamine in these areas in value-based decision making. Finally, treatment with most dopaminergic drugs affected response latencies and number of trials completed, which was also seen after infusion of D2, but not D1 receptor-acting drugs into the striatum. Together, our data support the idea that dopamine D1 and D2 receptors have complementary functions in learning on the basis of emotionally valenced feedback, and provide evidence that dopamine facilitates value-based and motivated behaviors through distinct striatal regions.

SUBMITTER: Verharen JPH

PROVIDER: S-EPMC6897916 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Differential contributions of striatal dopamine D1 and D2 receptors to component processes of value-based decision making.

Verharen Jeroen P H JPH Adan Roger A H RAH Vanderschuren Louk J M J LJMJ

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20190629 13

Dopamine has been implicated in value-based learning and decision making by signaling reward prediction errors and facilitating cognitive flexibility, incentive motivation, and voluntary movement. Dopamine receptors can roughly be divided into the D1 and D2 subtypes, and it has been hypothesized that these two types of receptors have an opposite function in facilitating reward-related and aversion-related behaviors, respectively. Here, we tested the contribution of striatal dopamine D1 and D2 re ...[more]

PMID: 31254972

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Project description:Many neurological disorders and diseases including drug addiction are associated with specific neuronal cell types in the brain. The striatum, a region that plays a critically important role in the development of addictive drug-related behavior, provides a good example of the cellular heterogeneity challenges associated with analyses of specific neuronal cell types. Such studies are needed to identify the adaptive changes in neuroproteomic signaling that occur in response to diseases such as addiction. The striatum contains two major cell types, D1 and D2 type dopaminoceptive medium spiny neurons (MSNs), whose cell bodies and processes are intermingled throughout this region. Since little is known about the proteomes of these two neuronal cell populations, we have begun to address this challenge by using fluorescence-activated nuclear sorting (FANS) to isolate nuclei-containing fractions from striatum from D1 and D2 "Translating Ribosome Affinity Purification" (TRAP) mice. This approach enabled us to devise and implement a robust and reproducible workflow for preparing samples from specific MSN cell types for mass spectrometry analyses. These analyses quantified at least 685 proteins in each of four biological replicates of 50 K sorted nuclei from two D1 mice/replicate and from each of four biological replicates of 50 K sorted nuclei from two D2 mice/replicate. Proteome analyses identified 87 proteins that were differentially expressed in D1 versus D2 MSN nuclei and principal component analysis (PCA) of these proteins separated the 8 biological replicates into specific cell types. Central network analysis of the 87 differentially expressed proteins identified Hnrnpd and Hnmpa2b1 in D1 and Cct2 and Cct7 in D2 as potential central interactors. This workflow can now be used to improve our understanding of many neurological diseases including characterizing the short and long-term impact of drugs of abuse on the proteomes of these two dopaminoceptive neuronal populations.

Project description:Individuals differ in their tendencies to seek positive decision outcomes or to avoid negative ones. At the neurobiological level, our model suggests that phasic changes in dopamine support learning to reinforce good decisions via striatal D1 receptors, and to avoid maladaptive choices via striatal D2 receptors. Accordingly, in a previous study individual differences in positive and negative learning were strongly modulated by two genetic polymorphisms factors related to striatal D1 and D2 function, respectively. Nevertheless, whereas the role for dopamine in positive learning is relatively well accepted, that in learning to avoid negative outcomes is more controversial. Here we further explore D2-receptor-related genetic contributions to probabilistic avoidance in humans, in light of recent data showing that particular DRD2 polymorphisms are associated with functional modulation of receptor expression [Zhang Y, Bertolino A, Fazio L, Blasi G, Rampino A, Romano R, Lee M-LT, Xiao T, Papp A, Wang D, Sadée W (2007) Polymorphisms in human dopamine d2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc Natl Acad Sci U S A 104(51):20552-20557]. We find that a promoter polymorphism rs12364283 associated with transcription and D2 receptor density was strongly and selectively predictive of avoidance-based decisions. Two further polymorphisms (rs2283265 and rs1076560) associated with relatively reduced presynaptic relative to postsynaptic D2 receptor expression were predictive of relative impairments in negative compared to positive decisions. These previously undocumented effects of DRD2 polymorphisms were largely independent of those we reported previously for the C957T polymorphism (rs6277) associated with striatal D2 density. In contrast, effects of the commonly studied Taq1A polymorphism on reinforcement-based decisions were due to indirect association with C957T. Taken together these findings suggest multiple D2-dependent genetic mechanisms contributing to avoidance. We discuss these effects in the context of neurocomputational models of reinforcement leaning in the basal ganglia.

Dataset Information

Differential contributions of striatal dopamine D1 and D2 receptors to component processes of value-based decision making.

Publications

Differential contributions of striatal dopamine D1 and D2 receptors to component processes of value-based decision making.

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