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      Dissociable dopamine dynamics for learning and motivation.

      Nature

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          Abstract

          The dopamine projection from ventral tegmental area (VTA) to nucleus accumbens (NAc) is critical for motivation to work for rewards, and reward-driven learning. How dopamine supports both functions is unclear. Dopamine spiking can encode prediction errors, vital learning signals in computational theories of adaptive behavior. By contrast, dopamine release ramps up as animals approach rewards, mirroring reward expectation. This mismatch might reflect differences in behavioral tasks, slower changes in dopamine cell spiking, or spike-independent modulation of dopamine release. Here we compare spiking of identified VTA dopamine cells with NAc dopamine release in the same decision-making task. Cues indicating upcoming reward increased both spiking and release. Yet NAc core dopamine release also covaried with dynamically-evolving reward expectations, without corresponding changes in VTA dopamine cell spiking. Our results suggest a fundamental difference in how dopamine release is regulated to achieve distinct functions: broadcast burst signals promote learning, while local control drives motivation.

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          Most cited references39

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          Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex.

          Anatomical and functional refinements of the meso-limbic dopamine system of the rat are discussed. Present experiments suggest that dopaminergic neurons localized in the posteromedial ventral tegmental area (VTA) and central linear nucleus raphe selectively project to the ventromedial striatum (medial olfactory tubercle and medial nucleus accumbens shell), whereas the anteromedial VTA has few if any projections to the ventral striatum, and the lateral VTA largely projects to the ventrolateral striatum (accumbens core, lateral shell and lateral tubercle). These findings complement the recent behavioral findings that cocaine and amphetamine are more rewarding when administered into the ventromedial striatum than into the ventrolateral striatum. Drugs such as nicotine and opiates are more rewarding when administered into the posterior VTA or the central linear nucleus than into the anterior VTA. A review of the literature suggests that (1) the midbrain has corresponding zones for the accumbens core and medial shell; (2) the striatal portion of the olfactory tubercle is a ventral extension of the nucleus accumbens shell; and (3) a model of two dopamine projection systems from the ventral midbrain to the ventral striatum is useful for understanding reward function. The medial projection system is important in the regulation of arousal characterized by affect and drive and plays a different role in goal-directed learning than the lateral projection system, as described in the variation-selection hypothesis of striatal functional organization.
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            Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors

            Neuromodulatory systems exert profound influences on brain function. Understanding how these systems modify the operating mode of target circuits requires measuring spatiotemporally precise neuromodulator release. We developed dLight1, an intensity-based genetically encoded dopamine indicator, to enable optical recording of dopamine dynamics with high spatiotemporal resolution in behaving mice. We demonstrated the utility of dLight1 by imaging dopamine dynamics simultaneously with pharmacological manipulation, electrophysiological or optogenetic stimulation, and calcium imaging of local neuronal activity. dLight1 enabled chronic tracking of learning-induced changes in millisecond dopamine transients in striatum. Further, we used dLight1 to image spatially distinct, functionally heterogeneous dopamine transients relevant to learning and motor control in cortex. We also validated our sensor design platform for developing norepinephrine, serotonin, melatonin, and opioid neuropeptide indicators.
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              Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression.

              The dopamine system is unique among the brain's modulatory systems in that it has discrete projections to specific brain regions involved in motor behaviour, cognition and emotion. Dopamine neurons exhibit several activity patterns - including tonic and phasic firing - that are determined by a combination of endogenous pacemaker conductances and regulation by multiple afferent systems. Emerging evidence suggests that disruptions in these regulatory systems may underlie the pathophysiology of several psychiatric disorders, including schizophrenia and depression.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                13 May 2019
                22 May 2019
                June 2019
                22 November 2019
                : 570
                : 7759
                : 65-70
                Affiliations
                [1 ]Department of Neurology, University of California, San Francisco
                [2 ]Department of Neuroscience, Brown University
                [3 ]Department of Chemistry, University of Michigan, Ann Arbor.
                [4 ]Neuroscience Graduate Program, University of California, San Francisco
                [5 ]Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis.
                [6 ]Weill Institute for Neurosciences and Kavli Institute for Fundamental Neuroscience, University of California, San Francisco.
                Author notes

                Contributions. A.M. performed and analyzed the electrophysiology and photometry, and applied the computational model. J.P. performed and analyzed the microdialysis, with assistance from J.W. and supervision by R.K. A.H. developed the behavioral task and initial photometry setup, and performed the voltammetry. L.V. performed retrograde tracing and analysis. T.P. and L.T. developed the dLight sensor and shared expertise. J.D.B. designed and supervised the study, and wrote the manuscript.

                [*]

                equal contributions.

                Article
                NIHMS1528213
                10.1038/s41586-019-1235-y
                6555489
                31118513
                6b0bc9f7-03a4-4286-8b87-558204efef98

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