Liu, C., Goel, P. & Kaeser, P. S. Spatial and temporal scales of dopamine transmission. Nat. Rev. Neurosci. 22, 345â358 (2021).
Grace, A. A. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat. Rev. Neurosci. 17, 524â532 (2016).
da Silva, J. A., Tecuapetla, F., Paixao, V. & Costa, R. M. Dopamine neuron activity before action initiation gates and invigorates future movements. Nature 554, 244â248 (2018).
Howe, M. W. & Dombeck, D. A. Rapid signalling in distinct dopaminergic axons during locomotion and reward. Nature 535, 505â510 (2016).
Dodson, P. D. et al. Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism. Proc. Natl Acad. Sci. USA 113, E2180âE2188 (2016).
Jin, X. & Costa, R. M. Start/stop signals emerge in nigrostriatal circuits during sequence learning. Nature 466, 457â462 (2010).
Berke, J. D. What does dopamine mean? Nat. Neurosci. https://doi.org/10.1038/s41593-018-0152-y (2018).
Coddington, L. T. & Dudman, J. T. Learning from action: reconsidering movement signaling in midbrain dopamine neuron activity. Neuron 104, 63â77 (2019).
Schultz, W. Multiple dopamine functions at different time courses. Annu. Rev. Neurosci. 30, 259â288 (2007).
Schultz, W., Dayan, P. & Montague, P. R. A neural substrate of prediction and reward. Science 275, 1593â1599 (1997).
Kim, H. R. et al. A unified framework for dopamine signals across timescales. Cell 183, 1600â1616.e25 (2020).
Amo, R. et al. A gradual temporal shift of dopamine responses mirrors the progression of temporal difference error in machine learning. Nat. Neurosci. 25, 1082â1092 (2022).
Watabe-Uchida, M., Eshel, N. & Uchida, N. Neural circuitry of reward prediction error. Annu. Rev. Neurosci. 40, 373â394 (2017).
Poewe, W. et al. Parkinson disease. Nat. Rev. Dis. Primers 3, 17013 (2017).
Cotzias, G. C., Van Woert, M. H. & Schiffer, L. M. Aromatic amino acids and modification of parkinsonism. N. Engl. J. Med. 276, 374â379 (1967).
Carlsson, A. A paradigm shift in brain research. Science 294, 1021â1024 (2001).
Carlsson, A. On the problem of the mechanism of action of some psychopharmaca. Psychiatr. Neurol. 140, 220â222 (1960).
Bakhurin, K. et al. Force tuning explains changes in phasic dopamine signaling during stimulus-reward learning. Preprint at bioRxiv https://doi.org/10.1101/2023.04.23.537994 (2023).
Jeong, H. et al. Mesolimbic dopamine release conveys causal associations. Science 378, eabq6740 (2022).
Berridge, K. C., Robinson, T. E. & Aldridge, J. W. Dissecting components of reward: âlikingâ, âwantingâ, and learning. Curr. Opin. Pharmacol. 9, 65â73 (2009).
Niv, Y., Daw, N. D., Joel, D. & Dayan, P. Tonic dopamine: opportunity costs and the control of response vigor. Psychopharmacology 191, 507â520 (2007).
Hamilos, A. E. et al. Slowly evolving dopaminergic activity modulates the moment-to-moment probability of reward-related self-timed movements. eLife 10, e62583 (2021).
Mohebi, A. et al. Dissociable dopamine dynamics for learning and motivation. Nature 570, 65â70 (2019).
Howe, M. et al. Coordination of rapid cholinergic and dopaminergic signaling in striatum during spontaneous movement. eLife 8, e44903 (2019).
Yagishita, S. et al. A critical time window for dopamine actions on the structural plasticity of dendritic spines. Science 345, 1616â1620 (2014).
Chaudhury, D. et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493, 532â536 (2013).
Crego, A. C. G. et al. Complementary control over habits and behavioral vigor by phasic activity in the dorsolateral striatum. J. Neurosci. 40, 2139â2153 (2020).
Bova, A. et al. Precisely timed dopamine signals establish distinct kinematic representations of skilled movements. eLife 9, e61591 (2020).
Howard, C. D., Li, H., Geddes, C. E. & Jin, X. Dynamic nigrostriatal dopamine biases action selection. Neuron 93, 1436â1450.e8 (2017).
Liu, C. et al. An action potential initiation mechanism in distal axons for the control of dopamine release. Science 375, 1378â1385 (2022).
Sun, F. et al. Next-generation GRAB sensors for monitoring dopaminergic activity in vivo. Nat. Methods 17, 1156â1166 (2020).
Patriarchi, T. et al. An expanded palette of dopamine sensors for multiplex imaging in vivo. Nat. Methods 17, 1147â1155 (2020).
Liu, C., Kershberg, L., Wang, J., Schneeberger, S. & Kaeser, P. S. Dopamine secretion is mediated by sparse active zone-like release sites. Cell 172, 706â718.e15 (2018).
Banerjee, A. et al. Molecular and functional architecture of striatal dopamine release sites. Neuron 110, 248â265.e9 (2022).
Robinson, B. G. et al. RIM is essential for stimulated but not spontaneous somatodendritic dopamine release in the midbrain. eLife 8, e47972 (2019).
Zych, S. M. & Ford, C. P. Divergent properties and independent regulation of striatal dopamine and GABA co-transmission. Cell Rep. 39, 110823 (2022).
Parker, J. G. et al. Absence of NMDA receptors in dopamine neurons attenuates dopamine release but not conditioned approach during Pavlovian conditioning. Proc. Natl Acad. Sci. USA 107, 13491â13496 (2010).
Zweifel, L. S. et al. Disruption of NMDAR-dependent burst firing by dopamine neurons provides selective assessment of phasic dopamine-dependent behavior. Proc. Natl Acad. Sci. USA 106, 7281â7288 (2009).
Grace, A. A. & Bunney, B. S. The control of firing pattern in nigral dopamine neurons: burst firing. J. Neurosci. 4, 2877â2890 (1984).
Grace, A. A. & Bunney, B. S. The control of firing pattern in nigral dopamine neurons: single spike firing. J. Neurosci. 4, 2866â2876 (1984).
Banerjee, A., Lee, J., Nemcova, P., Liu, C. & Kaeser, P. S. Synaptotagmin-1 is the Ca2+ sensor for fast striatal dopamine release. eLife 9, e58359 (2020).
Ungerstedt, U. Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol. Scand. Suppl. 367, 69â93 (1971).
Keefe, K. A., Salamone, J. D., Zigmond, M. J. & Stricker, E. M. Paradoxical kinesia in parkinsonism is not caused by dopamine release. Studies in an animal model. Arch. Neurol. 46, 1070â1075 (1989).
Lebowitz, J. J. et al. Synaptotagmin-1 is a Ca2+ sensor for somatodendritic dopamine release. Cell Rep. 42, 111915 (2023).
German, P. W. & Fields, H. L. Rat nucleus accumbens neurons persistently encode locations associated with morphine reward. J. Neurophysiol. 97, 2094â2106 (2007).
Tsutsui-Kimura, I. et al. Distinct temporal difference error signals in dopamine axons in three regions of the striatum in a decision-making task. eLife 9, e62390 (2020).
Berridge, C. W., Stratford, T. L., Foote, S. L. & Kelley, A. E. Distribution of dopamine β-hydroxylase-like immunoreactive fibers within the shell subregion of the nucleus accumbens. Synapse 27, 230â241 (1997).
Schroeter, S. et al. Immunolocalization of the cocaine- and antidepressant-sensitive l-norepinephrine transporter. J. Comp. Neurol. 420, 211â232 (2000).
Antonini, A. et al. Effect of levodopaâcarbidopa intestinal gel on dyskinesia in advanced Parkinsonâs disease patients. Mov. Disord. 31, 530â537 (2016).
Flagel, S. B. et al. A selective role for dopamine in stimulus-reward learning. Nature 469, 53â57 (2011).
Dolan, R. J. & Dayan, P. Goals and habits in the brain. Neuron 80, 312â325 (2013).
Wang, J. X. et al. Prefrontal cortex as a meta-reinforcement learning system. Nat. Neurosci. 21, 860â868 (2018).
Wang, A. Y., Miura, K. & Uchida, N. The dorsomedial striatum encodes net expected return, critical for energizing performance vigor. Nat. Neurosci. 16, 639â647 (2013).
Dudman, J. T. & Krakauer, J. W. The basal ganglia: from motor commands to the control of vigor. Curr. Opin. Neurobiol. 37, 158â166 (2016).
Seiler, J. L. et al. Dopamine signaling in the dorsomedial striatum promotes compulsive behavior. Curr. Biol. 32, 1175â1188.e5 (2022).
van Elzelingen, W. et al. Striatal dopamine signals are region specific and temporally stable across action-sequence habit formation. Curr. Biol. 32, 1163â1174.e6 (2022).
Wyvell, C. L. & Berridge, K. C. Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: enhancement of reward âwantingâ without enhanced âlikingâ or response reinforcement. J. Neurosci. 20, 8122â8130 (2000).
Cagniard, B. et al. Dopamine scales performance in the absence of new learning. Neuron 51, 541â547 (2006).
Yin, H. H., Zhuang, X. & Balleine, B. W. Instrumental learning in hyperdopaminergic mice. Neurobiol. Learn. Mem. 85, 283â288 (2006).
Jain, S. et al. Adaptor protein-3 produces synaptic vesicles that release phasic dopamine. Proc. Natl Acad. Sci. USA 120, e2309843120 (2023).
Kaeser, P. S. et al. RIM1α and RIM1β are synthesized from distinct promoters of the RIM1 gene to mediate differential but overlapping synaptic functions. J. Neurosci. 28, 13435â13447 (2008).
Kaeser, P. S. et al. RIM proteins tether Ca2+ channels to presynaptic active zones via a direct PDZ-domain interaction. Cell 144, 282â295 (2011).
Zhou, Q. et al. Architecture of the synaptotagminâSNARE machinery for neuronal exocytosis. Nature 525, 62â67 (2015).
Backman, C. M. et al. Characterization of a mouse strain expressing Cre recombinase from the 3â² untranslated region of the dopamine transporter locus. Genesis 44, 383â390 (2006).
Allen Mouse Brain Atlas [mouse, P56, coronal 2011] (Allen Institute for Brain Science, 2004); https://atlas.brain-map.org.
Chen, T.-W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295â300 (2013).
Rudolph, S. et al. Cerebellum-specific deletion of the GABAA receptor δ subunit leads to sex-specific disruption of behavior. Cell Rep. 33, 108338 (2020).
Newell, A., Yang, K. & Deng, J. Stacked hourglass networks for human pose estimation. In Computer VisionâECCV 2016. Lecture Notes in Computer Science vol. 9912 (eds Leibe, B., Matas, J., Sebe, N. & Welling, M.) 484â499 (Springer, 2016).
Mathis, A. et al. DeepLabCut: markerless pose estimation of user-defined body parts with deep learning. Nat. Neurosci. 21, 1281â1289 (2018).
Nath, T. et al. Using DeepLabCut for 3D markerless pose estimation across species and behaviors. Nat. Protoc. 14, 2152â2176 (2019).
Hutchison, M. A. et al. Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior. Mol. Psychiatry 23, 1213â1225 (2018).
Uchida, N. & Mainen, Z. F. Speed and accuracy of olfactory discrimination in the rat. Nat. Neurosci. 6, 1224â1229 (2003).
Menegas, W. et al. Dopamine neurons projecting to the posterior striatum form an anatomically distinct subclass. eLife 4, e10032 (2015).
Nguyen, N. D. et al. Cortical reactivations predict future sensory responses. Nature 625, 110â118 (2024).
Cai, X. & Kaeser, P. Data table for Cai et al., 2024. Zenodo https://doi.org/10.5281/zenodo.13329864 (2024).
Brimblecombe, K. R., Gracie, C. J., Platt, N. J. & Cragg, S. J. Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains. J. Physiol. 593, 929â946 (2015).
Tedford, H. W. & Zamponi, G. W. Direct G protein modulation of Cav2 calcium channels. Pharmacol. Rev. 58, 837â862 (2006).
Pereira, D. B. et al. Fluorescent false neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum. Nat. Neurosci. 19, 578â586 (2016).
Delignat-Lavaud, B. et al. Synaptotagmin-1-dependent phasic axonal dopamine release is dispensable for basic motor behaviors in mice. Nat. Commun. 14, 4120 (2023).
Kaeser, P. S. & Regehr, W. G. Molecular mechanisms for synchronous, asynchronous, and spontaneous neurotransmitter release. Annu. Rev. Physiol. 76, 333â363 (2014).
