Fluorescence detection of dopamine signaling to the primate striatum in relation to stimulus–reward associations
Edited by Ilya E. Monosov, Washington University in St. Louis, St. Louis, MO; received December 24, 2024; accepted February 14, 2025 by Editorial Board Member Michael E. Goldberg
Significance
Reward-anticipatory behavior following a reward-predicting stimulus is achieved through Pavlovian conditioning. Dopamine (DA) released within the striatum, the main input station of the basal ganglia, plays a key role in this behavior. However, it remains unclear what type of DA signal is conveyed to the striatum in relation to stimulus-reward associations. To detect DA transients in the anterior striatal sectors responsible for the stimulus-reward associations, we applied fiber photometry with a fluorescent DA sensor to monkeys being engaged in a Pavlovian conditioning task. Our study demonstrates that this technique is useful to capture the DA transients in brain structures of the task-performing monkeys, and that the DA transients vary depending on the striatal territories.
Abstract
Dopamine (DA) signals to the striatum play critical roles in shaping and sustaining stimulus-reward associations. In primates, however, the dynamics of the DA signals remain unknown since conventional methods are not necessarily appropriate in terms of the spatiotemporal resolution or chemical specificity sufficient for detecting the DA signals. In our study, fiber photometry with a fluorescent DA sensor was employed to identify reward-related DA transients in the monkey striatum. This technique, which directly monitors local DA release, reveals a reward prediction error signal in the anterior putamen originating from midbrain DA neurons. Further, DA transients in the head of the caudate nucleus exhibit a value-based response to reward-predicting stimuli. These signals have been found to arise from two separate groups of DA neurons in the substantia nigra pars compacta. The present results demonstrate that fluorescence DA monitoring is applicable to detect DA signals in the primate striatum for investigating their roles.
Data, Materials, and Software Availability
All study data are included in the article and/or SI Appendix.
Acknowledgments
We thank Naoko Suda-Hashimoto, Akihisa Kaneko, Kei Kimura, Emiko Tanaka, and Andi Zheng for technical assistance and Maki Fujiwara and Mayuko Nakano for vector production. This work was supported by JST CREST Grant Number JPMJCR1853 (to M.T.), JSPS KAKENHI Grant Numbers 20H05955 (to H.A.), 22K06484 (to H.A.), 22H05157 (to K.-i.I.), and 23H02781 (to K.-i.I.).
Author contributions
H.A. designed research; G.Y., H.A., S.N., and K.-i.I. performed research; G.Y. and H.A. analyzed data; and G.Y., H.A., W.S., and M.T. wrote the paper.
Competing interests
The authors declare no competing interest.
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References
1
W. Schultz, P. Apicella, T. Ljungberg, Responses of monkey dopamine neurons to reward and conditioned-stimuli during successive steps of learning a delayed-response task. J. Neurosci. 13, 900–913 (1993).
2
J. Hollerman, W. Schultz, Dopamine neurons report an error in the temporal prediction of reward during learning. Nat. Neurosci. 1, 304–309 (1998).
3
R. Kawagoe, Y. Takikawa, O. Hikosaka, Reward-predicting activity of dopamine and caudate neurons–A possible mechanism of motivational control of saccadic eye movement. J. Neurophysiol. 91, 1013–1024 (2004).
4
J. Clark, A. Collins, C. Sanford, P. Phillips, Dopamine encoding of Pavlovian incentive stimuli diminishes with extended training. J. Neurosci. 33, 3526–3532 (2013).
5
W. Stauffer et al., Dopamine neuron-specific optogenetic stimulation in rhesus macaques. Cell 166, 1564–1571 (2016).
6
R. van Zessen et al., Cue and reward evoked dopamine activity is necessary for maintaining learned Pavlovian associations. J. Neurosci. 41, 5004–5014 (2021).
7
Y. Takikawa, R. Kawagoe, O. Hikosaka, A possible role of midbrain dopamine neurons in short- and long-term adaptation of saccades to position-reward mapping. J. Neurophysiol. 92, 2520–2529 (2004).
8
M. D. Davis, T. G. Heffner, L. W. Cooke, Dopamine agonist-induced inhibition of neurotransmitter release from the awake squirrel monkey putamen as measured by microdialysis. J. Neurochem. 68, 659–666 (1997).
9
B. S. Kolachana, R. C. Saunders, D. R. Weinberger, An improved methodology for routine in vivo microdialysis in non-human primates. J. Neurosci. Methods 55, 1–6 (1994).
10
E. Schluter, A. Mitz, J. Cheer, B. Averbeck, Real-time dopamine measurement in awake monkeys. Plos One 9, e98692 (2014).
11
H. N. Schwerdt et al., Long-term dopamine neurochemical monitoring in primates. Proc. Natl. Acad. Sci. U.S.A. 114, 13260–13265 (2017).
12
K. Yoshimi et al., Phasic reward responses in the monkey striatum as detected by voltammetry with diamond microelectrodes. Neurosci. Res. 71, 49–62 (2011).
13
K. Yoshimi, S. Kumada, A. Weitemier, T. Jo, M. Inoue, Reward-induced phasic dopamine release in the monkey ventral striatum and putamen. PLoS One 10, e0130443 (2015).
14
J. Ariansen et al., Monitoring extracellular pH, oxygen, and dopamine during reward delivery in the striatum of primates. Front. Behav. Neurosci. 6, 36 (2012).
15
H. Schwerdt et al., Dopamine and beta-band oscillations differentially link to striatal value and motor control. Sci. Adv. 6, eabb9226 (2020).
16
T. Kodama et al., Oral administration of methylphenidate (Ritalin) affects dopamine release differentially between the prefrontal cortex and striatum: A microdialysis study in the monkey. J. Neurosci. 37, 2387–2394 (2017).
17
T. Patriarchi et al., Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors. Science 360, eaat4422 (2018).
18
F. Sun et al., A genetically encoded fluorescent sensor enables rapid and specific detection of dopamine in flies, fish, and mice. Cell 174, 481–496 (2018).
19
A. Mohebi et al., Dissociable dopamine dynamics for learning and motivation. Nature 570, 65–70 (2019).
20
A. G. Salinas et al., Distinct sub-second dopamine signaling in dorsolateral striatum measured by a genetically-encoded fluorescent sensor. Nat. Commun. 14, 5915 (2023).
21
A. Rios et al., Reward expectation enhances action-related activity of nigral dopaminergic and two striatal output pathways. Commun. Biol. 6, 914 (2023).
22
T. W. Bernklau, B. Righetti, L. S. Mehrke, S. N. Jacob, Striatal dopamine signals reflect perceived cue-action-outcome associations in mice. Nat. Neurosci. 27, 747–757 (2024).
23
O. Hikosaka, M. Sakamoto, S. Usui, Functional-properties of monkey caudate neurons.3. activities related to expectation of target and reward. J. Neurophysiol. 61, 814–832 (1989).
24
L. Tremblay, J. Hollerman, W. Schultz, Modifications of reward expectation-related neuronal activity during learning in primate striatum. J. Neurophysiol. 80, 964–977 (1998).
25
R. Kawagoe, Y. Takikawa, O. Hikosaka, Expectation of reward modulates cognitive signals in the basal ganglia. Nat. Neurosci. 1, 411–416 (1998).
26
H. Cromwell, W. Schultz, Effects of expectations for different reward magnitudes on neuronal activity in primate striatum. J. Neurophysiol. 89, 2823–2838 (2003).
27
K. Nakamura, G. S. Santos, R. Matsuzaki, H. Nakahara, Differential reward coding in the subdivisions of the primate caudate during an oculomotor task. J. Neurosci. 32, 15963–15982 (2012).
28
A. Parent, A. Mackey, L. Debellefeuille, The subcortical afferents to caudate nucleus and putamen in primate: A fluorescence retrograde double labeling study. Neuroscience 10, 1137–1150 (1983).
29
Y. Smith, A. Parent, Differential connections of caudate nucleus and putamen in the squirrel monkey (Saimiri sciureus). Neuroscience 18, 347–371 (1986).
30
P. Montague, P. Dayan, T. Sejnowski, A framework for mesencephalic dopamine systems based on predictive Hebbian learning. J. Neurosci. 16, 1936–1947 (1996).
31
W. Schultz, P. Dayan, P. Montague, A neural substrate of prediction and reward. Science 275, 1593–1599 (1997).
32
R. Suri, W. Schultz, A neural network model with dopamine-like reinforcement signal that learns a spatial delayed response task. Neuroscience 91, 871–890 (1999).
33
M. Watabe-Uchida, N. Eshel, N. Uchida, H. Zoghbi, Neural circuitry of reward prediction error. Annu. Rev. Neurosci. 40, 373–394 (2017).
34
I. Tsutsui-Kimura 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).
35
C. Fiorillo, P. Tobler, W. Schultz, Discrete coding of reward probability and uncertainty by dopamine neurons. Science 299, 1898–1902 (2003).
36
M. Joshua, A. Adler, R. Mitelman, E. Vaadia, H. Bergman, Midbrain dopaminergic neurons and striatal cholinergic interneurons encode the difference between reward and aversive events at different epochs of probabilistic classical conditioning trials. J. Neurosci. 28, 11673–11684 (2008).
37
M. Matsumoto, O. Hikosaka, Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature 459, 837–841 (2009).
38
A. Lak, W. R. Stauffer, W. Schultz, Dopamine neurons learn relative chosen value from probabilistic rewards. Elife 5, e18044 (2016).
39
J. K. White et al., A neural network for information seeking. Nat. Commun. 10, 5168 (2019).
40
S. N. Haber, J. L. Fudge, N. R. McFarland, Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. J. Neurosci. 20, 2369–2382 (2000).
41
T. Ljungberg, P. Apicella, W. Schultz, Responses of monkey midbrain dopamine neurons during delayed alternation performance. Brain Res. 567, 337–341 (1991).
42
N. Eshel, J. Tian, M. Bukwich, N. Uchida, Dopamine neurons share common response function for reward prediction error. Nat. Neurosci. 19, 479–486 (2016).
43
N. Nakatsuka, A. M. Andrews, Differentiating siblings: The case of dopamine and norepinephrine. ACS Chem. Neurosci. 8, 218–220 (2017).
44
M. L. Heien, M. A. Johnson, R. M. Wightman, Resolving neurotransmitters detected by fast-scan cyclic voltammetry. Anal. Chem. 76, 5697–5704 (2004).
45
R. Amo, N. Uchida, M. Watabe-Uchida, Glutamate inputs send prediction error of reward, but not negative value of aversive stimuli, to dopamine neurons. Neuron 112, 1001–1019 (2024).
46
A. Mohebi, W. Wei, L. Pelattini, K. Kim, J. D. Berke, Dopamine transients follow a striatal gradient of reward time horizons. Nat. Neurosci. 27, 737–746 (2024).
47
E. H. Simpson et al., Lights, fiber, action! A primer on in vivo fiber photometry. Neuron 112, 718–739 (2024).
48
M. A. Labouesse, R. B. Cola, T. Patriarchi, GPCR-based dopamine sensors-A detailed guide to inform sensor choice for in vivo imaging. Int. J. Mol. Sci. 21, 8048 (2020).
49
C. Klein Herenbrink et al., Multimodal detection of dopamine by sniffer cells expressing genetically encoded fluorescent sensors. Commun. Biol. 5, 578 (2022).
50
S. Kakade, P. Dayan, Dopamine: Generalization and bonuses. Neural Netw. 15, 549–559 (2002).
51
H. F. Kim, A. Ghazizadeh, O. Hikosaka, Separate groups of dopamine neurons innervate caudate head and tail encoding flexible and stable value memories. Front. Neuroanat. 8, 120 (2014).
52
N. F. Parker et al., Reward and choice encoding in terminals of midbrain dopamine neurons depends on striatal target. Nat. Neurosci. 19, 845–854 (2016).
53
M. W. Howe, D. A. Dombeck, Rapid signalling in distinct dopaminergic axons during locomotion and reward. Nature 535, 505–510 (2016).
54
W. Dabney et al., A distributional code for value in dopamine-based reinforcement learning. Nature 577, 671–675 (2020).
55
P. Kosillo, Y. F. Zhang, S. Threlfell, S. J. Cragg, Cortical control of striatal dopamine transmission via striatal cholinergic interneurons. Cereb. Cortex 26, 4160–4169 (2016).
56
P. F. Kramer et al., Synaptic-like axo-axonal transmission from striatal cholinergic interneurons onto dopaminergic fibers. Neuron 110, 2949–2960 (2022).
57
H. Zhang, D. Sulzer, Glutamate spillover in the striatum depresses dopaminergic transmission by activating group I metabotropic glutamate receptors. J. Neurosci. 23, 10585–10592 (2003).
58
T. N. Lerner et al., Intact-brain analyses reveal distinct information carried by SNc dopamine subcircuits. Cell 162, 635–647 (2015).
59
R. Avvisati et al., Distributional coding of associative learning in discrete populations of midbrain dopamine neurons. Cell Rep. 43, 114080 (2024).
60
J. W. De Jong, K. M. Fraser, S. Lammel, Mesoaccumbal dopamine heterogeneity: What do dopamine firing and release have to do with it? Annu. Rev. Neurosci. 45, 109–129 (2022).
61
W. Menegas, K. Akiti, R. Amo, N. Uchida, M. Watabe-Uchida, Dopamine neurons projecting to the posterior striatum reinforce avoidance of threatening stimuli. Nat. Neurosci. 21, 1421–1430 (2018).
62
J. Cox, I. Witten, Striatal circuits for reward learning and decision-making. Nat. Rev. Neurosci. 20, 482–494 (2019).
63
E. Lynd-Balta, S. N. Haber, The organization of midbrain projections to the striatum in the primate: Sensorimotor-related striatum versus ventral striatum. Neuroscience 59, 625–640 (1994).
64
J. L. Fudge et al., Beyond the classic VTA: Extended amygdala projections to DA-striatal paths in the primate. Neuropsychopharmacology 42, 1563–1576 (2017).
65
I. G. Dopeso-Reyes et al., Calbindin content and differential vulnerability of midbrain efferent dopaminergic neurons in macaques. Front. Neuroanat. 8, 146 (2014).
66
W. M. Pauli et al., Distinct contributions of ventromedial and dorsolateral subregions of the human substantia nigra to appetitive and aversive learning. J. Neurosci. 35, 14220–14233 (2015).
67
H. F. Kim, A. Ghazizadeh, O. Hikosaka, Dopamine neurons encoding long-term memory of object value for habitual behavior. Cell 163, 1165–1175 (2015).
68
M. Paquet, M. Tremblay, J. J. Soghomonian, Y. Smith, AMPA and NMDA glutamate receptor subunits in midbrain dopaminergic neurons in the squirrel monkey: An immunohistochemical and in situ hybridization study. J. Neurosci. 17, 1377–1396 (1997).
69
O. Garritsen, E. Y. van Battum, L. M. Grossouw, R. J. Pasterkamp, Development, wiring and function of dopamine neuron subtypes. Nat. Rev. Neurosci. 24, 134–152 (2023).
70
N. L. Del Rey et al., Calbindin and Girk2/Aldh1a1 define resilient vs. vulnerable dopaminergic neurons in a primate Parkinson’s disease model. NPJ Parkinsons Dis. 10, 165 (2024).
71
H. Amita, H. F. Kim, K. Inoue, M. Takada, O. Hikosaka, Optogenetic manipulation of a value-coding pathway from the primate caudate tail facilitates saccadic gaze shift. Nat. Commun. 11, 1876 (2020).
72
K. S. Saleem, N. Logothetis, A Combined MRI and Histology Atlas of the Rhesus Monkey Brain in Stereotaxic Coordinates (Academic Press/Elsevier, London, ed. 2, 2007).
73
S. Tanabe et al., A note on retrograde gene transfer efficiency and inflammatory response of lentiviral vectors pseudotyped with FuG-E vs. FuG-B2 glycoproteins. Sci. Rep. 9, 3567 (2019).
74
K. Kimura et al., A mosaic adeno-associated virus vector as a versatile tool that exhibits high levels of transgene expression and neuron specificity in primate brain. Nat. Commun. 14, 4762 (2023).
75
A. Weiss, W. Liguore, J. Domire, D. Button, J. McBride, Intra-striatal AAV2.retro administration leads to extensive retrograde transport in the rhesus macaque brain: Implications for disease modeling and therapeutic development. Sci. Rep. 10, 6970 (2020).
76
G. Paxinos, C. Watson, The Rat Brain in Stereotaxic Coordinates (Academic Press/Elsevier, London, ed. 6, 2007).
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Copyright © 2025 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Data, Materials, and Software Availability
All study data are included in the article and/or SI Appendix.
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Received: December 24, 2024
Accepted: February 14, 2025
Published online: March 13, 2025
Published in issue: March 18, 2025
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Acknowledgments
We thank Naoko Suda-Hashimoto, Akihisa Kaneko, Kei Kimura, Emiko Tanaka, and Andi Zheng for technical assistance and Maki Fujiwara and Mayuko Nakano for vector production. This work was supported by JST CREST Grant Number JPMJCR1853 (to M.T.), JSPS KAKENHI Grant Numbers 20H05955 (to H.A.), 22K06484 (to H.A.), 22H05157 (to K.-i.I.), and 23H02781 (to K.-i.I.).
Author contributions
H.A. designed research; G.Y., H.A., S.N., and K.-i.I. performed research; G.Y. and H.A. analyzed data; and G.Y., H.A., W.S., and M.T. wrote the paper.
Competing interests
The authors declare no competing interest.
Notes
This article is a PNAS Direct Submission I.E.M. is a guest editor invited by the Editorial Board.
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Fluorescence detection of dopamine signaling to the primate striatum in relation to stimulus–reward associations, Proc. Natl. Acad. Sci. U.S.A.
122 (11) e2426861122,
https://doi.org/10.1073/pnas.2426861122
(2025).
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