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From avoidance to new action: the multifaceted role of the striatal indirect pathway

Nature Reviews Neuroscience volume 26, pages 438–449 (2025)Cite this article

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Abstract

A hallmark of optimal reinforcement learning is that an agent learns to avoid actions that lead to negative outcomes while still exploring alternative actions that could lead to better outcomes. Although the basal ganglia have been hypothesized to contribute to this computation, the mechanisms by which they do so are still unclear. Here, we focus on the function of the striatal indirect pathway and propose that it is regulated by a synaptic plasticity rule that allows an animal to avoid actions that lead to suboptimal outcomes. We consider current theories of striatal indirect pathway function in light of recent experimental findings and discuss studies that suggest that indirect pathway activity is potentiated by the suppression of dopamine release in the striatum. Furthermore, we highlight recent studies showing that activation of the indirect pathway can trigger an action, allowing animals to explore new actions while suppressing suboptimal actions. We show how our framework can reconcile previously conflicting results regarding the indirect pathway and suggest experiments for future investigation.

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Fig. 1: Models describing the function of direct and indirect striatal projection neurons.
Fig. 2: A framework for reinforcement learning in indirect striatal projection neurons.
Fig. 3: Task-dependent heterogeneity in dopamine suppression.
Fig. 4: Activation of indirect striatal projection neurons leads to alternative action.
Fig. 5: Circuit mechanisms mediating exploration via competition.

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References

  1. Thorndike, E. L. Animal intelligence: an experimental study of the associative processes in animals. Psychol. Rev. 5, 551–553 (1898).

    Article  Google Scholar 

  2. Kravitz, A. V. & Kreitzer, A. C. Striatal mechanisms underlying movement, reinforcement, and punishment. Physiology (Bethesda) https://doi.org/10.1152/physiol.00004.2012 (2012).

  3. Tye, K. M. Neural circuit motifs in valence processing. Neuron 100, 436–452 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Berridge, K. C. Affective valence in the brain: modules or modes? Nat. Rev. Neurosci. 20, 225–234 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hikida, T., Kimura, K., Wada, N., Funabiki, K. & Nakanishi, S. Distinct roles of synaptic transmission in direct and indirect striatal pathways to reward and aversive behavior. Neuron 66, 896–907 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Kravitz, A. V. et al. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 466, 622–626 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kravitz, A. V., Tye, L. D. & Kreitzer, A. C. Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nat. Neurosci. 15, 816–818 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tai, L.-H., Lee, A. M., Benavidez, N., Bonci, A. & Wilbrecht, L. Transient stimulation of distinct subpopulations of striatal neurons mimics changes in action value. Nat. Neurosci. 15, 1281–1289 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cox, J. & Witten, I. B. Striatal circuits for reward learning and decision-making. Nat. Rev. Neurosci. 20, 482–494 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Freeze, B. S., Kravitz, A. V., Hammack, N., Berke, J. D. & Kreitzer, A. C. Control of basal ganglia output by direct and indirect pathway projection neurons. J. Neurosci. 33, 18531–18539 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Roseberry, T. K. et al. Cell-type-specific control of brainstem locomotor circuits by basal ganglia. Cell 164, 526–537 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cruz, B. F. et al. Action suppression reveals opponent parallel control via striatal circuits. Nature 607, 521–526 (2022).

    Article  CAS  PubMed  Google Scholar 

  13. Oldenburg, I. A. & Sabatini, B. L. Antagonistic but not symmetric regulation of primary motor cortex by basal ganglia direct and indirect pathways. Neuron 86, 1174–1181 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yttri, E. A. & Dudman, J. T. Opponent and bidirectional control of movement velocity in the basal ganglia. Nature 533, 402–406 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sheng, M., Lu, D., Shen, Z. & Poo, M. Emergence of stable striatal D1R and D2R neuronal ensembles with distinct firing sequence during motor learning. Proc. Natl Acad. Sci. USA 116, 11038–11047 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Durieux, P. F., Schiffmann, S. N. & de Kerchove d’Exaerde, A. Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions. EMBO J. 31, 640–653 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Bonnavion, P. et al. Striatal projection neurons coexpressing dopamine D1 and D2 receptors modulate the motor function of D1- and D2-SPNs. Nat. Neurosci. 27, 1783–1793 (2024).

    Article  CAS  PubMed  Google Scholar 

  18. Isett, B. R. et al. The indirect pathway of the basal ganglia promotes transient punishment but not motor suppression. Neuron 111, 2218–2231.e4 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Geddes, C. E., Li, H. & Jin, X. Optogenetic editing reveals the hierarchical organization of learned action sequences. Cell 174, 32–43.e15 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nonomura, S. et al. Monitoring and updating of action selection for goal-directed behavior through the striatal direct and indirect pathways. Neuron 99, 1302–1314.e5 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Lee, J. & Sabatini, B. L. Striatal indirect pathway mediates exploration via collicular competition. Nature 599, 645–649 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jin, X. & Costa, R. M. Start/stop signals emerge in nigrostriatal circuits during sequence learning. Nature 466, 457–462 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zalocusky, K. A. et al. Nucleus accumbens D2R cells signal prior outcomes and control risky decision-making. Nature 531, 642–646 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. LeBlanc, K. H. et al. Striatopallidal neurons control avoidance behavior in exploratory tasks. Mol. Psychiatry 25, 491–505 (2020).

    Article  PubMed  Google Scholar 

  25. Lee, S. J. et al. Cell-type-specific asynchronous modulation of PKA by dopamine in learning. Nature 590, 451–456 (2021).

    Article  CAS  PubMed  Google Scholar 

  26. Iino, Y. et al. Dopamine D2 receptors in discrimination learning and spine enlargement. Nature 579, 555–560 (2020).

    Article  CAS  PubMed  Google Scholar 

  27. Cohen, J. Y., Haesler, S., Vong, L., Lowell, B. B. & Uchida, N. Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature 482, 85–88 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Matsumoto, H., Tian, J., Uchida, N. & Watabe-Uchida, M. Midbrain dopamine neurons signal aversion in a reward-context-dependent manner. eLife 5, e17328 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Matsumoto, M. & Hikosaka, O. Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature 459, 837–841 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Schultz, W., Dayan, P. & Montague, P. R. A neural substrate of prediction and reward. Science 275, 1593–1599 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Tecuapetla, F., Jin, X., Lima, S. Q. & Costa, R. M. Complementary contributions of striatal projection pathways to action initiation and execution. Cell 166, 703–715 (2016).

    Article  CAS  PubMed  Google Scholar 

  32. Nelson, A. B. & Kreitzer, A. C. Reassessing models of basal ganglia function and dysfunction. Annu. Rev. Neurosci. 37, 117–135 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bariselli, S., Fobbs, W. C., Creed, M. C. & Kravitz, A. V. A competitive model for striatal action selection. Brain Res. 1713, 70–79 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Klaus, A., Alves da Silva, J. & Costa, R. M. What, if, and when to move: basal ganglia circuits and self-paced action initiation. Annu. Rev. Neurosci. 42, 459–483 (2019).

    Article  CAS  PubMed  Google Scholar 

  35. Park, J., Coddington, L. T. & Dudman, J. T. Basal ganglia circuits for action specification. Annu. Rev. Neurosci. 43, 485–507 (2020).

    Article  CAS  PubMed  Google Scholar 

  36. Mink, J. W. The basal ganglia: focused selection and inhibition of competing motor programs. Prog. Neurobiol. 50, 381–425 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Alexander, G. E. & Crutcher, M. D. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci. 13, 266–271 (1990).

    Article  CAS  PubMed  Google Scholar 

  38. Cui, G. et al. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature 494, 238–242 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tecuapetla, F., Matias, S., Dugue, G. P., Mainen, Z. F. & Costa, R. M. Balanced activity in basal ganglia projection pathways is critical for contraversive movements. Nat. Commun. 5, 4315 (2014).

    Article  CAS  PubMed  Google Scholar 

  40. Meng, C. et al. Spectrally resolved fiber photometry for multi-component analysis of brain circuits. Neuron 98, 707–717.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jeon, H. et al. Topographic connectivity and cellular profiling reveal detailed input pathways and functionally distinct cell types in the subthalamic nucleus. Cell Rep. 38, 110439 (2022).

    Article  CAS  PubMed  Google Scholar 

  42. Lee, J., Wang, W. & Sabatini, B. L. Anatomically segregated basal ganglia pathways allow parallel behavioral modulation. Nat. Neurosci. 23, 1388–1398 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Foster, N. N. et al. The mouse cortico-basal ganglia–thalamic network. Nature 598, 188–194 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Klaus, A. et al. The spatiotemporal organization of the striatum encodes action space. Neuron 95, 1171–1180.e7 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bateup, H. S. et al. Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors. Proc. Natl Acad. Sci. USA 107, 14845–14850 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Carvalho Poyraz, F. et al. Decreasing striatopallidal pathway function enhances motivation by energizing the initiation of goal-directed action. J. Neurosci. 36, 5988–6001 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Tritsch, N. X. & Sabatini, B. L. Dopaminergic modulation of synaptic transmission in cortex and striatum. Neuron 76, 33–50 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hunnicutt, B. J. et al. A comprehensive excitatory input map of the striatum reveals novel functional organization. eLife 5, e19103 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Azcorra, M. et al. Unique functional responses differentially map onto genetic subtypes of dopamine neurons. Nat. Neurosci. 26, 1762–1774 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gokce, O. et al. Cellular taxonomy of the mouse striatum as revealed by single-cell RNA-seq. Cell Rep. 16, 1126–1137 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Plotkin, J. L., Day, M. & Surmeier, D. J. Synaptically driven state transitions in distal dendrites of striatal spiny neurons. Nat. Neurosci. 14, 881–888 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shen, W., Flajolet, M., Greengard, P. & Surmeier, D. J. Dichotomous dopaminergic control of striatal synaptic plasticity. Science 321, 848–851 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yagishita, S. et al. A critical time window for dopamine actions on the structural plasticity of dendritic spines. Science 345, 1616–1620 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kreitzer, A. C. & Malenka, R. C. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson’s disease models. Nature 445, 643–647 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Matsuda, W. et al. Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J. Neurosci. 29, 444–453 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Calabresi, P. et al. Abnormal synaptic plasticity in the striatum of mice lacking dopamine D2 receptors. J. Neurosci. 17, 4536–4544 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Gerdeman, G. L., Partridge, J. G., Lupica, C. R. & Lovinger, D. M. It could be habit forming: drugs of abuse and striatal synaptic plasticity. Trends Neurosci. 26, 184–192 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Bromberg-Martin, E. S., Matsumoto, M. & Hikosaka, O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68, 815–834 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hikida, T. et al. Pathway-specific modulation of nucleus accumbens in reward and aversive behavior via selective transmitter receptors. Proc. Natl Acad. Sci. USA 110, 342–347 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. González-Redondo, Á. et al. Reinforcement learning in a spiking neural model of striatum plasticity. Neurocomputing 548, 126377 (2023).

    Article  Google Scholar 

  61. Mikhael, J. G. & Bogacz, R. Learning reward uncertainty in the basal ganglia. PLOS Comput. Biol. 12, e1005062 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Collins, A. G. E. & Frank, M. J. Opponent actor learning (OpAL): modeling interactive effects of striatal dopamine on reinforcement learning and choice incentive. Psychol. Rev. 121, 337–366 (2014).

    Article  PubMed  Google Scholar 

  63. Blackwell, K. T. & Doya, K. Enhancing reinforcement learning models by including direct and indirect pathways improves performance on striatal dependent tasks. PLOS Comput. Biol. 19, e1011385 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lindsey, J., Markowitz, J. E., Gillis, W. F., Datta, S. R. & Litwin-Kumar, A. Dynamics of striatal action selection and reinforcement learning. eLife 13, RP101747 (2024).

    Article  Google Scholar 

  65. Fee, M. Oculomotor learning revisited: a model of reinforcement learning in the basal ganglia incorporating an efference copy of motor actions. Front. Neural Circuits 6, 38 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Frank, M. J. Dynamic dopamine modulation in the basal ganglia: a neurocomputational account of cognitive deficits in medicated and nonmedicated parkinsonism. J. Cogn. Neurosci. 17, 51–72 (2005).

    Article  PubMed  Google Scholar 

  67. Redgrave, P. & Gurney, K. The short-latency dopamine signal: a role in discovering novel actions? Nat. Rev. Neurosci. 7, 967–975 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Markowitz, J. E. et al. The striatum organizes 3D behavior via moment-to-moment action selection. Cell 174, 44–58.e17 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Parker, J. G. et al. Diametric neural ensemble dynamics in parkinsonian and dyskinetic states. Nature 557, 177–182 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Fee, M. S. The role of efference copy in striatal learning. Curr. Opin. Neurobiol. 25, 194–200 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Varin, C., Cornil, A., Houtteman, D., Bonnavion, P. & de Kerchove d’Exaerde, A. The respective activation and silencing of striatal direct and indirect pathway neurons support behavior encoding. Nat. Commun. 14, 4982 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Weglage, M. et al. Complete representation of action space and value in all dorsal striatal pathways. Cell Rep. 36, 109437 (2021).

    Article  CAS  PubMed  Google Scholar 

  73. Barbera, G. et al. Spatially compact neural clusters in the dorsal striatum encode locomotion relevant information. Neuron 92, 202–213 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Reiner, A., Hart, N. M., Lei, W. & Deng, Y. Corticostriatal projection neurons—dichotomous types and dichotomous functions. Front. Neuroanat. 4, 142 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Deng, Y. et al. Differential organization of cortical inputs to striatal projection neurons of the matrix compartment in rats. Front. Syst. Neurosci. 9, 51 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Lei, W., Jiao, Y., Mar, N. D. & Reiner, A. Evidence for differential cortical input to direct pathway versus indirect pathway striatal projection neurons in rats. J. Neurosci. 24, 8289–8299 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wolff, S. B. E., Ko, R. & Ölveczky, B. P. Distinct roles for motor cortical and thalamic inputs to striatum during motor skill learning and execution. Sci. Adv. 8, eabk0231 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kawai, R. et al. Motor cortex is required for learning but not for executing a motor skill. Neuron 86, 800–812 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. de Jong, J. W. et al. A neural circuit mechanism for encoding aversive stimuli in the mesolimbic dopamine system. Neuron 101, 133–151.e7 (2019).

    Article  PubMed  Google Scholar 

  80. Yang, H. et al. Pain modulates dopamine neurons via a spinal–parabrachial–mesencephalic circuit. Nat. Neurosci. 24, 1402–1413 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Matsumoto, M. & Hikosaka, O. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447, 1111–1115 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Rios, A. et al. Reward expectation enhances action-related activity of nigral dopaminergic and two striatal output pathways. Commun. Biol. 6, 914 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Mohebi, A. et al. Dissociable dopamine dynamics for learning and motivation. Nature 570, 65–70 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hamid, A. A. et al. Mesolimbic dopamine signals the value of work. Nat. Neurosci. 19, 117–126 (2016).

    Article  CAS  PubMed  Google Scholar 

  86. Phillips, C. D., Hodge, A. T., Myers, C. C., Leventhal, D. K. & Burgess, C. R. Striatal dopamine contributions to skilled motor learning. J. Neurosci. 44, e0240242024 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Menegas, W., Akiti, K., Amo, R., Uchida, N. & Watabe-Uchida, M. Dopamine neurons projecting to the posterior striatum reinforce avoidance of threatening stimuli. Nat. Neurosci. 21, 1421–1430 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Engel, L. et al. Dopamine neurons drive spatiotemporally heterogeneous striatal dopamine signals during learning. Curr. Biol. 34, 3086–3101.e4 (2024).

    Article  CAS  PubMed  Google Scholar 

  89. Lerner, T. N. et al. Intact-brain analyses reveal distinct information carried by SNc dopamine subcircuits. Cell 162, 635–647 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Yuan, L., Dou, Y.-N. & Sun, Y.-G. Topography of reward and aversion encoding in the mesolimbic dopaminergic system. J. Neurosci. 39, 6472–6481 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hamid, A. A., Frank, M. J. & Moore, C. I. Wave-like dopamine dynamics as a mechanism for spatiotemporal credit assignment. Cell 184, 2733–2749.e16 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Horvitz, J. C. Mesolimbocortical and nigrostriatal dopamine responses to salient non-reward events. Neuroscience 96, 651–656 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Green, I., Amo, R. & Watabe-Uchida, M. Shifting attention to orient or avoid: a unifying account of the tail of the striatum and its dopaminergic inputs. Curr. Opin. Behav. Sci. 59, 101441 (2024).

    Article  PubMed  Google Scholar 

  94. Dhawale, A. K., Wolff, S. B. E., Ko, R. & Ölveczky, B. P. The basal ganglia control the detailed kinematics of learned motor skills. Nat. Neurosci. 24, 1256–1269 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Lemke, S. M., Ramanathan, D. S., Guo, L., Won, S. J. & Ganguly, K. Emergent modular neural control drives coordinated motor actions. Nat. Neurosci. 22, 1122–1131 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bolkan, S. S. et al. Opponent control of behavior by dorsomedial striatal pathways depends on task demands and internal state. Nat. Neurosci. 25, 345–357 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Rothenhoefer, K. M. et al. Effects of ventral striatum lesions on stimulus-based versus action-based reinforcement learning. J. Neurosci. 37, 6902–6914 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Yartsev, M. M., Hanks, T. D., Yoon, A. M. & Brody, C. D. Causal contribution and dynamical encoding in the striatum during evidence accumulation. eLife 7, e34929 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Guo, L., Walker, W. I., Ponvert, N. D., Penix, P. L. & Jaramillo, S. Stable representation of sounds in the posterior striatum during flexible auditory decisions. Nat. Commun. 9, 1534 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Cregg, J. M., Sidhu, S. K., Leiras, R. & Kiehn, O. Basal ganglia–spinal cord pathway that commands locomotor gait asymmetries in mice. Nat. Neurosci. 27, 716–727 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Takahashi, M., Sugiuchi, Y. & Shinoda, Y. Topographic organization of excitatory and inhibitory commissural connections in the superior colliculi and their functional roles in saccade generation. J. Neurophysiol. 104, 3146–3167 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Takahashi, M., Sugiuchi, Y., Izawa, Y. & Shinoda, Y. Commissural excitation and inhibition by the superior colliculus in tectoreticular neurons projecting to omnipause neuron and inhibitory burst neuron regions. J. Neurophysiol. 94, 1707–1726 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Doykos, T. K., Gilmer, J. I., Person, A. L. & Felsen, G. Monosynaptic inputs to specific cell types of the intermediate and deep layers of the superior colliculus. J. Comp. Neurol. 528, 2254–2268 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Sooksawate, T., Isa, K., Behan, M., Yanagawa, Y. & Isa, T. Organization of GABAergic inhibition in the motor output layer of the superior colliculus. Eur. J. Neurosci. 33, 421–432 (2011).

    Article  PubMed  Google Scholar 

  105. Mailly, P., Charpier, S., Menetrey, A. & Deniau, J.-M. Three-dimensional organization of the recurrent axon collateral network of the substantia nigra pars reticulata neurons in the rat. J. Neurosci. 23, 5247–5257 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Brown, J., Pan, W.-X. & Dudman, J. T. The inhibitory microcircuit of the substantia nigra provides feedback gain control of the basal ganglia output. eLife 3, e02397 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Dobbs, L. K. et al. Dopamine regulation of lateral inhibition between striatal neurons gates the stimulant actions of cocaine. Neuron 90, 1100–1113 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Doya, K. Complementary roles of basal ganglia and cerebellum in learning and motor control. Curr. Opin. Neurobiol. 10, 732–739 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Yin, H. H. & Knowlton, B. J. The role of the basal ganglia in habit formation. Nat. Rev. Neurosci. 7, 464–476 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Balleine, B. W., Delgado, M. R. & Hikosaka, O. The role of the dorsal striatum in reward and decision-making: fig. 1. J. Neurosci. 27, 8161–8165 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Yin, H. H., Knowlton, B. J. & Balleine, B. W. Lesions of dorsolateral striatum preserve outcome expectancy but disrupt habit formation in instrumental learning. Eur. J. Neurosci. 19, 181–189 (2004).

    Article  PubMed  Google Scholar 

  112. Yin, H. H., Ostlund, S. B., Knowlton, B. J. & Balleine, B. W. The role of the dorsomedial striatum in instrumental conditioning. Eur. J. Neurosci. 22, 513–523 (2005).

    Article  PubMed  Google Scholar 

  113. Yin, H. H., Knowlton, B. J. & Balleine, B. W. Inactivation of dorsolateral striatum enhances sensitivity to changes in the action–outcome contingency in instrumental conditioning. Behav. Brain Res. 166, 189–196 (2006).

    Article  PubMed  Google Scholar 

  114. Kwak, S. & Jung, M. W. Distinct roles of striatal direct and indirect pathways in value-based decision making. eLife 8, e46050 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Peak, J., Chieng, B., Hart, G. & Balleine, B. W. Striatal direct and indirect pathway neurons differentially control the encoding and updating of goal-directed learning. eLife 9, e58544 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Matamales, M. et al. Local D2- to D1-neuron transmodulation updates goal-directed learning in the striatum. Science 367, 549–555 (2020).

    Article  CAS  PubMed  Google Scholar 

  117. Dezfouli, A. & Balleine, B. W. Habits, action sequences and reinforcement learning. Eur. J. Neurosci. 35, 1036–1051 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Dezfouli, A. & Balleine, B. W. Actions, action sequences and habits: evidence that goal-directed and habitual action control are hierarchically organized. PLOS Comput. Biol. 9, e1003364 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Dezfouli, A., Lingawi, N. W. & Balleine, B. W. Habits as action sequences: hierarchical action control and changes in outcome value. Philos. Trans. R. Soc. B Biol. Sci. 369, 20130482 (2014).

    Article  Google Scholar 

  120. Kopec, C. D., Erlich, J. C., Brunton, B. W., Deisseroth, K. & Brody, C. D. Cortical and subcortical contributions to short-term memory for orienting movements. Neuron 88, 367–377 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sinnamon, H. M. & Galer, B. S. Head movements elicited by electrical stimulation of the anteromedial cortex of the rat. Physiol. Behav. 33, 185–190 (1984).

    Article  CAS  PubMed  Google Scholar 

  122. van der Meer, M. A. & Redish, A. D. Ventral striatum: a critical look at models of learning and evaluation. Curr. Opin. Neurobiol. 21, 387–392 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Floresco, S. B. The nucleus accumbens: an interface between cognition, emotion, and action. Annu. Rev. Psychol. 66, 25–52 (2015).

    Article  PubMed  Google Scholar 

  124. Kelley, A. E. Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning. Neurosci. Biobehav. Rev. 27, 765–776 (2004).

    Article  PubMed  Google Scholar 

  125. Mannella, F., Gurney, K. & Baldassarre, G. The nucleus accumbens as a nexus between values and goals in goal-directed behavior: a review and a new hypothesis. Front. Behav. Neurosci. 7, 135 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Chen, R. et al. Decoding molecular and cellular heterogeneity of mouse nucleus accumbens. Nat. Neurosci. 24, 1757–1771 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Vicente, A. M., Galvão-Ferreira, P., Tecuapetla, F. & Costa, R. M. Direct and indirect dorsolateral striatum pathways reinforce different action strategies. Curr. Biol. 26, R267–R269 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. El-Boustani, S. et al. Locally coordinated synaptic plasticity of visual cortex neurons in vivo. Science 360, 1349–1354 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Rolotti, S. V. et al. Local feedback inhibition tightly controls rapid formation of hippocampal place fields. Neuron 110, 783–794.e6 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Soares-Cunha, C. et al. Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion. Mol. Psychiatry 25, 3241–3255 (2020).

    Article  CAS  PubMed  Google Scholar 

  131. Hughes, R. N. et al. Ventral tegmental dopamine neurons control the impulse vector during motivated behavior. Curr. Biol. 30, 2681–2694.e5 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Coddington, L. T., Lindo, S. E. & Dudman, J. T. Mesolimbic dopamine adapts the rate of learning from action. Nature 614, 294–302 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Jeong, H. et al. Mesolimbic dopamine release conveys causal associations. Science 378, eabq6740 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Gershman, S. J. et al. Explaining dopamine through prediction errors and beyond. Nat. Neurosci. 27, 1645–1655 (2024).

    Article  CAS  PubMed  Google Scholar 

  135. Coddington, L. T. & Dudman, J. T. Learning from action: reconsidering movement signaling in midbrain dopamine neuron activity. Neuron 104, 63–77 (2019).

    Article  CAS  PubMed  Google Scholar 

  136. Reynolds, J. N. J., Hyland, B. I. & Wickens, J. R. A cellular mechanism of reward-related learning. Nature 413, 67–70 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Reynolds, J. N. J. & Wickens, J. R. Dopamine-dependent plasticity of corticostriatal synapses. Neural Netw. 15, 507–521 (2002).

    Article  PubMed  Google Scholar 

  138. Mathis, A. et al. DeepLabCut: markerless pose estimation of user-defined body parts with deep learning. Nat. Neurosci. 21, 1281–1289 (2018).

    Article  CAS  PubMed  Google Scholar 

  139. Pereira, T. D. et al. SLEAP: a deep learning system for multi-animal pose tracking. Nat. Methods 19, 486–495 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Marshall, J. D. et al. Continuous whole-body 3D kinematic recordings across the rodent behavioral repertoire. Neuron 109, 420–437.e8 (2021).

    Article  CAS  PubMed  Google Scholar 

  141. Bollu, T. et al. Cortex-dependent corrections as the tongue reaches for and misses targets. Nature 594, 82–87 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Xu, D. et al. Cortical processing of flexible and context-dependent sensorimotor sequences. Nature 603, 464–469 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank members of the Sabatini laboratory for helpful discussions.

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  1. Jaeeon Lee

    Present address: Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, Cambridge, MA, USA

  2. These authors contributed equally: Jaeeon Lee, Bernardo L. Sabatini.

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  1. Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA

    Jaeeon Lee & Bernardo L. Sabatini

  2. Kempner Institute for the Study of Natural and Artificial Intelligence, Harvard University, Boston, MA, USA

    Bernardo L. Sabatini

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Lee, J., Sabatini, B.L. From avoidance to new action: the multifaceted role of the striatal indirect pathway. Nat. Rev. Neurosci. 26, 438–449 (2025). https://doi.org/10.1038/s41583-025-00925-2

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