Temporally restricted dopaminergic control of reward-conditioned movements

Lee, Kwang; Claar, Leslie D.; Hachisuka, Ayaka; Bakhurin, Konstantin I.; Nguyen, Jacquelyn; Fanselow, Michael; Gill, Jay; Masmanidis, Sotiris C.

doi:10.1038/s41593-019-0567-0

Cited by 60 publications

(81 citation statements)

References 56 publications

(99 reference statements)

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“…Activation of dopamine neurons both in VTA and SNc are known to reinforce preceding behaviors (Ilango et al, 2014;Keiflin et al, 2019;Lee et al, 2020;Saunders et al, 2018). The differences in dopamine axon signals that we observed in instrumental behaviors can provide specific constraints on the behaviors learned through dopamine-mediated reinforcement in these striatal regions.…”

Section: Discussionmentioning

confidence: 76%

Distinct temporal difference error signals in dopamine axons in three regions of the striatum in a decision-making task

Tsutsui-Kimura

Matsumoto

Uchida

et al. 2020

Preprint

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Different regions of the striatum regulate different types of behavior. However, how dopamine signals differ across striatal regions and how dopamine regulates different behaviors remain unclear. Here, we compared dopamine axon activity in the ventral, dorsomedial, and dorsolateral striatum, while mice performed in a perceptual and value-based decision task. Surprisingly, dopamine axon activity was similar across all three areas. At a glance, the activity multiplexed different variables such as stimulus-associated values, confidence and reward feedback at different phases of the task. Our modeling demonstrates, however, that these modulations can be inclusively explained by moment-by-moment changes in the expected reward, i.e. the temporal difference error. A major difference between these areas was the overall activity level of reward responses: reward responses in dorsolateral striatum (DLS) were positively shifted, lacking inhibitory responses to negative prediction error. Tenets of habit and skill can be explained by this positively biased dopamine signal in DLS.

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Section: Discussionmentioning

confidence: 76%

Distinct temporal difference error signals in dopamine axons in three regions of the striatum in a decision-making task

Tsutsui-Kimura

Matsumoto

Uchida

et al. 2020

Preprint

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“…As a result, it is impossible to distinguish NLRP3 inflammasome activity directly related to inclusion of the hyperactivated transgene from wild-type NLRP3 inflammasome activity in glia resulting from the neuronal perturbation. For this reason, we are unable to determine with certainty that the Nlrp3 L351P allele was not expressed inappropriately in glia, although we believe this to be unlikely due to previous studies utilizing this strain and our characterization of microglia and astrocytes [ 49 – 52 ]. Despite the shortcomings of this model system, the inclusion of an endogenous Nlrp3 allele was likely a critical factor in our discovery of an expanding neuroinflammatory phenotype resulting from expression of the Nlrp3 L351P allele of neurons, a finding of importance as we work to understand the earliest stages of neuroinflammation in neurodegenerative disease.…”

Section: Discussionmentioning

confidence: 90%

“…006660). The Slc6a3 IRESCre strain is now convincingly validated and in wide use [ 49 – 51 ], originally characterized using the ROSA reporter line to express CRE specifically within neuronal populations of the mesencephalon [ 52 ]. This process generated mice that selectively express the hyperactive Nlrp3 alleles only when the endogenous murine Nlrp3 gene is expressed in dopaminergic neurons.…”

Section: Methodsmentioning

confidence: 99%

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice

Herrmann

Anderson

Martinez

et al. 2020

J Neuroinflammation

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Background: An association between neuroinflammation and age-related neurologic disorders has been established but the molecular mechanisms and cell types involved have not been thoroughly characterized. Activity of the proinflammatory NLRP3 inflammasome is implicated in Alzheimer's and Parkinson's disease and our recent studies in patients suggest that dopaminergic neurons within the degenerating mesencephalon express NLRP3 throughout the progression of PD. Here, we directly test the impact of enhanced inflammasome activity in mesencephalic neurons by characterizing motor function, tissue integrity, and neuroinflammation in aging mice harboring hyperactivating mutations within the endogenous murine Nlrp3 locus, enabled only in cells expressing the dopaminergic neuron-specific Slc6a3 promoter. Methods: We compared mice harboring inducible alleles encoding the cryopyrin-associated periodic syndrome activating mutations Nlrp3 A350V and Nlrp3 L351P inserted into the endogenous mouse Nlrp3 locus. Tissue specific expression was driven by breeding these animals with mice expressing Cre recombinase under the control of the dopaminergic neuron-specific Slc6a3 promoter. The experimental mice, designed to express hyperactive NLRP3 only when the endogenous mouse Nlrp3 promotor is active in dopaminergic neurons, were analyzed throughout 18 months of aging using longitudinal motor function assessments. Biochemical and histologic analyses of mesencephalic tissues were conducted in 1-and 18-month-old animals. Results: We observed progressive and significant deficits in motor function in animals expressing Nlrp3 L351P , compared with animals expressing Nlrp3 WT and Nlrp3 A350V. Age-dependent neuroinflammatory changes in the mesencephalon were noted in all animals. Analysis of GFAP-immunoreactive astrocytes in the substantia nigra revealed a significant increase in astrocyte number in animals expressing Nlrp3 L351P compared with Nlrp3 WT and Nlrp3 A350V. Further analysis of Nlrp3 L351P striatal tissues indicated genotype specific gliosis, elevated Il1b expression, and both morphologic and gene expression indicators of proinflammatory A1 astrocytes.

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“…One explores the direct effect of DA signal on NMDARs and VGCCs [12], and the other models DA-delay dependence in Ca 2+ dynamics through a Ca 2+ buffer [13]. However, those models predict 100-ms and 20-s time windows, respectively, and it still remains obscure about the mechanisms of the in-between time window of~2 s, which is required for DA-mediated reward conditioning [14]. Further, a pharmacological experiment showed that RP depends on the other type of AC, Ca 2+ -sensitive type 1 AC (AC1) [4], which is also expressed in the striatum [15].…”

Section: Introductionmentioning

confidence: 99%

Signaling models for dopamine-dependent temporal contiguity in striatal synaptic plasticity

et al. 2020

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Animals remember temporal links between their actions and subsequent rewards. We previously discovered a synaptic mechanism underlying such reward learning in D1 receptor (D1R)-expressing spiny projection neurons (D1 SPN) of the striatum. Dopamine (DA) bursts promote dendritic spine enlargement in a time window of only a few seconds after paired pre-and post-synaptic spiking (pre-post pairing), which is termed as reinforcement plasticity (RP). The previous study has also identified underlying signaling pathways; however, it still remains unclear how the signaling dynamics results in RP. In the present study, we first developed a computational model of signaling dynamics of D1 SPNs. The D1 RP model successfully reproduced experimentally observed protein kinase A (PKA) activity, including its critical time window. In this model, adenylate cyclase type 1 (AC1) in the spines/thin dendrites played a pivotal role as a coincidence detector against pre-post pairing and DA burst. In particular, pre-post pairing (Ca 2+ signal) stimulated AC1 with a delay, and the Ca 2+-stimulated AC1 was activated by the DA burst for the asymmetric time window. Moreover, the smallness of the spines/thin dendrites is crucial to the short time window for the PKA activity. We then developed a RP model for D2 SPNs, which also predicted the critical time window for RP that depended on the timing of pre-post pairing and phasic DA dip. AC1 worked for the coincidence detector in the D2 RP model as well. We further simulated the signaling pathway leading to Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) activation and clarified the role of the downstream molecules of AC1 as the integrators that turn transient input signals into persistent spine enlargement. Finally, we discuss how such timing windows guide animals' reward learning.

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Temporally restricted dopaminergic control of reward-conditioned movements

Cited by 60 publications

References 56 publications

Distinct temporal difference error signals in dopamine axons in three regions of the striatum in a decision-making task

Distinct temporal difference error signals in dopamine axons in three regions of the striatum in a decision-making task

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice

Signaling models for dopamine-dependent temporal contiguity in striatal synaptic plasticity

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