Functional Dissection of Basal Ganglia Inhibitory Inputs onto Substantia Nigra Dopaminergic Neurons

Evans, Rebekah C.; Twedell, Emily L; Zhu, Manhua; Ascencio, Jefferson; Zhang, Renshu; Khaliq, Zayd M.

doi:10.1016/j.celrep.2020.108156

Cited by 71 publications

(116 citation statements)

References 111 publications

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“…This work provides new insight into the relationship between striatal patches and dopamine release, demonstrating that optogenetic stimulation of patch projections suppresses dopamine release in the dorsal striatum (Figure 6). Previous studies have supported this notion demonstrating anatomical (Crittenden et al, 2016; Fujiyama et al, 2011; Gerfen, 1985; Watabe-Uchida et al, 2012) and functional connectivity (Evans et al, 2020; McGregor et al, 2019). Patches could therefore regulate habitual behavior by sculpting dopamine release across learning.…”

Section: Discussionmentioning

confidence: 64%

“…We injected Sepw1-NP67 mice with an AAV encoding either Cre-dependent light-gated cation channel ChR2 or YFP in the dorsal striatum, which resulted in enriched ChR2 expression in striatal patches (Figure 1D). We then implanted fiber optics targeting cell bodies of striatal patch neurons, patch terminals in SNc (Evans et al, 2020), or at patch terminals in entopeduncular nucleus (Stephenson-Jones et al, 2016; Wallace et al, 2017; Figure 1A + B) with the expectation that these two pathways may differentially modulate habitual responding due to potentially opposing effects on dopamine neurons. However, no implantation site-dependent differences were observed in performance during training, habit probes, open field, or place preference tasks (p > 0.05), therefore fiber optic placement groups were collapsed into a general “ChR2” group for comparison with YFP controls (individual group data is shown in supporting figures matching main figure numbers; Supporting Figures 2–5).…”

Section: Resultsmentioning

confidence: 99%

“…As striatal patches are a unique striatal output population projecting to SNc (Crittenden et al, 2016; Davis et al, 2018; Evans et al, 2020), optogenetic stimulation of patches may alter responding by modulating dopamine release. We aimed to investigate this possibility by eliciting phasic increases in striatal dopamine with electrical stimulation of the pedunculopontine tegmental nucleus (PPTg; Forster and Blaha, 2003; Zweifel et al, 2009) with and without simultaneous optogenetic activation of patch projections.…”

Section: Resultsmentioning

confidence: 99%

“…Adding a layer of complexity to the medial-lateral striatal divide is the existence of two neurochemically distinct subcompartments: small, labyrinthine islands called patches or striosomes (comprising 15% of striatal volume), and surrounding ‘matrix’ tissue (85% of striatal volume; Gerfen, 1992; Graybiel and Ragsdale, 1978). In addition to unique cellular markers (Crittenden and Graybiel, 2011), patches are characterized by unique connectivity, providing the predominant anatomical and functional striatal input to midbrain dopaminergic neurons (Evans et al, 2020; Gerfen, 1985). Additionally, habenula-projecting neurons of the entopeduncular nucleus receive preferential input from patches (Stephenson-Jones et al, 2016; Wallace et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Optogenetic interrogation of the role of striatal patches in habit formation and inhibition of striatal dopamine

Nadel

Pawelko²,

Scott³

et al. 2020

Preprint

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Habits are inflexible behaviors that can be maladaptive in diseases including drug addiction. The striatum is integral to habit formation, and interspersed throughout the striatum are patches, or striosomes, which are characterized by unique gene expression relative to the surrounding matrix. Recent work has indicated that patches are necessary for habit formation, but how patches contribute to habits remains partially understood. Here, using optogenetics, we modulated striatal patches in Sepw1-NP67 mice during habit formation. We find that patch activation during operant training impairs habit formation, and conversely, that acute patch stimulation after reward devaluation can drive habitual reward seeking. Patch stimulation invigorates general locomotion but is not inherently rewarding. Finally, we use fast-scan cyclic voltammetry to demonstrate that patch stimulation suppresses dopamine release in dorsal striatum in vivo. Overall, this work provides novel insight into the role of the patch compartment in habit formation, and potential interactions with dopamine signaling.

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Section: Discussionmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Optogenetic interrogation of the role of striatal patches in habit formation and inhibition of striatal dopamine

Nadel

Pawelko²,

Scott³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Here, a notable difference in the DLS was a lack of dips below baseline despite similarly suppressive effects of reward expectation across regions. Based on these collective findings, we therefore would predict that most effects observed within the DMS in the current study would be largely similar in the accumbens core (Covey & Cheer, 2019), and although we also would expect suppression in the DLS, we also might not expect negative prediction errors to cause dips below Lerner et al, 2015;Menegas et al, 2015), the majority of which are predominantly inhibitory GABAergic projections (Tepper and Lee, 2007;Brazhnik et al, 2008;Evans et al, 2020).…”

Section: Discussionmentioning

confidence: 67%

Nigrostriatal Dopamine Signals Sequence-Specific Action-Outcome Prediction Errors

Hollon

Williams

Howard

et al. 2021

Preprint

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Dopamine has been suggested to encode cue-reward prediction errors during Pavlovian conditioning. While this theory has been widely applied to reinforcement learning concerning instrumental actions, whether dopamine represents action-outcome prediction errors and how it controls sequential behavior remain largely unknown. Here, by training mice to perform optogenetic intracranial self-stimulation, we examined how self-initiated goal-directed behavior influences nigrostriatal dopamine transmission during single as well as sequential instrumental actions. We found that dopamine release evoked by direct optogenetic stimulation was dramatically reduced when delivered as the consequence of the animal’s own action, relative to non-contingent passive stimulation. This action-induced dopamine suppression was specific to the reinforced action, temporally restricted to counteract the expected outcome, and exhibited sequence-selectivity consistent with hierarchical control of sequential behavior. Together these findings demonstrate that nigrostriatal dopamine signals sequence-specific prediction errors in action-outcome associations, with fundamental implications for reinforcement learning and instrumental behavior in health and disease.

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DARPP‐32 cells and neuropil define striosomal system and isolated matrix cells in human striatum

Arasaratnam

Song

Yoshida

et al. 2023

J of Comparative Neurology

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The dorsal striatum forms a central node of the basal ganglia interconnecting the neocortex and thalamus with circuits modulating mood and movement. Striatal projection neurons (SPNs) include relatively intermixed populations expressing D1‐type or D2‐type dopamine receptors (dSPNs and iSPNs) that give rise to the direct (D1) and indirect (D2) output systems of the basal ganglia. Overlaid on this organization is a compartmental organization, in which a labyrinthine system of striosomes made up of sequestered SPNs is embedded within the larger striatal matrix. Striosomal SPNs also include D1‐SPNs and D2‐SPNs, but they can be distinguished from matrix SPNs by many neurochemical markers. In the rodent striatum the key signaling molecule, DARPP‐32, is a exception to these compartmental expression patterns, thought to befit its functions through opposite actions in both D1‐ and D2‐expressing SPNs. We demonstrate here, however, that in the dorsal human striatum, DARPP‐32 is concentrated in the neuropil and SPNs of striosomes, especially in the caudate nucleus and dorsomedial putamen, relative to the matrix neuropil in these regions. The generally DARPP‐32‐poor matrix contains scattered DARPP‐32‐positive cells. DARPP‐32 cell bodies in both compartments proved negative for conventional intraneuronal markers. These findings raise the potential for specialized DARPP‐32 expression in the human striosomal system and in a set of DARPP‐32‐positive neurons in the matrix. If DARPP‐32 immunohistochemical positivity predicts differential functional DARPP‐32 activity, then the distributions demonstrated here could render striosomes and dispersed matrix cells susceptible to differential signaling through cAMP and other signaling systems in health and disease. DARPP‐32 is highly concentrated in cells and neuropil of striosomes in post‐mortem human brain tissue, particularly in the dorsal caudate nucleus. Scattered DARPP‐32‐positive cells are found in the human striatal matrix. Calbindin and DARPP‐32 do not colocalize within every spiny projection neuron in the dorsal human caudate nucleus.

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Functional Dissection of Basal Ganglia Inhibitory Inputs onto Substantia Nigra Dopaminergic Neurons

Cited by 71 publications

References 111 publications

Optogenetic interrogation of the role of striatal patches in habit formation and inhibition of striatal dopamine

Optogenetic interrogation of the role of striatal patches in habit formation and inhibition of striatal dopamine

Nigrostriatal Dopamine Signals Sequence-Specific Action-Outcome Prediction Errors

DARPP‐32 cells and neuropil define striosomal system and isolated matrix cells in human striatum

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