Coincidence of cholinergic pauses, dopaminergic activation and depolarisation of spiny projection neurons drives synaptic plasticity in the striatum

Reynolds, John N. J.; Avvisati, Riccardo; Dodson, Paul D.; Fisher, Simon D.; Oswald, Manfred J.; Wickens, Jeffery R.; Zhang, Yan-Feng

doi:10.1038/s41467-022-28950-0

Cited by 42 publications

(34 citation statements)

References 51 publications

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“…These phasic responses are thought to stand out from the basal, steady concentration of DA and ACh that brain circuits normally bathe in to affect behavior. In the mammalian striatum, rewards evoke a phasic increase in extracellular DA 3-5 and a phasic decrease in ACh 6-8 , the coincidence of which is critical for DA to act as a teaching signal, as muscarinic M4 receptors oppose DA-dependent synaptic plasticity on direct-pathway striatal projection neurons (SPNs) 15-17 . Recent studies have also implicated phasic elevations in DA in the initiation and invigoration of self-paced movements 18-21 , and ACh has been proposed to help striatal circuits distinguish between DA signals related to motor performance and learning 12-14,22,23 .…”

Section: Main Textmentioning

confidence: 99%

Intrinsic reward-like dopamine and acetylcholine dynamics in striatum

Krok

Mistry

et al. 2022

Preprint

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External rewards like food and money are potent modifiers of behavior. Pioneering studies established that these salient sensory stimuli briefly interrupt the tonic cell-autonomous discharge of neurons that produce the neuromodulators dopamine (DA) and acetylcholine (ACh): midbrain DA neurons (DANs) fire a burst of action potentials that broadly elevates DA levels in striatum at the same time as striatal cholinergic interneurons (CINs) produce a characteristic pause in firing. These phasic responses are thought to create unique, temporally-limited conditions that motivate action and promote learning. However, the dynamics of DA and ACh outside explicitly-rewarded situations remain poorly understood. Here we show that extracellular levels of DA and ACh fluctuate spontaneously in the striatum of mice and maintain the same temporal relationship as that evoked by reward. We show that this neuromodulatory coordination does not arise from direct interactions between DA and ACh within striatum. Periodic fluctuations in ACh are instead controlled by glutamatergic afferents, which act to locally synchronize spiking of striatal cholinergic interneurons. Together, our findings reveal that striatal neuromodulatory dynamics are autonomously organized by distributed extra-striatal afferents across behavioral contexts. The dominance of intrinsic reward-like rhythms in DA and ACh offers novel insights for explaining how reward-associated neural dynamics emerge and how the brain motivates action and promotes learning from within.

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Section: Main Textmentioning

confidence: 99%

Intrinsic reward-like dopamine and acetylcholine dynamics in striatum

Krok

Mistry

et al. 2022

Preprint

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“…It has been hypothesized that CIN pauses are time windows that allow DA to potentiate corticostriatal and thalamostriatal synapses 70 . Consistent with this, a precise in vivo coincidence of CIN pauses, DAN activation, and striatal spiny projection neuron (SPN) depolarization is required for long-term potentiation of corticostriatal synapses with SPNs 71 . In the 2ABT, different reward outcomes yield unique patterns of neurotransmitter release, the combination of which could tune the plasticity of striatal synapses in distinct ways to drive behavior.…”

Section: Discussionmentioning

confidence: 61%

Local and long-distance inputs dynamically regulate striatal acetylcholine during decision making

Chantranupong

Beron

Zimmer

et al. 2022

Preprint

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Within the basal ganglia, striatal dopamine (DA) and acetylcholine (Ach) are essential for the selection and reinforcement of motor actions and decision making. In vitro studies have revealed a circuit local to the striatum by which each of these two neurotransmitters directly regulates release of the other. Ach, released by a unique population of cholinergic interneurons (CINs), drives DA release via direct axonal depolarization. In turn, DA inhibits CIN activity via dopamine D2 receptors (D2R). Whether and how this circuit contributes to striatal function in vivo remains unknown. To define the in vivo role of this circuit, we monitored Ach and DA signals in the ventrolateral striatum of mice performing a reward-based decision-making task. We establish that DA and Ach exhibit multiphasic and anticorrelated transients that are modulated by decision history and reward outcome. However, CIN perturbations reveal that DA dynamics and reward-prediction error encoding do not require Ach release by CINs. On the other hand, CIN-specific deletion of D2Rs shows that DA inhibits Ach levels in a D2R-dependent manner, and loss of this regulation impairs decision-making. To determine how other inputs to striatum shape Ach signals, we assessed the contribution of projections from cortex and thalamus and found that glutamate release from both sources is required for Ach release. Altogether, we uncover a dynamic relationship between DA and Ach during decision making and reveal modes of CIN regulation by local DA signals and long-range cortical and thalamic inputs. These findings deepen our understanding of the neurochemical basis of decision making and behavior.

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“…Dopamine depletion alone produces an increased expression of enkephalin (and 5-HT1B [ 24 ]) in D2-MSNs. Enkephalin expression is especially sensitive to cortical input [ 32 ], and the increased expression after dopamine depletion is considered to reflect the effect of disinhibited glutamate inputs (in interaction with other neurotransmitters, for example, acetylcholine [ 33 , 34 ]), due to the loss of inhibitory D2 receptor tone in these neurons (see [ 13 ]). Our present findings demonstrate that, after dopamine depletion alone, the increases in the enkephalin and 5-HT1B expression were overall also positively correlated with local levels of PDE10A expression, suggesting a role for PDE10A in these molecular changes in D2-MSNs as well.…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase 10A (PDE10A): Regulator of Dopamine Agonist-Induced Gene Expression in the Striatum

Bonate

Kurek

Hrabak

et al. 2022

Cells

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Dopamine and other neurotransmitters have the potential to induce neuroplasticity in the striatum via gene regulation. Dopamine receptor-mediated gene regulation relies on second messenger cascades that involve cyclic nucleotides to relay signaling from the synapse to the nucleus. Phosphodiesterases (PDEs) catalyze cyclic nucleotides and thus potently control cyclic nucleotide signaling. We investigated the role of the most abundant striatal PDE, PDE10A, in striatal gene regulation by assessing the effects of PDE10A inhibition (by a selective PDE10A inhibitor, TP-10) on gene regulation and by comparing the basal expression of PDE10A mRNA throughout the striatum with gene induction by dopamine agonists in the intact or dopamine-depleted striatum. Our findings show that PDE10A expression is most abundant in the sensorimotor striatum, intermediate in the associative striatum and lower in the limbic striatum. The inhibition of PDE10A produced pronounced increases in gene expression that were directly related to levels of local PDE10A expression. Moreover, the gene expression induced by L-DOPA after dopamine depletion (by 6-OHDA), or by psychostimulants (cocaine, methylphenidate) in the intact striatum, was also positively correlated with the levels of local PDE10A expression. This relationship was found for gene markers of both D1 receptor- and D2 receptor-expressing striatal projection neurons. Collectively, these results indicate that PDE10A, a vital part of the dopamine receptor-associated second messenger machinery, is tightly linked to drug-induced gene regulation in the striatum. PDE10A may thus serve as a potential target for modifying drug-induced gene regulation and related neuroplasticity.

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Coincidence of cholinergic pauses, dopaminergic activation and depolarisation of spiny projection neurons drives synaptic plasticity in the striatum

Cited by 42 publications

References 51 publications

Intrinsic reward-like dopamine and acetylcholine dynamics in striatum

Intrinsic reward-like dopamine and acetylcholine dynamics in striatum

Local and long-distance inputs dynamically regulate striatal acetylcholine during decision making

Phosphodiesterase 10A (PDE10A): Regulator of Dopamine Agonist-Induced Gene Expression in the Striatum

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