Striatal Dopamine Release Is Triggered by Synchronized Activity in Cholinergic Interneurons

Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
Neuron (Impact Factor: 15.05). 07/2012; 75(1):58-64. DOI: 10.1016/j.neuron.2012.04.038
Source: PubMed


Striatal dopamine plays key roles in our normal and pathological goal-directed actions. To understand dopamine function, much attention has focused on how midbrain dopamine neurons modulate their firing patterns. However, we identify a presynaptic mechanism that triggers dopamine release directly, bypassing activity in dopamine neurons. We paired electrophysiological recordings of striatal channelrhodopsin2-expressing cholinergic interneurons with simultaneous detection of dopamine release at carbon-fiber microelectrodes in striatal slices. We reveal that activation of cholinergic interneurons by light flashes that cause only single action potentials in neurons from a small population triggers dopamine release via activation of nicotinic receptors on dopamine axons. This event overrides ascending activity from dopamine neurons and, furthermore, is reproduced by activating ChR2-expressing thalamostriatal inputs, which synchronize cholinergic interneurons in vivo. These findings indicate that synchronized activity in cholinergic interneurons directly generates striatal dopamine signals whose functions will extend beyond those encoded by dopamine neuron activity.

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Available from: Sarah Threlfell, Apr 28, 2014
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    • "Stimulation of dopamine D1 receptors prolongs striatal membrane depolarizations (Hern andez-L opez et al., 1997), which may underlie the immediate focusing effect of dopamine on behavior. Thus, the synaptic dopamine actions, despite their heterogeneity (Threlfell et al., 2012: Roeper, 2013; Chuhma et al., 2014), are overall consistent with the behavioral dopamine functions in learning and approach. "
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    ABSTRACT: Rewards are defined by their behavioral functions in learning (positive reinforcement), approach behavior, economic choices and emotions. Dopamine neurons respond to rewards with two components, similar to higher order sensory and cognitive neurons. The initial, rapid, unselective dopamine detection component reports all salient environmental events irrespective of their reward association. It is highly sensitive to factors related to reward and thus detects a maximal number of potential rewards. It senses also aversive stimuli but reports their physical impact rather than their aversiveness. The second response component processes reward value accurately and starts early enough to prevent confusion with unrewarded stimuli and objects. It codes reward value as a numeric, quantitative utility prediction error, consistent with formal concepts of economic decision theory. Thus, the dopamine reward signal is fast, highly sensitive and appropriate for driving and updating economic decisions. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 08/2015; DOI:10.1002/cne.23880 · 3.23 Impact Factor
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    • "These include acetylcholinesterase, choline acetyltransferase , muscarinic acetylcholine (ACh) receptors, and nicotinic acetylcholine receptors (nAChRs). Recently, nAChRs have emerged as crucial regulators of DA transmission (Rice and Cragg, 2004; Zhang and Sulzer, 2004; Exley and Cragg, 2008; Cachope et al., 2012; Threlfell et al., 2012), and many groups are actively searching for novel compounds designed to specifically manipulate nAChRs in the DA system. nAChRs in the central nervous system are either homomeric a7 receptors or heteromeric 0306-4522/Ó 2015 IBRO. "
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    ABSTRACT: Acetylcholine acts through nicotinic and muscarinic acetylcholine (ACh) receptors in ventral midbrain and striatal areas to influence dopamine (DA) transmission. This cholinergic control of DA transmission is important for processes such as attention and motivated behavior, and is manipulated by nicotine in tobacco products. Identifying and characterizing the key ACh receptors involved in cholinergic control of DA transmission could lead to small molecule therapeutics for treating disorders involving attention, addiction, Parkinson's disease, and schizophrenia. α6-containing nicotinic acetylcholine receptors (nAChRs) are highly and specifically expressed in midbrain DA neurons, making them an attractive drug target. Here, we used genetic, pharmacological, behavioral, and biophysical approaches to study this nAChR subtype. For many experiments, we used mice expressing mutant α6 nAChRs ("α6L9S" mice) that increase the sensitivity of these receptors to agonists such as ACh and nicotine. Taking advantage of a simple behavioral phenotype exhibited by α6L9S mice, we compared the ability of full versus partial α6∗ nAChR agonists to activate α6∗ nAChRs in vivo. Using local infusions of both agonists and antagonists into brain, we demonstrate that neurons and nAChRs in the midbrain are sufficient to account for this behavioral response. To complement these behavioral studies, we studied the ability of in vivo α6∗ nAChR activation to support plasticity changes in midbrain DA neurons that are relevant to behavioral sensitization and addiction. By coupling local infusion of drugs and brain slice patch clamp electrophysiology, we show that activating α6∗ nAChRs in midbrain DA areas is sufficient to enhance glutamatergic transmission in VTA DA neurons. Together, these results from in vivo studies strongly suggest that α6∗ nAChRs expressed by VTA DA neurons are positioned to strongly influence both DA-mediated behaviors and the induction of synaptic plasticity by nicotine. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 07/2015; 304. DOI:10.1016/j.neuroscience.2015.07.052 · 3.36 Impact Factor
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    • "Thus, abnormalities in DA P r could be masked by nAChR activation which restores DA activity-dependence to a prelesion state. This is most likely because nAChRs very powerfully increase the apparent DA P r by ~100–300% (Rice and Cragg, 2004; Threlfell et al., 2012; Zhang and Sulzer, 2004; Zhou et al., 2001). Such a powerful effect is expected to dominate and eclipse other mechanisms located in DA axons that regulate DA P r , increasing P r maximally and causing a ceiling effect which ensures that no difference in signalling is detectable Fig. 4. nAChR activity masks effects of a lesion. "
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    ABSTRACT: Dopamine function is disturbed in Parkinson's disease (PD), but whether and how release of dopamine from surviving neurons is altered has long been debated. Nicotinic acetylcholine receptors (nAChRs) on dopamine axons powerfully govern dopamine release and could be critical contributing factors. We revisited whether fundamental properties of dopamine transmission are changed in a parkinsonian brain and tested the potentially profound masking effects of nAChRs. Using real-time detection of dopamine in mouse striatum after a partial 6-hydroxydopamine lesion and under nAChR inhibition, we reveal that dopamine signals show diminished sensitivity to presynaptic activity. This effect manifested as diminished contrast between DA release evoked by lowest versus highest frequencies. This reduced activity-dependence was underpinned by loss of short-term facilitation of dopamine release, consistent with an increase in release probability (Pr). With nAChRs active, the reduced activity-dependence of dopamine release after a parkinsonian lesion was masked. Consequently, moment-by-moment variation in activity of nAChRs may lead to dynamic co-variation in dopamine signal impairments in PD. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 06/2015; 82. DOI:10.1016/j.nbd.2015.06.015 · 5.08 Impact Factor
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