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.

Download full-text


Available from: Sarah Threlfell, Apr 28, 2014
27 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "This mainly seems to be the result of H 3 receptor activation, consistent with previous observations (Arias-Montano et al., 2001), although for the direct pathway D 1 -expressing MSNs part of this negative modulation seems to be the result of histamine acting at H 2 receptors. This latter result could be explained by histamine acting at the cholinergic interneurons of the striatum (Munakata and Akaike, 1994; Bell et al., 2000) with the released acetylcholine acting at the GABergic synapses on D 1 -expressing MSNs (Sugita et al., 1991; Koos and Tepper, 2002), although other neuromodulatory afferents might well be involved (Prast et al., 1999a; Threlfell et al., 2012). Indeed, a prominent role for histamine in modulating cholinergic neurons was recently reported for the basal forebrain (Zant et al., 2012) and suggested in mouse models of L-DOPA induced dyskinesia (Lim et al., 2015 "
    [Show abstract] [Hide abstract]
    ABSTRACT: The neuromodulator histamine is released throughout the brain during periods of wakefulness. Combined with an abundant expression of histamine receptors, this suggests potential widespread histaminergic control of neural circuit activity. However, the effect of histamine on many of these circuits is unknown. In this review we will discuss recent evidence for histaminergic modulation of the basal ganglia circuitry, and specifically its main input nucleus; the striatum. Furthermore, we will discuss recent findings of histaminergic dysfunction in several basal ganglia disorders, including in Parkinson's disease and most prominently, in Tourette's syndrome, which has led to a resurgence of interest in this neuromodulator. Combined, these recent observations not only suggest a central role for histamine in modulating basal ganglia activity and behaviour, but also as a possible target in treating basal ganglia disorders. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 08/2015; DOI:10.1016/j.neuropharm.2015.08.013 · 5.11 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
Show more