Meaningful silences: how dopamine listens to the ACh pause

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Mesostriatal dopaminergic neurons (DANs) and striatal cholinergic neurons (tonically active neurons, TANs) participate in signalling the behavioural or reward-related significance of stimuli in the environment. An antagonistic balance between dopamine (DA) and ACh is well known to regulate postsynaptic signal integration in the striatum. Recent findings have revealed additional presynaptic ACh–DA interactions of previously unappreciated sophistication. Striatal ACh acts presynaptically to polarize powerfully how opposing DAN activities are transduced into DA release. Furthermore, characteristic reward-related activities of TANs and DANs are temporally coincident but differently variant with reward probability. Reward-related DA signals could therefore be governed by the concomitant activity in TANs. This article discusses the dynamic implications for DA signalling when these phenomena act in concert. TAN pauses might powerfully enhance the contrast, or salience, of DA signals offered by reward-related bursts, and even by reward omission-related pauses, in DANs. Through such mechanisms, TAN–DAN interactions would be functionally cooperative.

Introduction

Striatal dopamine (DA) and ACh and their interactions are fundamental to striatal function. These functions include motor response selections of the basal ganglia, and the signalling of motivational or reward-related information. Mesostriatal dopaminergic neurons (DANs) and striatal cholinergic interneurons (tonically active neurons or TANs 1, 2, 3, 4) appear pivotal for signalling unexpected primary rewards in addition to the learning and signalling of environmental cues that predict reward (or more generally, events of high salience) 5, 6, 7, 8, 9, 10. There is a longstanding hypothesis of an antagonistic balance between DA and ACh in normal striatal function 4, 5, 9, 11. This ACh–DA balance hypothesis arose from the alleviation of the debilitating motor dysfunctions of Parkinson's disease by pro-DA treatments on the one hand, and anti-cholinergic treatments on the other 11, 12. Furthermore, on a cellular level, DA and ACh can have opposing effects on excitability of striatal output neurons and on long-term corticostriatal plasticity 5, 9, 11, 13, 14, 15, 16, 17, 18. Long-term potentiation (LTP) of corticostriatal synaptic efficacy is thought to participate in key aspects of reward-related learning, such as the acquisition of incentive value by previously neutral stimuli, learning of stimulus–response associations, and development of habits. This learning subsequently governs the translation of reward-related signals into contextually appropriate behavioural responses (reviewed elsewhere, e.g. 10, 19).

Yet in the working striatum, DA and ACh systems do not necessarily act in opposition; the balance of their actions depends pivotally on the dynamic availability of each neurotransmitter. In fact, several recent studies have revealed functional cooperativity between DA and ACh systems, of a power and complexity far greater than previously appreciated 17, 20, 21, 22, 23, 24. This cooperativity can arise from at least two interacting sources: coincidences in the timing of activity in the parent neurons that shape the dynamic availability of each transmitter; and the effects of ACh on the release of DA from DAN terminals. For example, ACh acting at nicotinic ACh receptors (nAChRs) located presynaptically on dopaminergic axon terminals 22, 25 can either facilitate or inhibit DA release, depending on DAN firing frequency 20, 21. In addition, DAN and TAN populations signal reward-related events by dynamically modifying their firing frequencies 7, 17, 26, 27 in a manner that appears synchronous [17]. Thus, ACh–DA presynaptic interactions and their postsynaptic consequences will be temporally dynamic. A complete understanding of how DA and ACh govern the processing of reward-related information by the striatum requires consideration of the consequences of these interactions.

What could be the consequences and function(s) of coincident changes in TAN and DAN activity during reward-related signalling? In other words, what reward-related information might coincident changes in TAN and DAN activity signal over and above the information encoded by either population alone? This article will focus on how the presynaptic effects of ACh on DA release 20, 21, 28, in concert with correlated patterns of activity in DANs and TANs [17], now enable us to address the following questions: what effect could the TAN pause that accompanies reward-related signalling 17, 26, 27 have on the generation of concomitant DA signals? Do TAN pauses effectively reduce ACh neurotransmission at striatal nAChRs? Might a TAN pause govern DA signals associated with reward omission, in addition to presentation? Available data now suggest that ACh could operate a powerful filter on DA signal generation, through which a TAN pause promotes the saliency of any concomitant reward-related activity in DANs.

Section snippets

Distinct but coincident reward-related activity in dopaminergic and cholinergic neurons

DANs and TANs both have fundamental but complex roles in reward-related signalling and reinforcement learning 7, 9, 10, 16, 18, 29, 30, 31, 32, 33, 34, 35. Rewards themselves can be described in part as ‘…the environmental incentives we return to after having previously contacted them’ [36] and can be natural (e.g. food or drink) or artificial (e.g. drugs of addiction). Rewards can also be described as having reinforcement value whereby positive reinforcers (or rewards) increase (reinforce) the

Gating of dynamic DA release probability by ACh at presynaptic nAChRs

How a given pattern and frequency of DAN activity is relayed into striatal DA release transients will depend on the processing or filtering of DAN activity at axonal release sites. Such presynaptic filtering will be governed by use-dependent short-term changes, or ‘plasticity’, in DA release probability 51, 52, and also by neuromodulation by any transmitters that act at auto- or hetero-receptors on the terminal membrane. Therefore, we cannot assume that reward-related DAN activity corresponds

ACh gates DA signals according to DAN activity

This filtering of ongoing DA release probabilities by nAChRs also depends on the frequency of DAN activity 20, 21: the shorter the inter-pulse interval (i.e. the higher the DAN firing frequency), the greater the relief from short-term depression during nAChR inhibition (Figure 3c). Elimination of nAChR activity, in effect, reduces initial DA release probability but in turn permits a high-frequency pass filtering that facilitates burst release. Consequently, reduced nAChR activity can enhance

Listening to the TAN pause – the sound of silence?

These data imply that any physiological reduction in endogenous ACh activity at striatal nAChRs could similarly influence the contrast, or ‘salience’ to striatal neurons, of any change in DA signalling when DANs change firing rate. The TAN pause is one obvious candidate cause of a reduction in the endogenous ACh signal. By reducing ACh activity at nAChRs on dopaminergic axons, the TAN pause could powerfully promote the contrast in DA signalling due to coincident changes in DAN activity, as

Upping the ups and downing the downs?

As we have seen, the TAN pause has the potential to amplify DA signals associated with the DAN burst upon exposure to reward-related stimuli (or positive reward-prediction errors), and also to diminish further the reduction in DA activity associated with the DAN pause upon reward omission (or negative prediction errors). However, it remains to be resolved whether or how DANs can adequately encode negative prediction errors [70]. Whereas positive prediction errors are quantitatively correlated

Summary and further perspectives on ACh–DA interactions

Synchronized neuronal activities and a reciprocal control of neurotransmitter release by TANs and DANs would offer a highly dynamic outcome for striatal computation. A TAN pause not only might provide a dynamic window for when and how DA signals are processed postsynaptically by the striatum [17], but also, through a catalogue of presynaptic nAChRs, might govern what strength of DA signal is generated. The TAN pause might promote the saliency of a concomitant change in DAN activity, whatever

Acknowledgements

I gratefully acknowledge support from the Michael J. Fox Foundation (USA), the Parkinson's Disease Society (UK), and the Paton Fellowship (Department of Pharmacology, University of Oxford).

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