Invited reviewReward and aversion in a heterogeneous midbrain dopamine system
Introduction
As investigators have delved deeper into the brain's neuronal networks underlying complex behaviors using innovative techniques such as optogenetics, it has become clear that previous notions about the functions and connectivity of individual cell types in the mammalian brain need to be revised. Nowhere is this more apparent than for midbrain dopamine (DA) cells. Over the past decade our view of the midbrain DA system has changed from a simple organization of anatomically separate DA neurons in the substantia nigra and ventral tegmental area (VTA) to a more complex system of DA neuron subtypes with different axonal projection and inputs, distinct anatomical, molecular and electrophysiological features (Ikemoto, 2007; Lammel et al., 2008, 2011, 2012; Margolis et al., 2006, 2008) as well as additional co-transmitters such as GABA (Tritsch et al., 2012) and glutamate (El Mestikawy et al., 2011). In addition, it is well established that midbrain DA neurons are intermingled and connected with different subpopulations of GABAergic and glutamatergic neurons (Hnasko et al., 2012; Margolis et al., 2012; Yamaguchi et al., 2011). Thus, perhaps not surprisingly, DA neuron activity has been associated with a variety of brain functions including the signaling of reward, aversion, salience, uncertainty and novelty (Bromberg-Martin et al., 2010; Schultz, 2007; Ungless et al., 2010). Classic work demonstrated that midbrain DA neurons evince characteristic phasic responses to rewards and cues that predict rewards, and are inhibited by aversive events (Schultz, 1997; Ungless et al., 2004). Furthermore, it has been suggested by many investigators that drugs of abuse hijack the brain's “reward system” and that among the most important neural circuit modifications that contribute to the development of addiction are changes in the properties of excitatory synapses on midbrain VTA DA neurons (Luscher and Malenka, 2011). Here, we provide an overview of how different circuits involving distinct VTA DA neuron subpopulations may contribute to the role of DA in reward- and aversion-related behaviors. In addition, we highlight how these circuits may contribute to drug addiction.
Section snippets
Heterogeneity of the mesocorticolimbic dopamine system
Midbrain DA neurons are mainly located in three nuclei, the VTA (A10), the retrorubral field (RRF, A8) and substantia nigra pars compacta (SNc, A9) as well as sparsely scattered in the substantia nigra pars reticulata (SNp). The two major subnuclei of the VTA are the parabrachial pigmented (PBP) and paranigral (PN) nuclei. Furthermore, the caudal linear nucleus (CLi), interfascicular nucleus (IF), and rostral linear nucleus of the raphe (RLi) are often also considered VTA subregions (Oades and
Dopamine neuron activity during reward and aversion
For decades investigators have been studying the relationship between midbrain DA neuron activity and reward (Schultz, 1997, 2007, 2012; Wise and Rompre, 1989). The central role of DA neuron activity in reward-related processes has been well-established by electrophysiological studies. Single unit recordings in primates performing an operant task showed that putative DA neurons are phasically excited (i.e. they exhibit burst discharges of action potentials) by unexpected food rewards (Schultz,
Afferent control of dopamine neuron activity
The VTA receives both excitatory and inhibitory inputs from a broad distribution of brain areas (Geisler et al., 2007; Sesack and Grace, 2010; Watabe-Uchida et al., 2012). Activation of postsynaptic NMDA receptors are particularly important for driving high-frequency bursts of action potentials (Korotkova et al., 2004) and are critical for reward-dependent learning (Zweifel et al., 2009). Clearly, an important line of research is to determine the anatomical connectivity of afferents to VTA
VTA dopamine neurons and stress-induced depression
Chronic stress is an important diathesis for depression in humans and is used to generate rodent models of depression. It has long been postulated that malfunction of the brain's reward circuitry may play an important role in mediating key symptoms of stress-elicited behaviors, including depression (Friedman et al., 2008; Nestler and Carlezon, 2006; Willner, 1991; Yadid and Friedman, 2008). Here we will briefly review the effects of stress on midbrain DA neurons. Both chronic restraint stress
Effects of drugs of abuse on VTA dopamine neuron excitatory synapses
The mesocorticolimbic DA system has a central role in the acquisition of behaviors that are inappropriately reinforced by drugs of abuse. Drugs of abuse such as cocaine, morphine, nicotine and amphetamine have different pharmacological effects (for recent review see Luscher and Malenka, 2011) yet they all significantly impact reward and motivation at least in part by increasing DA release in the NAc. However, there is a growing body of evidence that motivational stimuli, stress, as well as
Conclusions
We have attempted to concisely summarize the evidence supporting the idea that VTA DA neurons are heterogeneous not only in regard to their anatomical, molecular and electrophysiological properties but also in their response to salient appetitive and aversive stimuli. Heterogeneity in DA neurons and their behavioral functions has also been observed in Drosophila (Claridge-Chang et al., 2009; Krashes et al., 2009; Liu et al., 2012), suggesting strong evolutionary pressure to conserve such
Acknowledgements
Work in the authors' laboratory is supported by grants from the Simons Foundation Autism Research Initiative and NIH (to R.C.M.). S.L. is supported by a fellowship from the German Academy of Sciences Leopoldina. B.K.L. is supported by a Davis Foundation Postdoctoral Fellowship in Eating Disorders Research.
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These authors contributed equally.