Reward and aversion in a heterogeneous midbrain dopamine system

Highlights

• Midbrain dopamine neurons have heterogeneous molecular and physiological properties.

• DA neurons may have distinct behavioral functions based on their projection targets.

• Inputs to the ventral tegmental area synapse on different neuron subpopulations.

• DA neurons participate in distinct circuits mediating partially distinct functions.

Abstract

The ventral tegmental area (VTA) is a heterogeneous brain structure that serves a central role in motivation and reward processing. Abnormalities in the function of VTA dopamine (DA) neurons and the targets they influence are implicated in several prominent neuropsychiatric disorders including addiction and depression. Recent studies suggest that the midbrain DA system is composed of anatomically and functionally heterogeneous DA subpopulations with different axonal projections. These findings may explain a number of previously confusing observations that suggested a role for DA in processing both rewarding as well as aversive events. Here we will focus on recent advances in understanding the neural circuits mediating reward and aversion in the VTA and how stress as well as drugs of abuse, in particular cocaine, alter circuit function within a heterogeneous midbrain DA system.

This article is part of a Special Issue entitled ‘NIDA 40th Anniversary Issue’.

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.