Heterogeneity of the midbrain dopamine system: Implications for Parkinson disease.

Abstract

The midbrain dopaminergic (DA) system is composed primarily of neurons in the substantia nigra pars compacta (SNc, area A10) and ventral tegmental area (VTA, area A9). These include at least 5 neuron subpopulations with distinct patterns of gene expression, electrophysiologic properties, projections to the striatum and cerebral cortex, and response to environmental stimuli. They are involved in several key brain functions, including action selection, motor performance, motivation and reward-based learning, working memory, and cognition. Midbrain DA neurons are activated by alerting signals involved in rapid detection of potentially relevant sensory cues. Most increase their activity in response to reward stimuli and are inhibited by aversive stimuli, thereby coding motivational value for learning reward-oriented behavior. Others are activated by aversive stimuli and code motivational salience of the stimulus. These different types of midbrain DA neurons are anatomically segregated and have specific afferent and efferent connections supporting specific aspects of behavior. Neurons encoding motivational value are located in the VTA and medial SNc and project primarily to the nucleus accumbens (NAc) and ventromedial prefrontal cortex and support Pavlovian learning of actions leading to successful outcomes. Neurons encoding motivational salience are located in the dorsolateral SNc and project to the dorsomedial striatum (primarily the caudate) and dorsolateral prefrontal cortex and modulate goal-oriented behavior. Neurons in the ventral tier of the SNc project to the dorsolateral striatum (putamen) and regulate habit formation and automatic motor behavior. Several features of ventral tier SNc neurons render them susceptible to oxidative stress and the subsequent neurodegeneration underlying Parkinson disease (PD). Involvement of other SNc and VTA neurons may contribute to nonmotor aspects of PD, such as depression, cognitive dysfunction, and impulse dyscontrol, in response to DA agonists. All these topics have been extensively discussed in several reviews.1–18