NEUROSCIENCE. Illuminating anhedonia.

T he mesolimbic dopamine (DA) system is part of the brain’s reward circuitry (see the figure). It controls an individual’s responses to rewards such as food, social interactions, and money, and is therefore an important determinant of motivation. Midbrain DA neurons projecting to the striatum are causally involved in reward-like processes. Less clear is how another apparent target of midbrain DA neurons, the ventromedial prefrontal cortex (vmPFC), may contribute to the reward system. On page 41 of this issue, Ferenczi et al. (1) report using a unique combination of optogenetic tools and functional magnetic resonance brain imaging (fMRI) in conscious rats to investigate the underlying mechanisms of the competitive relationships of these two brain regions over striatal function and reward-like behavior. The findings have implications for understanding and treating affective symptoms in disorders such as depression, schizophrenia, and addiction. Evidence of a reward system was derived from experiments in rats some 40 years ago and has been confirmed by recent studies showing that rodents will choose to receive optogenetic stimulation of midbrain DA neurons [which were engineered to be activated by light (2)]. The findings have been paralleled in humans by fMRI; thus, the anticipation of reward evokes increased activity in the human ventral striatum. This correlated with indirect measures (from positron emission tomography) of DA release in the striatum (3). Exposure to both primary rewards (e.g., pleasant tastes and sights) and conditioned or symbolic rewards (such as money) leads to increased activity in the vmPFC (4). It is therefore paradoxical that hyperactivity of this region has also been linked in humans to anhedonia, the inability to feel pleasure (5, 6). Removing this hyperactivity has been a target for various antidepressant treatments, including pharmacotherapy, cognitive therapy, and deep brain stimulation. Ferenczi et al. asked whether the effect of enhancing midbrain DA neuron activity is blunted by influences from the rat medial PFC. DA-containing midbrain neurons in the rat were exposed to laser light (via implanted optic fibers) to activate ion channels (opsins) that were either inhibitory or excitatory. Stimulation via excitation acted as a reward, as rats chose to turn on such stimulation. Stimulation also produced an increased blood oxygen level–dependent (BOLD) fMRI response in the striatum, just as would have been predicted from prior human studies. Moreover, this activation of the striatum was DA-dependent, as exposure to DA receptor antagonists blocked both the rewarding effects and the BOLD signature. A key question is the precise physiological nature of this potent rewarding effect; there