Illuminating anhedonia

T. W. Robbins
2015 Science  
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
more » ... 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 are at least two reasons for thinking it may not always be equivalent to other forms of reward. Stimulant drugs such as cocaine are presumed to produce their rewarding effects, at least partly, by increasing tonic (background) levels of striatal DA rather than by increasing phasic DA release in the striatum as a consequence of mesolimbic DA neuron activity. In the study of Ferenczi et al., phasic stimulation of midbrain DA neurons not only activated regions of the dorsal and ventral striatum, but also activated regions of the cerebral cortex (the retrosplenial cortex), although surprisingly not the vmPFC itself, as has been shown in studies of natural reward anticipation and feedback in humans (4). Ferenczi et al. used a clever optogenetic stimulation method to drive an asynchronous enhancement of medial PFC hyperexcitability in awake rats, thereby mimicking states in human patients with depression; increased BOLD responses in the vmPFC to happy (but not sad) stimuli have been correlated with anhedonia ratings (5, 6) . Hyperexcitability of the medial PFC suppressed sucrose preference in the rat, but not drinking per se, and curtailed social interaction without affecting general locomotor activity, suggestive of a specific inhibitory effect of medial PFC on reward-motivated behavior. The same medial PFC hyperexcitability also suppressed the striatal responses to optically stimulated DA neurons in the midbrain, and abolished a behavioral preference for the place associated with midbrain DA neuron stimulation. More generally, the state of medial PFC hyperexcitability elicited greater connectivity between the medial PFC, lateral orbitofrontal cortex (OFC), and ventral striatum by enhancing synchronous firing. This greater synchronous connectivity correlated with reduced sucrose preference (through mechanisms that are still obscure). This is reminiscent of the discovery of greater connectivity of the subgenual cingulate cortex with nodes of the "default network," including the OFC, the thalamus, and the precuneus in depressed patients (5) and of the association of vmPFC activity with anhedonia during the processing of positive emotional information in nonclinical individuals (6). Whether this NEUROSCIENCE Illuminating anhedonia Optogenetics and fMRI reveal the brain circuitry of anhedonia Ventromedial prefrontal cortex (vmPFC) Prefrontal cortex Midbrain (VTA) Dorsal striatum Ventral striatum Nucleus accumbens Mesolimbic DA pathway Mesocortical DA pathway Inhibitory efect of optogenetic stimulation (possible sites) Reward circuitry. Shown are approximate anatomical relationships in the human brain between the midbrain dopamine (DA) pathways from the ventral tegmental area (VTA) to the nucleus accumbens (part of the ventral striatum) and the vmPFC, and reciprocal influences (mediated by glutamate) of the vmPFC. The vmPFC includes the medial orbitofrontal cortex and parts of the ventral cingulate cortex, including the subgenual cingulate cortex. Ferenzi et al. show that the rewarding effects of optogenetic stimulation of the VTA were counteracted by optogeneticallyinduced hyperexcitability of the vmPFC to mimic behavioral anhedonia-like symptoms in rats, presumably via descending pathways to the subcortical regions including the striatum and VTA.
doi:10.1126/science.aad9698 pmid:26721987 fatcat:zibk3ywj2nbx7ld3qiuin2d2pu