This technological tour-de-force combined cutting-edge optogenetic methods with small-animal brain imaging to explore frontal lobe modulation of basic reward processes. The findings may have implications for understanding anhedonia, a debilitating psychiatric symptom that cuts across multiple disorders but is particularly prevalent in depression.

A cutting-edge combination of optogenetic techniques and small-animal fMRI imaging was used to study the influence of ‘top-down’ medial prefrontal cortex (mPFC) control over reward function in rats. Optogenetic stimulation of the ventral tegmental area (VTA, site of origin of ascending dopamine pathways), which the investigators demonstrated was highly rewarding, activated fMRI BOLD signals in several forebrain regions — including the ventral striatum, a site strongly involved in mediating both food and drug reward. Optogenetic stimulation of the mPFC, using an innovative stabilized step-function opsin (SSFO), incurred a wave of widespread functional connectivity changes among various cortical and subcortical structures and suppressed the ability of dopaminergic activation to engage reward-related areas of the striatum. Activation of the mPFC also diminished several reward-related behaviors, including the place preference engendered by optogenetic stimulation of the VTA. Overall, these results suggest that abnormally elevated mPFC activity globally suppresses or impairs the function of the reward system, an insight that extends findings that have accrued using more traditional techniques.

Regarding clinical implications of the work, the authors review human fMRI studies showing abnormally elevated frontal activity in depression, and suggest that the present findings illuminate the underlying mechanistic basis of anhedonia resulting from dysfunctional PFC hyperactivity. Hence, the present findings could have important implications for understanding the etiology of depression, and perhaps also for identifying new treatment strategies for this devastating psychiatric illness.

Noteworthy technical aspects of the study include the use of an innovative optogenetic tool to manipulate mPFC neurons in vivo: the stabilized step-function opsin (SSFO). ‘Traditional’ optogenetic tools are light-responsive ion channel complexes (e.g., channelrhodopsins, halorhodopsins) and are triggered by a pulse of laser or high-intensity LED light to either provoke or inhibit (depending upon the specific opsin) neuronal activity. These neuronal activity changes are coincident with the temporal duration of the light pulse. Hence, to evoke a neuronal activity change that is extended in time, a prolonged pulse is required — which could incur non-specific tissue damage. SSFOs circumvent this problem because the kinetics of channel inactivation are far slower relative to traditional opsins, thereby enabling a single, brief optogenetic light pulse to trigger a prolonged change in neuronal activity. Furthermore, SSFOs are responsive to two different light frequencies. One frequency turns the SSFO ‘on’, the other immediately switches the SSFO ‘off’, thereby enabling tight control over the off-set of opsin-driven activity changes. The SSFO used in the present study was a modified excitatory channelrhodopsin (ChR2). When triggered with blue light, evidence suggests that this protein provokes a subthreshold level of depolarization in mPFC output neurons, rendering those neurons hypersensitive to naturally occurring excitatory drive. This mechanism may better mimic actual mPFC dysfunction underlying various psychopathologies than the traditional optogenetic approach, in which the light pulse itself drives action potentials regardless of endogenous excitatory afferent drive. Another important methodological feature of the study was the development of small-rodent fMRI scanning protocols that do not require that the animal be anesthetized, thereby enabling an assessment of motivational or affective process in the awake animal.

by Faculty Member F1000 expert

Brian Baldo
F1000 Neuroscience
University of Wisconsin-Madison, Madison, WI, USA.


Motivation for reward drives adaptive behaviors, whereas impairment of reward perception and experience (anhedonia) can contribute to psychiatric diseases, including depression and schizophrenia. We sought to test the hypothesis that the medial prefrontal cortex (mPFC) controls interactions among specific subcortical regions that govern hedonic responses. By using optogenetic functional magnetic resonance imaging to locally manipulate but globally visualize neural activity in rats, we found that dopamine neuron stimulation drives striatal activity, whereas locally increased mPFC excitability reduces this striatal response and inhibits the behavioral drive for dopaminergic stimulation. This chronic mPFC overactivity also stably suppresses natural reward-motivated behaviors and induces specific new brainwide functional interactions, which predict the degree of anhedonia in individuals. These findings describe a mechanism by which mPFC modulates expression of reward-seeking behavior, by regulating the dynamical interactions between specific distant subcortical regions.

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DOI: 10.1126/science.aac9698