Scientific Understanding of Consciousness
Prefrontal cortical regulation of reward-related behavior
Science 01 Jan 2016: Vol. 351, Issue 6268
Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior
Emily A. Ferenczi, et.al.
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
Neurosciences Program, Stanford University, Stanford, CA 94305, USA.
Brain Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA.
Department of Neurobiology and Behavior, Cornell University, Ithaca, NY 14853, USA.
Department of Psychology, Stanford University, Stanford, CA 94305, USA.
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
Department of Radiology, Stanford University, Stanford, CA, 94305, USA.
Howard Hughes Medical Institute, Stanford University, Stanford, CA, 94305, USA.
The drive to seek and experience reward is conserved across species and, in mammals, involves interactions between subcortical dopaminergic systems and limbic structures such as the striatum. Impairment of this process, observed across a number of psychiatric conditions, is the clinical symptom of anhedonia (loss of enjoyment). The neural mechanisms underlying anhedonia are unknown but could result from abnormal interactions between cortical and subcortical reward circuits. We sought to test the hypothesis that elevated medial prefrontal cortex (mPFC) excitability (a clinical feature associated with anhedonia) exerts suppressive control over the interactions between two distant subcortical regions: the dopaminergic midbrain and the striatum.
Clinical imaging studies have detected elevated activity in the mPFC in human patients with depression, and treatment is associated with normalization of this overactivity and improvement of anhedonic symptoms. Additionally, human studies have identified areas of the brain that respond to reward anticipation and experience, and this response can be suppressed in psychiatric disease. However, the source of this reward signal and the mechanisms underlying its modulation have not been causally demonstrated. We have integrated a diverse set of chronic and acute optogenetic tools with functional magnetic resonance imaging (fMRI) to provide a bridge between the causal, cellular specificity of rodent optogenetics and the brainwide observations that characterize human neuroimaging, with the goal of locally manipulating and globally visualizing neural activity to understand the regulation of reward-seeking behavior.
We demonstrate that stimulation of midbrain dopamine neurons drives both striatal fMRI blood oxygen level–dependent (BOLD) activity and reward-seeking behavior, and we show that these are correlated across individuals. We additionally find that silencing of dopamine neurons suppresses activity in the striatum, as well as in other brain regions (such as the hypothalamus), and drives avoidance behavior. Having established this bidirectional control of reward-seeking behavior, we then tested for perturbation of this circuitry via elevation of mPFC excitability. We observed suppression of striatal responses to dopamine, as well as the behavioral drive to seek out dopamine neuron stimulation and other natural rewarding stimuli. Finally, we demonstrate that stably elevated mPFC excitability synchronizes corticolimbic BOLD and electrophysiological activity, which in turn can predict anhedonic behavior in individual animals.
Our findings from experiments involving local cell-specific control, simultaneously with global unbiased observation of neural activity, reveal that the mPFC exerts top-down control over midbrain dopaminergic interactions with the striatum and that, when elevated, activity in the mPFC can suppress natural reward-related behavior. Furthermore, we observe that cortical-subcortical neural dynamics work in concert to regulate reward processing. All of these findings have implications for our understanding of natural reward-related physiology and behavior, as well as the pathogenesis of anhedonia.
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