Dopamine-Mediated Alterations in Brain-Wide Functional Dynamics Measured by fMRI

Abstract

Drug addiction is a complex, multifaceted disease characterized by compulsive drug-seeking and drug-taking behavior despite adverse consequences. In accordance with its complex nature, several neural systems are likely to be dysregulated to promote maladaptive behaviors associated with addiction. For instance, dopaminergic signaling within the mesolimbic dopamine (DA) system is thought to be critical for reward prediction, an adaptive process that likely goes awry in addiction. While it is well known that DA release events occur in mesolimbic terminal fields such as the nucleus accumbens (NAc) in response to reward predictive cues, including those associated with drugs of abuse, how DA release events affect network adaptation across the entire brain has largely been unexplored. To address this, we selectively activated ventral tegmental area (VTA) dopaminergic (THVTA) neurons in transgenic rats and measured resulting changes in whole-brain activity using stimulus-evoked functional magnetic resonance imaging (fMRI). We demonstrated DAergic modulation activates several anatomically distinct regions throughout the brain, many of which receive little to no direct dopaminergic input. We also showed that explicit pairing of midbrain dopamine neuron activity and a sensory stimulus can dramatically enhance the brain-wide representation of that specific sensory stimulus. Next, since drugs of abuse increase extracellular DA in the mesolimbic pathway of the brain, we utilized a rodent model of addiction to explore whether functional connectivity is altered after self-administration of cocaine. We found that cocaine self-administration orchestrates dynamic shifts in functional connectivity across many anatomically defined neuronal network nodes. Overall, these findings suggest that DA not only controls plasticity in direct target regions, but may effectively modulate brain-wide network plasticity as well. This research may provide critical insight into the circuit-level maladaptations that underlie compulsive drug-seeking behavior, and the chronic cycles of abstinence and relapse that characterize addiction in humans.Doctor of Philosoph