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

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

Amygdala and bed nucleus of the stria terminalis circuitry: Implications for addiction-related behaviors

Complex motivated behavioral processes, such as those that can go awry following substance abuse and other neuropsychiatric disorders, are mediated by a distributive network of neurons that reside throughout the brain. Neural circuits within the amygdala regions, such as the basolateral amygdala (BLA), and downstream targets such as the bed nucleus of the stria terminalis (BNST), are critical neuroanatomical structures for orchestrating emotional behavioral responses that may influence motivated actions such as the reinstatement of drug seeking behavior. Here, we review the functional neurocircuitry of the BLA and the BNST, and discuss how these circuits may guide maladaptive behavioral processes such as those seen in addiction. Thus, further study of the functional connectivity within these brain regions and others may provide insight for the development of new treatment strategies for substance use disorders

Coordination of Brain-Wide Activity Dynamics by Dopaminergic Neurons

Several neuropsychiatric conditions, such as addiction and schizophrenia, may arise in part from dysregulated activity of ventral tegmental area dopaminergic (THVTA) neurons, as well as from more global maladaptation in neurocircuit function. However, whether THVTA activity affects large-scale brain-wide function remains unknown. Here we selectively activated THVTA neurons in transgenic rats and measured resulting changes in whole-brain activity using stimulus-evoked functional magnetic resonance imaging. Applying a standard generalized linear model analysis approach, our results indicate that selective optogenetic stimulation of THVTA neurons enhanced cerebral blood volume signals in striatal target regions in a dopamine receptor-dependent manner. However, brain-wide voxel-based principal component analysis of the same data set revealed that dopaminergic modulation activates several additional anatomically distinct regions throughout the brain, not typically associated with dopamine release events. Furthermore, explicit pairing of THVTA neuronal activation with a forepaw stimulus of a particular frequency expanded the sensory representation of that stimulus, not exclusively within the somatosensory cortices, but brain-wide. These data suggest that modulation of THVTA neurons can impact brain dynamics across many distributed anatomically distinct regions, even those that receive little to no direct THVTA input

Coordination of Brain-Wide Activity Dynamics by Dopaminergic Neurons

Several neuropsychiatric conditions, such as addiction and schizophrenia, may arise in part from dysregulated activity of ventral tegmental area dopaminergic (TH(VTA)) neurons, as well as from more global maladaptation in neurocircuit function. However, whether TH(VTA) activity affects large-scale brain-wide function remains unknown. Here we selectively activated TH(VTA) neurons in transgenic rats and measured resulting changes in whole-brain activity using stimulus-evoked functional magnetic resonance imaging. Applying a standard generalized linear model analysis approach, our results indicate that selective optogenetic stimulation of TH(VTA) neurons enhanced cerebral blood volume signals in striatal target regions in a dopamine receptor-dependent manner. However, brain-wide voxel-based principal component analysis of the same data set revealed that dopaminergic modulation activates several additional anatomically distinct regions throughout the brain, not typically associated with dopamine release events. Furthermore, explicit pairing of TH(VTA) neuronal activation with a forepaw stimulus of a particular frequency expanded the sensory representation of that stimulus, not exclusively within the somatosensory cortices, but brain-wide. These data suggest that modulation of TH(VTA) neurons can impact brain dynamics across many distributed anatomically distinct regions, even those that receive little to no direct TH(VTA) input