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.

Forming and breaking associations between emotionally salient environmental stimuli and rewarding or aversive outcomes is an essential component of learned adaptive behavior. Importantly, when cue-reward contingencies degrade, animals must exhibit behavioral flexibility to extinguish prior learned associations. Understanding the specific neural circuit mechanisms that operate during the formation and extinction of conditioned behaviors is critical because dysregulation of these neural processes is hypothesized to underlie many of the maladaptive and pathological behaviors observed in various neuropsychiatric disorders in humans. The medial prefrontal cortex (mPFC) participates in the behavioral adaptations seen in both appetitive and aversive-cue-mediated responding, but the precise cell types and circuit mechanisms sufficient for driving these complex behavioral states remain largely unspecified. Here, we recorded and manipulated the activity of parvalbumin-positive fast spiking interneurons (PVϩ FSIs) in the prelimbic area (PrL) of the mPFC in mice. In vivo photostimulation of PVϩ FSIs resulted in a net inhibition of PrL neurons, providing a circuit blueprint for behavioral manipulations. Photostimulation of mPFC PVϩ cells did not alter anticipatory or consummatory licking behavior during reinforced training sessions. However, optical activation of these inhibitory interneurons to cues associated with reward significantly accelerated the extinction of behavior during non-reinforced test sessions. These data suggest that suppression of excitatory mPFC networks via increased activity of PVϩ FSIs may enhance reward-related behavioral flexibility.

Several neuropsychiatric conditions, such as addiction and schizophrenia, may arise in part from dysregulated activity of ventral tegmental area dopaminergic (TH) neurons, as well as from more global maladaptation in neurocircuit function. However, whether TH activity affects large-scale brain-wide function remains unknown. Here we selectively activated TH 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 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 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 neurons can impact brain dynamics across many distributed anatomically distinct regions, even those that receive little to no direct TH input.

These consistent findings in two markedly different treatment studies support the hypothesis that hERG1-mediated effects of antipsychotics may not be limited to their potential cardiovascular side effects but may also involve therapeutic actions related to the brainspecific 3.1 isoform of KCNH2.

Background Attention is the capacity to flexibly orient behaviors and thoughts towards a goal by selecting and integrating relevant contextual information. The dorsal cingulate (dCC) and prefrontal (PFC) cortices play critical roles in attention. Evidence indicates that catechol-O-methyltransferase (COMT) modulates dopaminergic tone in the PFC and dCC. Objective In this study, we explored the effect of tolcapone, a CNS penetrant COMT inhibitor that increases cortical dopamine levels, on brain activity during a Variable Attentional Control (VAC) task. Study Design We performed a double-blinded, placebo-controlled, counter-balanced trial with tolcapone (Tasmar, tablets, 100 mg three times a day for 1 day and then 200 mg three times a day for 6 days; ClinicalTrials.gov identifier: NCT00044083). Setting The study was conducted in the Clinical Center of the National Institute of Mental Health from 2005 to 2009. Patients Twenty healthy volunteers (11 males; mean age = 32.7 years) with good imaging and performance data on both arms of the study were investigated. Intervention Participants underwent 3T blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) while performing the event-related VAC task, which varies attention over three levels of load: LOW, INT (intermediate), and HIGH. Main Outcome Measure Changes in behavioral data and individual contrast images were analyzed using ANOVA with drug and task load as co-factors. Results There was a significant main effect of increasing task load, with resulting decreased accuracy and increased reaction time. While there was no significant effect of tolcapone on these behavioral measures, the neuroimaging data showed a significant effect on load-related changes in dCC, with significantly lower dCC activation on tolcapone compared with placebo. Further, neural activity in dCC correlated positively with COMT enzyme activity (i.e., lower COMT activity and presumably more dopamine was associated with lower activation in dCC, i.e., more efficient information processing). Conclusion Our results show that pharmacological reduction of COMT activity modulates the engagement of attentional mechanisms, selectively enhancing the efficiency of dCC processing in healthy volunteers, reflected as decreased activity for the same level of performance.