A GABAergic projection from the centromedial nuclei of the amygdala to ventromedial prefrontal cortex modulates reward behavior

The neural circuitry underlying mammalian reward behaviors involves several distinct nuclei throughout the brain. It is widely accepted that the midbrain dopamine (DA) neurons are critical for the reward-related behaviors. Recent studies have shown that the centromedial nucleus of the amygdala (CeMA) has a distinct role in regulating reward-related behaviors. However, the CeMA and ventromedial PFC (vmPFC) interaction in reward regulation remains poorly understood. Here, we identify and dissect a GABAergic projection that originates in the CeMA and terminates in the vmPFC (VGat-Cre(CeMA-vmPFC)) using viral-vector-mediated, cell-type-specific optogenetic techniques in mice. Pathway-specific optogenetic activation of the VGat-Cre(CeMA-vmPFC) circuit in awake, behaving animals produced a positive, reward-like phenotype in real-time place preference and increased locomotor activity in open-field testing. In sucrose operant conditioning, the photoactivation of these terminals increased nose-poking effort with no effect on licking behavior and robustly facilitated the extinction of operant behavior. However, photoactivation of these terminals did not induce self-stimulation in the absence of an external reward. The results described here suggest that the VGat-Cre(CeMA-vmPFC) projection acts to modulate existing reward-related behaviors. SIGNIFICANCE STATEMENT Many studies have shown that the interactions between the centromedial nucleus of the amygdala (CeMA) and ventromedial PFC (vmPFC) have critical roles for emotional regulation. However, most studies have associated this circuit with fear and anxiety behaviors and emphasized top-down processing from vmPFC to CeMA. Here, we provide new evidence for bottom-up CeMA to vmPFC influence on reward-related behaviors. Although previous work implicated the CeMA in incentive salience, our results isolate the investigation to a specific CeMA GABAergic projection to the vmPFC. This long-range GABAergic interaction between amygdala and frontal cortex adds a new dimension to the complex regulation of reward-related behaviors

Spatiotemporal Control of Opioid Signaling and Behavior

SummaryOptogenetics is now a widely accepted tool for spatiotemporal manipulation of neuronal activity. However, a majority of optogenetic approaches use binary on/off control schemes. Here, we extend the optogenetic toolset by developing a neuromodulatory approach using a rationale-based design to generate a Gi-coupled, optically sensitive, mu-opioid-like receptor, which we term opto-MOR. We demonstrate that opto-MOR engages canonical mu-opioid signaling through inhibition of adenylyl cyclase, activation of MAPK and G protein-gated inward rectifying potassium (GIRK) channels and internalizes with kinetics similar to that of the mu-opioid receptor. To assess in vivo utility, we expressed a Cre-dependent viral opto-MOR in RMTg/VTA GABAergic neurons, which led to a real-time place preference. In contrast, expression of opto-MOR in GABAergic neurons of the ventral pallidum hedonic cold spot led to real-time place aversion. This tool has generalizable application for spatiotemporal control of opioid signaling and, furthermore, can be used broadly for mimicking endogenous neuronal inhibition pathways

Ventral Striatum Reactivity and Coping Strategies Indirectly Link a PDYN Haplotype to Alcohol Use

Mentor: Ryan Bogdan From the Washington University Undergraduate Research Digest: WUURD, Volume 9, Issue 1, Fall 2013. Published by the Office of Undergraduate Research. Joy Zalis Kiefer Director of Undergraduate Research and Assistant Dean in the College of Arts & Sciences

A Novel GABAergic Projection Links Central Amygdala to Frontal Cortex and Mediates Reward Behaviors

From the Washington University Senior Honors Thesis Abstracts (WUSHTA), Spring 2015. Published by the Office of Undergraduate Research. Joy Zalis Kiefer, Director of Undergraduate Research and Associate Dean in the College of Arts & Sciences; Stacy Ross, Editor; Kristin G. Sobotka, Undergraduate Research Coordinator; Jennifer Kohl. Mentor: Michael R. Brucha

A novel GABAergic projection links central amygdala to frontal cortex and facilitates reward-like behavior

The neural circuitry underlying mammalian reward behaviors comprises several distinct nuclei throughout the brain. Previous research has indicated that inhibiting the infra-limbic area of the frontal cortex is rewarding to the animal, while activating the central amygdala during reward presentation increases future preference for that reward. Using viral vector-mediated, cell-type specific viral fluorescence tracing in transgenic mice, we identified a GABAergic projection originating in the central amygdala (CeA) that terminates in the infra-limbic area of the frontal cortex. Follow-up experiments to optogenetically activate this circuit in awake, behaving animals produced reward-like behaviors. We hypothesize that activity in these cells inhibits the infra-limbic cortex, and are in the process of in vivo electrophysiological recordings to support this claim. This long-range GABAergic interaction between amygdala and frontal cortex adds a new dimension to the complex regulation of stress- and reward-related behaviors and provides a potential mechanism for the emotional regulation of cognition