Project description:Rewards are essential for motivation, decision-making, memory, and mental health. We identified the subventricular tegmental nucleus (SVTg) as a brainstem reward center. In mice, reward and its prediction activate the SVTg, and SVTg stimulation leads to place preference, reduced anxiety, and accumbal dopamine release. Mice self-stimulate the SVTg, which can also be activated directly by the neocortex, resulting in effective inhibition of the lateral habenula, a region associated with depression. This mechanism may also explain why SVTg suppression induces aversion and increases fear. The translational relevance of these findings is supported by evidence in the rat, monkey, and human brainstem, establishing SVTg as a key hub for reward processing, emotional valence, and motivation.
Project description:All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance use disorders. Another recently appreciated mechanism of neural circuit plasticity is mediated through activity-regulated changes in myelin that can tune circuit function and influence cognitive behavior1. Here, we explored the role of myelin plasticity in dopaminergic circuity and reward learning. We demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by either optogenetic stimulation of dopaminergic neurons, optogenetic inhibition of GABAergic neurons, or administration of morphine or cocaine. These oligodendroglial changes are evident selectively within the ventral tegmental area (VTA), but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens (NAc). Genetic blockade of oligodendrogenesis dampens dopamine release dynamics in nucleus accumbens and impairs behavioral conditioning to morphine. Taken together, these findings underscore a critical role for oligodendrogenesis in reward learning and identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward.
Project description:The anatomical relationship of the brainstem is complex, which is the center of respiratory circulation in the human body. We used single cell RNA sequencing (scRNA-seq) to analyze the cellular molecular diversity of the fetal brainstem.
Project description:Purpose: The goal of this study to examine mRNA transcriptomic changes in reward-related brain regions of subjects with alcohol use disorder. Methods: Total RNAs were extracted from postmortem ventral tegmental area of 12 AUD and 12 control subjects. rRNA depletion RNA sequencing was performed and the sequence reads were processed using the bulk RNA-seq processing pipeline Pipeliner workflow (Federico et al. Front Genet 2019; 10, 614). AUD-associated mRNA transcriptomic changes were analyzed by the Limma-Voom method. Results: Differentially expressed mRNAs (absolute FC>2.0 & P<0.05) were identified in postmortem ventral tegmental area of subjects with alcohol use disorder (AUD). Chronic alcohol consumption may alter mRNA transcriptome profiles in reward-related brain regions, resulting in alcohol-induced neuroadaptations.
Project description:The objective of The Center for Alcohol Research in Epigenetics (CARE) is to identify gene regulatory pathways in ventral tegmental area (VTA) that are altered in response to chronic ethanol administration and withdrawal.
Project description:The recovery from acute myocardial infarction (AMI) is influenced by physiological and psychological factors. While the physiological effects have been extensively studied, the contribution of psychological factors and whether they can be modulated is not completely clear. Here we show that the activity of the reward system, a brain network involved in motivation and positive expectation, affects outcomes in mice following AMI. We found that chemogenetic activation of dopaminergic neurons in the ventral tegmental area (VTA) significantly attenuated the remodeling process following AMI, resulting in improved left-ventricular performance compared to controls. VTA activation was associated with modulation of the immune response following AMI and increased blood vessel formation in the damaged area, mediated, at least in part, by changes in liver-secreted proteins. Together, our findings reveal a potential mechanism by which specific brain activity can affect the multifactorial systemic and local tissue response to AMI, introducing a novel target for therapeutic interventions
Project description:The United States is currently facing a severe opioid epidemic, therefore addressing how opioids induce rewarding behaviors could be key to a solution for this medical and societal crisis. Recently, the endogenous cannabinoid system has emerged as a hot topic in the study of opioid reward but relatively little is known about how chronic opioid exposure may affect this system. In the present study, we investigated how chronic morphine may modulate the endogenous cannabinoid system in the ventral tegmental area (VTA), a critical region in the mesolimbic reward circuitry. Our studies found that the VTA expresses 32 different proteins or genes related to the endogenous cannabinoid system; 3 of these proteins or genes were significantly affected after chronic morphine exposure. We also investigated the effects of acute and chronic morphine treatment on the production of the primary endocannabinoids, 2-Arachidonoylglycerol (2-AG) and anandamide (AEA), and identified that acute, but not chronic, morphine treatment significantly reduced AEA production in the VTA; 2-AG levels were unchanged in either condition. Lastly, our studies exhibited a systemic enhancement of 2-AG tone via inhibition of monoacylglycerol lipase (MAGL)-mediated degradation and the pharmacological activation of cannabinoid receptor 2 (CB2R) significantly suppressed chronic morphine-induced conditioned place preference. Taken together, our studies offer a broad picture of chronic morphine-induced alterations of the VTA endogenous cannabinoid system, provide several uncharacterized targets that could be used to develop novel therapies, and identify how manipulation of the endocannabinoid system can mitigate opioid reward to directly address the ongoing opioid epidemic.
Project description:Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in VTA. By reducing H3Q5dop in VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated cue-induced dopamine release in nucleus accumbens and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in VTA.
Project description:Persistent transcriptional events in ventral tegmental area (VTA) and other reward relevant brain regions contribute to enduring behavioral adaptations that characterize substance use disorder (SUD). Recent data from our laboratory indicate that aberrant accumulation of the newly discovered histone post-translational modification (PTM), H3 dopaminylation at glutamine 5 (H3Q5dop), contributes significantly to cocaine-seeking behavior following prolonged periods of abstinence. It remained unclear, however, whether this modification is important for relapse vulnerability in the context of other drugs of abuse, such as opioids. Here, we showed that H3Q5dop plays a critical role in heroin-mediated transcriptional plasticity in midbrain. In rats undergoing abstinence from heroin self-administration (SA), we found acute and persistent accumulation of H3Q5dop in VTA. By attenuating H3Q5dop during abstinence, we both altered gene expression programs associated with heroin withdrawal and reduced heroin-primed reinstatement behavior. These findings thus establish an essential role for H3Q5dop, and its downstream transcriptional consequences, in opioid-induced plasticity in VTA.