Myelin plasticity in ventral tegmental area is required for opioid reward
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ABSTRACT:
PROVIDER: PRJNA1073462 | ENA |
REPOSITORIES: ENA
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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.
2024-02-10 | GSE255072 | GEO
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.
2021-04-08 | PXD023096 | Pride
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.
2022-02-20 | GSE169628 | GEO
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.
2021-10-13 | GSE182649 | GEO
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.
2020-05-19 | GSE124055 | GEO
Project description:Substantia nigra pars compacta (SNpc) is highly sensitive to normal aging and selectively degenerates in Parkinson's disease. However, ventral tegmental area (VTA), a region adjacent to SNpc, is less affected in PD. Until now, molecular mechanisms behind VTA aging have not been fully investigated using high throughput techniques. Here, aging-associated early changes in transcriptome of VTA were investigated comparing late middle-aged (18 months old) to young (2 months old) mice. Three age groups of C57 wild type mice were used in microarray analysis: young (2 months old), middle aged (10 months old), and late-middle aged (18 months old) mice. Four replicates were included in each age group and each replicate was pooled from 5 mice (5 mice/replicate x 4 replicates x 3 age groups). Total RNA was isolated from VTA for hybridization on Affymetrix microarrays.
2013-05-29 | E-GEOD-45044 | biostudies-arrayexpress
Project description:Dynamic interactions of neurons and glia in the ventral midbrain (VM) mediate reward and addiction behavior. We studied gene expression in 212,713 VM single nuclei from 95 human opioid overdose cases and drug-free controls. Chronic exposure to opioids left numerical proportions of VM glial and neuronal subtypes unaltered, while broadly affecting glial transcriptomes, involving 9.5 - 6.2% of expressed genes within microglia, oligodendrocytes, and astrocytes, with prominent activation of the immune response including interferon, NFkB signaling, and cell motility pathways, sharply contrasting with down-regulated expression of synaptic signaling and plasticity genes in VM non-dopaminergic neurons. VM transcriptomic reprogramming in the context of opioid exposure and overdose included 325 genes with genetic variation linked to substance use traits in the broader population, thereby pointing to heritable risk architectures in the genomic organization of the brain’s reward circuitry.
2023-08-18 | GSE240457 | GEO
Project description:Prenatal opioid exposure is a major health concern in the United States, with the incidence of neonatal opioid withdrawal syndrome (NOWS) escalating in recent years. NOWS is revealed upon cessation of in utero opioid exposure and is characterized by increased irritability, disrupted sleep patterns, high-pitched crying, and erratic feeding. The main pharmacological treatment strategy for alleviating symptoms is opioid maintenance therapy. The neural mechanisms mediating NOWS and the long-term neurobehavioral effects are poorly understood. We used a third trimester-approximate model in which neonatal outbred pups (Cartworth Farms White; CFW) were administered once-daily morphine (15 mg/kg, s.c.) from postnatal day (P) day 1 through P14 and were then assessed for behavioral and transcriptomic adaptations within the nucleus accumbens (NAc) on P15. We also investigated the long-term effects of perinatal morphine exposure on adult learning and reward sensitivity. We observed significant weight deficits, spontaneous thermal hyperalgesia, and altered ultrasonic vocalization (USV) profiles following repeated morphine and during spontaneous withdrawal. Transcriptome analysis of NAc from opioid-withdrawn P15 neonates via bulk mRNA sequencing identified an enrichment profile consistent with downregulation of myelin-associated transcripts. Despite the neonatal behavioral and molecular effects, there were no significant long-term effects of perinatal morphine exposure on adult spatial memory function in the Barnes Maze, emotional learning in fear conditioning, or in baseline or methamphetamine-potentiated reward sensitivity as measured via intracranial self-stimulation. Thus, the once daily third trimester-approximate exposure regimen, while inducing NOWS model traits and significant transcriptomic effects in neonates, had no significant long-term effects on adult behaviors.
2023-08-03 | GSE239919 | GEO
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.
2024-02-15 | GSE233921 | GEO
Project description:Substantia nigra pars compacta (SNpc) is highly sensitive to normal aging and selectively degenerates in Parkinson's disease. However, ventral tegmental area (VTA), a region adjacent to SNpc, is less affected in PD. Until now, molecular mechanisms behind VTA aging have not been fully investigated using high throughput techniques. Here, aging-associated early changes in transcriptome of VTA were investigated comparing late middle-aged (18 months old) to young (2 months old) mice.
2013-05-29 | GSE45044 | GEO