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The effect of Repeated Cross Fostering (RCF) on transcriptomic profiles of mouse Ventral Tegmental Areas across different sexes and strains

ABSTRACT: Early life experiences affecting the attachment bond formation can result in maladaptive behaviors acting on developmental trajectories and programming adult brain functions in a sex-dependent manner. Repeated Cross Fostering (RCF) manipulation in mice is able to interfere with attachment bond formation in mice. Using males and females from two different inbred strains of mouse, known to respond very differently to the RCF, we analyzed the effect of RCF on the ventral tegmental area (VTA)-transcriptome in a sex-specific manner. Through next-generation mRNA-Seq, we profiled VTA transcriptomes in RCF and control adult male and female mice from both backgrounds.

ORGANISM(S): Mus musculus

PROVIDER: GSE165922 | GEO | 2021/02/02

REPOSITORIES: GEO

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The effect of Repeated Cross Fostering (RCF) on transcriptomic profiles of mouse Ventral Tegmental Areas across different sexes and strains

Project description:The effect of Repeated Cross Fostering (RCF) on transcriptomic profiles of mouse Ventral Tegmental Areas across different sexes and strains

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Sex differences in the ventral tegmental area and nucleus accumbens proteome at baseline and following nicotine exposure

Project description:Sex differences in behaviors relevant to nicotine addiction have been observed in rodent models and human subjects. Behavioral, imaging and epidemiological studies also suggest underlying sex differences in mesolimbic dopamine signaling pathways. In this study we evaluated the proteome in the ventral tegmental area (VTA) and nucleus accumbens (NAc) shell in male and female mice. Experimental groups included two mouse strains (C3H/HeJ and C57BL/6J) at baseline, a sub-chronic, rewarding regimen of nicotine in C3H/HeJ mice, and chronic nicotine administration and withdrawal in C57BL/6J mice. Isobaric labeling with a TMT 10-plex system, sample fractionation, and tandem mass spectrometry were used to quantify changes in protein abundance. Similar or greater numbers of differentially regulated proteins were found between sexes at baseline in C3H/HeJ or C57BL/6J mice than within sexes following their respective regimen of nicotine administration. Despite differences by sex, strain, and nicotine exposure parameters, glial fibrillary acidic protein (GFAP) and dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32, Ppp1r1b) were repeatedly identified as significantly altered proteins, especially in the VTA. Further, network analyses showed sex- and nicotine-dependent regulation of a number of signaling pathways, including dopaminergic signaling. Sub-chronic nicotine exposure in female mice increased proteins related to dopaminergic signaling in the NAc shell but decreased them in the VTA, whereas the opposite pattern was observed in male mice. In contrast, dopaminergic signaling pathways were similarly upregulated in both male and female VTA after chronic nicotine and withdrawal. Overall, this study identifies significant sex differences in the proteome of the mesolimbic system, at baseline and after nicotine reward or withdrawal, which may help explain differential trajectories and susceptibility to nicotine addiction in males and females.

2021-06-28 | PXD023859 | Pride

Age-mediated transcriptomic changes in adult mouse brain ventral tegmental area

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.

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Age-mediated transcriptomic changes in adult mouse brain ventral tegmental area

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Dopaminylation of Histone H3 in Ventral Tegmental Area Regulates Cocaine-seeking

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.

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Opto-seq reveals input-specific immediate early gene induction in ventral tegmental area cell types

Project description:The ventral tegmental area (VTA) is a critical node in circuits governing motivated behavior and is home to diverse populations of neurons that release dopamine, GABA, glutamate, or combinations of these neurotransmitters. The VTA receives inputs from many brain regions, but a comprehensive understanding of input-specific activation of VTA neuronal subpopulations is lacking. To address this, we combined optogenetic stimulation of select VTA inputs with single-nucleus RNA sequencing (snRNAseq) and highly multiplexed in situ hybridization to identify distinct neuronal clusters and characterize their spatial distribution and activation patterns. Quantification of immediate early gene (IEG) expression revealed that different inputs activated select VTA subpopulations, which demonstrated cell-type specific IEG programs. Within dopaminergic subpopulations IEG induction levels correlated with differential expression of ion channel genes. This new transcriptomics-guided circuit analysis reveals the diversity of VTA activation driven by distinct inputs and provides a resource for future analysis of VTA cell types.

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Project description:This dataset contains single-nucleus RNA sequencing results from adult rat brain (ventral tegmenal area, or VTA). The goal of this experiment was to define the transcriptional landscapes of distinct cell types in the VTA. Single-cell sequencing was carried out with nuclei suspensions (sorted using flow cytometry) using the 10X Genomics Chromium single cell sequencing platform.

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Transcriptomic regulations underlying pair-bond formation and maintenance in the socially monogamous male and female prairie vole

Project description:Background: The ability to form enduring social bonds is characteristic of human nature and as a result, impairments in social affiliation are central features of severe neuropsychiatric disorders including autism spectrum disorders and schizophrenia. Due to its ability to form long-term pair-bonds, the socially monogamous prairie vole (Microtus ochrogaster) has emerged as an excellent model to study the neurobiology of social attachment. Despite the enduring nature of the bond, however, surprisingly few genes have been implicated in the pair-bonding process in either sex. Results: Using RNA-sequencing, we aimed at identifying the transcriptomic regulations in the nucleus accumbens (NAc) underlying the formation and maintenance of a pair-bond in male and female prairie voles and found sex-specific response patterns despite similar behavioral indicators of pair-bond establishment. Indeed, 24 hrs of cohabitation with an opposite-sex partner induced widespread transcriptomic changes that remained sustained to some extent in females after 3 weeks, but returned to baseline before a second set of regulations in males. This led to a highly sexually-biased NAc transcriptome in the later phase of the bond related to processes such as neurotransmission, protein turnover, and DNA transcription. In particular, we found sex-specific alterations of mitochondrial dynamics following cohabitation, with a shift towards fission in males. Conclusions: In addition to identifying the genes, networks, and pathways involved in the pair-bonding process in the NAc, our work illustrates the vast extent of sex differences in the molecular mechanisms underlying pair-bonding in prairie voles, and paves the way to further our understanding of the complex social bonding process.

2023-04-28 | GSE150080 | GEO

Histone H3 dopaminylation in ventral tegmental area underlies heroin-induced maladaptive plasticity

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

: The effects of chronic morphine on the endogenous cannabinoid system in the ventral tegmental area

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.

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