Persistent open chromatin state in early-life stress-activated cells of the VTA
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PROVIDER: PRJNA1117426 | ENA |
REPOSITORIES: ENA
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Project description:Early-life stress sensitizes individuals to subsequent stressors to increase lifetime risk for psychiatric disorders. Within the ventral tegmental area (VTA), a mesolimbic brain region implicated in stress response and mental health, early-life stress causes long-lasting changes in gene expression and chromatin modifications that in turn cause latent physiological and behavioral sensitivity to stress. These molecular consequences of early-life stress are indicative of epigenetic priming, a form of molecular memory in which developmental or environmental cues open chromatin at enhancers to facilitate transcriptional response to stimuli. However, the long term impact of early-life stress on chromatin architecture in the VTA was not yet known. Using a combination of activity-dependent cellular tagging and ATAC-sequencing, we find that early-life stress opens chromatin specifically in stress-activated cells of the VTA, that this remodeling persists into adulthood, and that opening chromatin at cis-regulatory elements including enhancers augments transcriptional response to adult stress. Together, this data supports enhancer priming within ELS-responsive cells in the VTA as a biological mechanism for lifelong stress sensitivity.
2025-09-09 | GSE268468 | GEO
Project description: Not available
| S-EPMC12528658 | biostudies-literature
Project description:Early-life stress increases sensitivity to subsequent stress, which has been observed at behavioral, neural activity, and gene expression levels. However, the molecular mechanisms underlying such long-lasting sensitivity are poorly understood. We tested the hypothesis that persistent changes in transcription and transcriptional potential were maintained at the level of the epigenome, through changes in chromatin. We used a combination of bottom-up mass spectrometry, viral-mediated epigenome-editing, RNA-sequencing, patch clamp electrophysiology of dopamine neurons, and behavioral quantification in a mouse model of early-life stress, focusing on the ventral tegmental area (VTA), a dopaminergic brain region critically implicated in motivation, reward learning, stress response, and mood and drug disorders. We found that early-life stress alters histone dynamics in VTA, including enrichment of histone-3 lysine-4 monomethylation — associated with open chromatin and primed or active enhancers — and the H3K4 monomethylase Setd7. Mimicking early-life stress through postnatal overexpression of Setd7 and enrichment of H3K4me1 in VTA sensitizes transcriptional, physiological, and behavioral response to adult stress, while knocking down Setd7 ameliorates the impact of ELS. These findings link early-life stress experience to long-term stress hypersensitivity within the brain's dopaminergic circuitry, providing a mechanism by which early-life stress increases risk for mood and anxiety disorders later in life.
2026-05-29 | GSE324599 | GEO
Project description:This study aimed at identifying rhythmically regulated transcripts in the ventral tegmental area (VTA) of mice. Punch biopsies of the VTA from C57BL/6 brain slices were prepared at 6 different timepoints across the day and analyzed for transcriptome regulation
2019-01-30 | GSE125812 | GEO
Project description:Background: As pain persists, it is often accompanied by the development of negative emotional states, such as depression. Approximately 50%-85% of patients with chronic pain experience depressive symptoms. Ventral tegmental area (VTA) γ--aminobutyric acid (GABA) neurons play a crucial role in regulating emotions. VTA GABA neurons can be mainly classified into those expressing somatostatin (SST) and parvalbumin (PV) neurons. The subtypes of VTA GABA neurons exhibit significant heterogeneity, but it remains unclear whether these subtypes mediate different functions in the development of chronic pain and depression. Inward rectifying potassium channel 4.1 (Kir4.1) is an important potassium channel mainly expressed in astrocytes and plays an important role in regulating neural activity. In lipopolysaccharide (LPS)-induced depression, Kir4.1 in lateral habenula (LHb) was upregulated. Lys05 (an inhibitor of Kir4.1) reversed the Kir4.1-driven depression-like phenotype. However, there was no study has reported the changes of Kir4.1 in chronic pain-induced depression or verified the therapeutic effects of Lys05 on it. Methods: We established chronic constriction injury (CCI) model to induce chronic pain in mice, and used the sugar preference test (SPT), tail suspension test (TST), and open field test (OFT) to detect depressive behavior in mice. Lys05 was injected to investigate the effect of Kir4.1 inhibitors on depression caused by chronic neuropathic pain. The adeno-associated virus (AAV) was designed to knockdown or overexpress the expression of Kir4.1 in VTA astrocytes. Using optogenetic manipulations and transgenic mice, specific activation of VTA GABASST neurons or VTA GABAPV neurons was used to explore which types of VTA GABA neurons Kir4.1 has effects on. Patch-clamp recording was applied to explore the effects of Kir4.1 on the excitability of different types of VTA neurons. Results: Lys05 could reverse the depressive behaviors induced by LPS. In detail, mice treated with 10 mg/kg Lys05 showed increased sucrose preference, decreased immobility durations in TST and increased percent center time in OFT. However, Lys05 didn’t show any specific response to depression behavior in CCI-induced depression mice. Then we found Kir4.1 expression decreased in VTA and LHb of CCI-induced depression mice. Next, we found knockdown of Kir4.1 in the VTA resulted mice became depression but with no hyperalgesia. Correspondingly, overexpress Kir4.1 in VTA astrocytes could reverse the chronic pain-induced depression like states. In the patch clamp, when knocked down Kir4.1 in VTA astrocytes, the excitability of dopamine neurons decreased, GABASST neurons increased, but GABAPV neurons did not change significantly. Specifically excitable VTA GABASST neurons could cause depression in mice, while excitable GABAPV neurons did not. Conclusion: Chronic pain decreases the expression of Kir4.1 in VTA astrocytes, which activates GABASST neurons and in turns inhibits DA neurons, then leads depression.
2025-12-01 | GSE283479 | GEO
Project description:Implications for neuroprotection in Parkinson's disease Parkinson’s disease and its characteristic symptoms are thought to arise from the progressive degeneration of specific midbrain dopamine (DA) neurons. In humans, DA neurons of the substantia nigra (SN) and their projections to the striatum show selective vulnerability, while neighboring DA neurons of the ventral tegmental area (VTA) are relatively spared from degeneration. This pattern of cell loss is mimicked in humans, primates, and certain rodents by the neurotoxin MPTP. In this study, we aimed to test the hypothesis that there are factors in the VTA that are potentially neuroprotective against MPTP and that these factors change over time. We have found a differential transcriptional response within the cells of the SN and VTA to sustained exposure to a low dose of MPTP. Specifically, the VTA has increased expression of 148 genes as an early response to MPTP and 113 genes as a late response to MPTP toxicity. This response encompasses many areas of cellular function, including protein regulation (Phf6) and ion/metal regulation (PANK2, Car4). Notably, these responses were largely absent from the cells of the SN. Our data show a clear dynamic response in maintaining the homeostasis and viability of the neurons in the VTA that is lacking in the SN after neurotoxin challenge. We used microarrays to analyze the differential response of the substantia nigra (SN) and ventral tegmental area (VTA) to a chronic low dose of the neurotoxin MPTP. Transgenic hTH-GFP mice were treated with MPTP (4mg/kg) for either 2 or 10 days. Control mice were given an equal volume of saline for 10 days. Dopamine neurons from the substantia nigra and ventral tegmental areas of control and MPTP treated animals were laser captured. The RNA was isolated and processed for microarray hybridization. Each group had three biological replicates, for a total of 18 samples. Three each in the following: Control SN, Control VTA, 2 day MPTP SN, 2 day MPTP VTA, 10 day MPTP SN, 10 day MPTP VTA. Samples were log2 transformed and RMA normalized using Agilent Genespring 10.0 GX.
2009-12-31 | E-GEOD-17542 | biostudies-arrayexpress
Project description:Projection-dependent ribosome profling from mouse mPFC. Ribosome from NAC- and VTA- projecting mPFC cells were immunoprecipited using GFP-trap (Chromotech). Translating mRNA was isolated and analyzed
2017-09-15 | GSE101185 | GEO
Project description:Individual responses to chronic stress vary, with some individuals remaining resilient while others exhibit susceptibility. The ventral tegmental area (VTA), a region involved in reward learning, and the lateral habenula (LHb), a region involved in aversive learning, have been implicated in the pathophysiology of stress-related mood disorders. Here, we seek to understand the molecular adaptations in these regions at the level of single cells that mediate susceptibility versus resilience. In particular, it remains unclear whether, at the level of gene expression, different cell-types within different brain regions mediate stress susceptibility versus resilience, or if these phenotypes are mediated by distinct trajectories within the same cell-types. To address this gap, we performed single-nucleus RNA-sequencing of LHb and VTA of mice subjected to chronic social defeat stress. While we found minimal gene expression changes in the LHb after stress, the VTA exhibited widespread, cell-type-specific transcriptional remodeling in resilient individuals and few gene expression changes in susceptible individuals. Across VTA cell-types, resilience was associated with the coordinated upregulation of genes involved in intercellular signaling and neural communication, with maintenance of receptor-ligand interaction strength in resilience that was not present in susceptibility. Within VTA neurons, gene expression changes were most prominent in glutamatergic and dopaminergic clusters. Multivariate analyses of dopamine and glutamate subclusters showed that resilient neurons diverged more from control than susceptible neurons, but along a similar trajectory, supporting a model in which resilience reflects greater stress-related adaptations in these cell-types. Together, these findings highlight the VTA as a key site of molecular plasticity in stress resilience and therefore a potential therapeutic target.
2025-12-09 | GSE303538 | GEO
Project description:Pitx3 is a transcription factor that is expressed in all midbrain dopaminergic (mDA) neurons during early development, but later becomes restricted in dopaminergic subsets of substantia nigra compacta (SNc) and of the ventral tegmental are (VTA) that are vulnerable to neurodegenerative stress (MPTP, 6-OHDA, rotenone, Parkinson's disease). Overall, in mice, Pitx3 is required for developmental survival of ventral SNc neurons and for postnatal survival of VTA neurons (after postnatal day 40). With the aim of determining the gene networks that distinguish Pitx3-vulnerable (Pitx3-positive) from Pitx3-resistant (Pitx3-negative) subsets of SNc and VTA, we performed a comparison at the transcriptome level between FAC-sorted mDA neurons of SNc and VTA that were obtained from wild-type and Pitx3-/- newborn mice. The latter mice have already lost the majority of their TH+Calb1- mDA neurons of ventral SNc (Pitx3-dependent), but their TH+Calb1+ neurons of dorsal SNc (Pitx3-independent), including all of VTA neurons (50% are Pitx3-dependent and 50% Pitx3-independent), are unaffected by Pitx3 deletion. At postnatal day 40, Pitx3-/- mice display a marked loss of dopaminergic subsets of VTA that normally co-express Pitx3 and Calb1 (Pitx3-dependent neurons of VTA).
2016-01-31 | GSE75777 | GEO
Project description:Rat VTA single nuclei RNA sequencing
| PRJNA1199325 | ENA