NPAS4 controls cell type-specific circuit adaptations underlying drug-seeking behavior
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA867708 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20993771_1.fastq.gz | Fastqsanger.gz | |||
| SRR20993771_2.fastq.gz | Fastqsanger.gz | |||
| SRR20993772_1.fastq.gz | Fastqsanger.gz | |||
| SRR20993772_2.fastq.gz | Fastqsanger.gz | |||
| SRR20993773_1.fastq.gz | Fastqsanger.gz |
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Project description:Use of addictive substances often creates powerful and enduring associations with external cues that act as relapse triggers in individuals recovering from a substance use disorder (SUD). In the reward-associated brain region, the nucleus accumbens (NAc), drug use or drug-associated cue exposure activates a subset of D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs), which typically promotes drug seeking, and a smaller subset of D2 dopamine receptor-expressing MSNs (D2-MSNs), which typically opposes drug seeking. The activity-regulated transcription factor, Neuronal PAS Domain Protein 4 (NPAS4), is activated in a small subset of NAc neurons during cocaine conditioning, and NAc NPAS4 is required for drug-context memories. Using a new Npas4-TRAP mouse combined with chemogenetics, we found that the during cocaine conditioning, the NPAS4-positive ensemble is required for drug-context associations. Single-cell transcriptomic analyses and in situ hybridization of NAc tissues from drug-conditioned mice revealed that NPAS4 is expressed predominantly in MSNs, and using cell type-specific molecular genetic approaches, we found that NPAS4 in D2-MSNs, but not D1-MSNs, was required for both drug-context associations and cue-reinstated cocaine seeking. Similarly, NPAS4 in NAc D2-MSNs, but not D1-MSNs, blocked cocaine experience-dependent strengthening of glutamatergic prefrontal cortical (PFC) inputs onto D2-MSNs. Analysis of differential gene expression in D2-MSNs revealed that NPAS4 and cocaine conditioning influence a gene expression program associated with synapses, dendrites, neuronal projections, dopamine, and cocaine. Together, our data reveal that NPAS4 functions during active cocaine use to maintain the imbalance of D1-MSN:D2-MSN activation and cue-induced drug seeking by suppressing excitatory drive onto relapse-opposing NAc D2-MSN circuits.
2023-08-31 | GSE210850 | GEO
Project description:Neuronal activity is critical for adaptive circuit remodeling but poses an inherent risk to the stability of the genome across the long lifespan of post-mitotic neurons1-5. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is not known. Here we identify an activity-dependent DNA repair mechanism via a new form of the NuA4/TIP60 chromatin modifier that assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex directly from the brain and demonstrate its functions in eliciting activity-dependent changes to neuronal transcriptomes and circuitry. By identifying the landscape of activity-induced DNA double-strand breaks in the brain, we show that the NPAS4:NuA4 complex binds to recurrently damaged regulatory elements and recruits additional DNA repair machinery to stimulate their repair. Gene regulatory elements bound by the NPAS4:NuA4 complex are partially protected from age-dependent accumulation of somatic mutations. Impaired NPAS4:NuA4 signaling leads to a cascade of cellular defects including dysregulated transcriptional responses to activity, loss of control over neuronal inhibition, and genome instability, culminating in reduced organismal lifespan. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental disorders and autism. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation and whose disruption may contribute to developmental disorders, neurodegeneration and aging.
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2022-06-23 | PXD033203 | Pride
Project description:Chronic social defeat stress induces anhedonia-like behavior deficits. We demonstrated that mPFC NPAS is requred for chronic social defeat stress-induced deficits in the sucrose preference and effort-based reward seeking behavior. We conducted the RNA-seq analysis for differential expression genes in the mouse mPFC samples of AAV-mediated Npas4 shRNA expression tissue.
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Project description:MicroRNAs are “master regulators” of gene expression. To investigate microRNAs involved in the incentive motivation for cocaine elicited by exposure to cocaine-associated cues, we conducted NanoString nCounter analyses of microRNA expression in the nucleus accumbens shell of male rats that had been tested for cue reactivity in a previous study. These rats had been trained to self-administer cocaine while living in isolate housing, then during a subsequent 21-day forced abstinence period they either stayed under isolate housing or switched to environmental enrichment (EE), as this EE intervention is known to decrease cocaine seeking. This allowed us to create groups of “high” and “low” cocaine seekers using a median split of cocaine-seeking behavior. We conducted a differential expression analysis across these two groups that identified 33 miRNAs that were differentially altered in the nucleus accumbens shell. Predicted mRNA targets of these microRNAs are implicated in synaptic plasticity and neuronal signaling. Some of these microRNAs have previously been implicated in substance use disorders, while others are predicted to target large numbers of cocaine-related genes. Of the 33 differentially expressed microRNAs, 8 were specifically downregulated in the low-seeking group and another set of 8 had expression levels that were significantly correlated with cocaine-seeking. These findings suggest that processes involved in cocaine-seeking behavior may alter, or be altered by, multiple microRNAs. Further research examining the mechanisms involved in these microRNA changes and their effects on signaling may reveal novel therapeutic targets for attenuating drug craving.
2020-12-25 | GSE153524 | GEO
Project description:we performed a DNA microarray experiment to identify activity-regulated genes that are misregulated in the absence of Npas4. Keywords: Primary neuron culture, depolarization, activity-dependent, Npas4
2008-09-24 | GSE11258 | GEO
Project description:We performed a DNA microarray experiment to identify activity-regulated genes that are misregulated in the absence of Npas4. Experiment Overall Design: We infected mouse hippocampal neurons with lentivirus expressing Npas4-RNAi or control-RNAi @ 3 DIV and depolarized the neurons @ 8 DIV with 50 mM of KCl for 0, 1, 3 or 6 hours. Neurons were lysed, mRNA isolated and hybridized to Affymetrix arrays. Data were collected from 3 independent experiments.
2008-10-26 | E-GEOD-11258 | biostudies-arrayexpress
Project description:Neuronal activity is critical for adaptive circuit remodeling but poses an inherent risk to the stability of the genome across the long lifespan of post-mitotic neurons. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is not known. Here we identify the first example of a neuronal-specific DNA repair mechanism via a new form of the NuA4/TIP60 chromatin modifier that assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex directly from the brain and demonstrate its function in eliciting activity-dependent changes to neuronal transcriptomes and neuronal circuitry. NPAS4:NuA4 binds at fragile regulatory regions that undergo neuronal activity-induced DNA double-strand breaks and recruits additional DNA repair machinery to stimulate the repair of these sites. Gene regulatory elements bound by the NPAS4:NuA4 complex are partially protected from age-dependent accumulation of somatic mutations. Impaired NPAS4:NuA4 signaling leads to a cascade of cellular defects including dysregulated transcriptional responses to activity, loss of control over neuronal inhibition, and genome instability, culminating in reduced longevity at the organismal level. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental disorders and autism. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation and whose disruption may contribute to developmental disorders, neurodegeneration and aging.
2022-12-16 | GSE175952 | GEO
Project description:Neuronal activity is critical for adaptive circuit remodeling but poses an inherent risk to the stability of the genome across the long lifespan of post-mitotic neurons. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is not known. Here we identify the first example of a neuronal-specific DNA repair mechanism via a new form of the NuA4/TIP60 chromatin modifier that assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex directly from the brain and demonstrate its function in eliciting activity-dependent changes to neuronal transcriptomes and neuronal circuitry. NPAS4:NuA4 binds at fragile regulatory regions that undergo neuronal activity-induced DNA double-strand breaks and recruits additional DNA repair machinery to stimulate the repair of these sites. Gene regulatory elements bound by the NPAS4:NuA4 complex are partially protected from age-dependent accumulation of somatic mutations. Impaired NPAS4:NuA4 signaling leads to a cascade of cellular defects including dysregulated transcriptional responses to activity, loss of control over neuronal inhibition, and genome instability, culminating in reduced longevity at the organismal level. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental disorders and autism. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation and whose disruption may contribute to developmental disorders, neurodegeneration and aging.
2022-12-16 | GSE175964 | GEO
Project description:Neuronal activity is critical for adaptive circuit remodeling but poses an inherent risk to the stability of the genome across the long lifespan of post-mitotic neurons. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is not known. Here we identify the first example of a neuronal-specific DNA repair mechanism via a new form of the NuA4/TIP60 chromatin modifier that assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex directly from the brain and demonstrate its function in eliciting activity-dependent changes to neuronal transcriptomes and neuronal circuitry. NPAS4:NuA4 binds at fragile regulatory regions that undergo neuronal activity-induced DNA double-strand breaks and recruits additional DNA repair machinery to stimulate the repair of these sites. Gene regulatory elements bound by the NPAS4:NuA4 complex are partially protected from age-dependent accumulation of somatic mutations. Impaired NPAS4:NuA4 signaling leads to a cascade of cellular defects including dysregulated transcriptional responses to activity, loss of control over neuronal inhibition, and genome instability, culminating in reduced longevity at the organismal level. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental disorders and autism. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation and whose disruption may contribute to developmental disorders, neurodegeneration and aging.
2022-12-16 | GSE175958 | GEO