Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models

Mews, Philipp; Cunningham, Ashley M.; Scarpa, Joseph R.; Ramakrishnan, Aarthi; Hicks, Emily M.; Bolnick, Sarah; Garamszegi, Susanna P.; Shen, Li; Mash, Deborah C.; Nestler, Eric J.

doi:10.1126/sciadv.add8946

Cited by 26 publications

(18 citation statements)

References 76 publications

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“…One such regulator is TWIST1, which was down-regulated in withdrawal but up-regulated upon cocaine challenge. Our previous research supports the involvement of TWIST protein family members in the response to cocaine exposure, highlighting the inhibitory role of TWIST2 as an upstream regulator in human CUD ( 23 ). Another identified upstream regulator is BDNF, which is known to influence synaptic plasticity and addictive behaviors in animals ( 72 , 73 , 75 , 76 ).…”

Section: Discussionsupporting

confidence: 84%

“…Probing the proteomic landscape—spanning membrane, cytosolic, and nuclear domains—is one approach to understanding the molecular foundations of CUD and one that importantly complements recent efforts at the transcriptomic level ( 23 – 28 ). The proteomic shifts in addiction-related disorders touch upon a plethora of cellular processes, from synaptic plasticity, neuropeptide dynamics, and intracellular signaling pathways to epigenetic modulation of cocaine-responsive gene expression ( 29 ).…”

Section: Introductionmentioning

confidence: 99%

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Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

Mews,

Sosnick,

Gurung

et al. 2024

Sci. Signal.

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Cocaine use disorder (CUD) is a chronic neuropsychiatric condition that results from enduring cellular and molecular adaptations. Among substance use disorders, CUD is notable for its rising prevalence and the lack of approved pharmacotherapies. The nucleus accumbens (NAc), a region that is integral to the brain’s reward circuitry, plays a crucial role in the initiation and continuation of maladaptive behaviors that are intrinsic to CUD. Leveraging advancements in neuroproteomics, we undertook a proteomic analysis that spanned membrane, cytosolic, nuclear, and chromatin compartments of the NAc in a mouse model. The results unveiled immediate and sustained proteomic modifications after cocaine exposure and during prolonged withdrawal. We identified congruent protein regulatory patterns during initial cocaine exposure and reexposure after withdrawal, which contrasted with distinct patterns during withdrawal. Pronounced proteomic shifts within the membrane compartment indicated adaptive and long-lasting molecular responses prompted by cocaine withdrawal. In addition, we identified potential protein translocation events between soluble-nuclear and chromatin-bound compartments, thus providing insight into intracellular protein dynamics after cocaine exposure. Together, our findings illuminate the intricate proteomic landscape that is altered in the NAc by cocaine use and provide a dataset for future research toward potential therapeutics.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

Mews,

Sosnick,

Gurung

et al. 2024

Sci. Signal.

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“…Gene ontology for “Biological Processes 2021” and “Molecular Functions 2021” databases were performed in R using the enrichR package with our filtered DEG lists as input (25% fold change (logFC) and p<0.05) 19,28 . Ingenuity Pathway Analysis (IPA; Qiagen) was used to predict upstream regulators associated with DEGs (25% fold change (logFC) and p<0.05) for each experimental condition.…”

Section: Methodsmentioning

confidence: 99%

“…Bioinformatic analyses were used to reveal gene expression patterns, biological functions, potential upstream regulators, and co-expression modules of gene networks in an NAc subregion-specific manner across behavioral conditions. To clinically leverage our transcriptomic findings, we integrated the present results with an available transcriptomic dataset of NAc samples from patients with cocaine use disorder (CUD) 19 . Understanding the behavioral and transcriptional correlates of different WD/Ext settings will provide actionable information to better manage relapse triggers and achieve long-term abstinence.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional characterization of cocaine withdrawal versus extinction within nucleus accumbens

Martínez-Rivera,

Holt,

Minier-Toribio

et al. 2024

Preprint

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Substance use disorder is characterized by a maladaptive imbalance wherein drug seeking persists despite negative consequences or drug unavailability. This imbalance correlates with neurobiological alterations some of which are amplified during forced abstinence, thereby compromising the capacity of extinction-based approaches to prevent relapse. Cocaine use disorder (CUD) exemplifies this phenomenon in which neurobiological modifications hijack brain reward regions such as the nucleus accumbens (NAc) to manifest craving and withdrawal-like symptoms. While increasing evidence links transcriptional changes in the NAc to specific phases of addiction, genome-wide changes in gene expression during withdrawal vs. extinction (WD/Ext) have not been examined in a context- and NAc-subregion-specific manner. Here, we used cocaine self-administration (SA) in rats combined with RNA-sequencing (RNA-seq) of NAc subregions (core and shell) to transcriptionally profile the impact of experiencing withdrawal in the home cage or in the previous drug context or experiencing extinction training. As expected, home-cage withdrawal maintained drug seeking in the previous drug context, whereas extinction training reduced it. By contrast, withdrawal involving repetitive exposure to the previous drug context increased drug-seeking behavior. Bioinformatic analyses of RNA-seq data revealed gene expression patterns, networks, motifs, and biological functions specific to these behavioral conditions and NAc subregions. Comparing transcriptomic analysis of the NAc of patients with CUD highlighted conserved gene signatures, especially with rats that were repetitively exposed to the previous drug context. Collectively, these behavioral and transcriptional correlates of several withdrawal-extinction settings reveal fundamental and translational information about potential molecular mechanisms to attenuate drug-associated memories.

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“…Two epigenome-wide studies using reduced representation bisulfite sequencing (RRBS) in a cohort of N=25 individuals with CUD and N=25 control individuals identified N=145 and N=173 CUD-associated differentially methylated regions (DMRs) in the nucleus accumbens (NAc) 18 and in the caudate nucleus (CN) 19 , respectively. Investigating the same brain regions in a different cohort (N=25 CUD cases, N=20 controls), another study characterized transcriptome-wide gene expression changes and reported on the upregulation of synaptic transmembrane transporter genes while immune processes were downregulated 20 . The largest study in the human PFC investigating CUD-associated transcriptomic changes (N=19 CUD, N=17 controls) identified N=883 nominally significant (p<0.05) differentially expressed genes (DEGs) in neuronal nuclei from the Brodmann Area 46 subregion 21 .…”

Section: Introductionmentioning

confidence: 99%

Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder

Zillich,

Belschner,

Avetyan

et al. 2024

Preprint

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Structural and functional changes of the brain are assumed to contribute to excessive cocaine intake, craving, and relapse in cocaine use disorder (CUD). Epigenetic and transcriptional changes were hypothesized as a molecular basis for CUD-associated brain alterations. Here we performed a multi-omics study of CUD by integrating epigenome-wide methylomic (N=42) and transcriptomic (N=25) data from the same individuals using postmortem brain tissue of Brodmann Area 9 (BA9). Of the N=1,057 differentially expressed genes (p<0.05), one gene, ZFAND2A, was significantly upregulated in CUD at transcriptome-wide significance (q<0.05). Differential alternative splicing (AS) analysis revealed N=98 alternatively spliced transcripts enriched in axon and dendrite extension pathways. Strong convergent overlap in CUD-associated expression deregulation was found between our BA9 cohort and independent replication datasets. Epigenomic, transcriptomic, and AS changes in BA9 converged at two genes, ZBTB4 and INPP5E. In pathway analyses, synaptic signaling, neuron morphogenesis, and fatty acid metabolism emerged as the most prominently deregulated biological processes. Drug repositioning analysis revealed glucocorticoid receptor targeting drugs as most potent in reversing the CUD expression profile. Our study highlights the value of multi-omics approaches for an in-depth molecular characterization and provides insights into the relationship between CUD-associated epigenomic and transcriptomic signatures in the human prefrontal cortex.

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Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models

Cited by 26 publications

References 76 publications

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

Transcriptional characterization of cocaine withdrawal versus extinction within nucleus accumbens

Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder

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