Key transcription factors mediating cocaine-induced plasticity in the nucleus accumbens

Teague, Collin; Nestler, Eric J.

doi:10.1038/s41380-021-01163-5

Cited by 61 publications

(41 citation statements)

References 169 publications

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“…Furthermore, our analysis identified bZIP motifs for AP1 family members (e.g., CREB, JUN, FOS) as enriched in TSRs up-regulated in both brain regions from rats exposed to cocaine compared to naive rats (Fig. 3B), which is consistent with previous findings showing activation of members of the AP1 family in addiction-related processes, such as ΔFOSB or CREB (Teague and Nestler, 2021). To validate the motif enrichment predictions, we next overlapped regulated TSRs with GR binding sites previously identified in the rat hippocampal neurons (Buurstede et al, 2021).…”

Section: Comparison Of Oxycodone/cocaine/naive Rats Reveals Activated and Repressed Regulatory Programs Associated With Addiction-like Besupporting

confidence: 92%

“…These neuroadaptations manifest as changes in excitability, synaptic function and structure, which ultimately contribute to the increased risk to relapse after prolonged abstinence (Dong et al, 2017). It is well known that different drugs of abuse act through distinct receptors, but engage convergent pathways that activate or repress the activity of transcriptional factors (TFs) or epigenetic regulators, which in turn drive changes in gene expression patterns (Pierce et al, 2018;Hamilton and Nestler, 2019;Teague and Nestler, 2021;Werner et al, 2021). Numerous studies have elucidated the role of key TFs in the regulation of gene expression patterns altered by repeated exposure to addictive drugs, including cocaine and opioids.…”

Section: Introductionmentioning

confidence: 99%

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Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction

Duttke

Montilla‐Perez

Chang

et al. 2022

Preprint

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Substance abuse and addiction represent a major public health problem that impacts multiple dimensions of society, including healthcare, economy, and workforce. In 2021, over 100,000 drug overdose deaths have been reported in the US with an alarming increase in fatalities related to opioids and psychostimulants. Understanding of the fundamental gene regulatory mechanisms underlying addiction and related behaviors could facilitate more effective treatments. To explore how repeated drug exposure alters gene regulatory networks in the brain, we combined capped small (cs)RNA-seq, which accurately captures nascent-like initiating transcripts from total RNA, with Hi-C and single nuclei (sn)ATAC-seq. We profiled initiating transcripts in two addiction-related brain regions, the prefrontal cortex (PFC) and the nucleus accumbens (NAc), from rats that were never exposed to drugs or were subjected to prolonged abstinence after oxycodone or cocaine intravenous self-administration (IVSA). Interrogating over 100,000 active transcription start regions (TSRs) revealed that most TSRs had hallmarks of bona-fide enhancers and highlighted the KLF/SP1, RFX and AP1 transcription factors families as central to establish brain-specific gene regulatory programs. Analysis of rats with addiction-like behaviors versus controls identified addiction-associated repression of transcription at regulatory enhancers recognized by nuclear receptor subfamily 3 group C (NR3C) factors, which include glucocorticoid receptors. Cell-type deconvolution analysis using snATAC-seq uncovered a potential role of glial cells in driving the gene regulatory programs associated with addiction-related phenotypes. These findings highlight the power of advanced transcriptomics methods to provide insight into how addiction perturbs gene regulatory programs in the brain.

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Section: Comparison Of Oxycodone/cocaine/naive Rats Reveals Activated and Repressed Regulatory Programs Associated With Addiction-like Besupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction

Duttke

Montilla‐Perez

Chang

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…They found that, on average, patients showed reduced rightward volume asymmetry of the nucleus accumbens, and concluded that disrupted structural asymmetry in this brain area might be a characteristic of addiction. The nucleus accumbens is a central component of the reward circuit in the brain ( Teague and Nestler, 2021 ). Since altered reward processing is a central component of substance-related and addictive disorders, this finding suggests that diagnosis-specific risk factors or symptom-specific risk factors, but not non-specific risk factors, link gray matter asymmetries and this group of disorders.…”

Section: Substance-related and Addictive Disordersmentioning

confidence: 99%

Asymmetry in the Central Nervous System: A Clinical Neuroscience Perspective

Mundorf

Peterburs

Ocklenburg

2021

Front. Syst. Neurosci.

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Recent large-scale neuroimaging studies suggest that most parts of the human brain show structural differences between the left and the right hemisphere. Such structural hemispheric asymmetries have been reported for both cortical and subcortical structures. Interestingly, many neurodevelopmental and psychiatric disorders have been associated with altered functional hemispheric asymmetries. However, findings concerning the relation between structural hemispheric asymmetries and disorders have largely been inconsistent, both within specific disorders as well as between disorders. In the present review, we compare structural asymmetries from a clinical neuroscience perspective across different disorders. We focus especially on recent large-scale neuroimaging studies, to concentrate on replicable effects. With the notable exception of major depressive disorder, all reviewed disorders were associated with distinct patterns of alterations in structural hemispheric asymmetries. While autism spectrum disorder was associated with altered structural hemispheric asymmetries in a broader range of brain areas, most other disorders were linked to more specific alterations in brain areas related to cognitive functions that have been associated with the symptomology of these disorders. The implications of these findings are highlighted in the context of transdiagnostic approaches to psychopathology.

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“…In contrast, Bdnf is expressed higher in D1 than A2a nuclei but showed similar co-enrichment of H3K4me3 and H3K27me3 in both A2a and D1 nuclei (data not shown). Taken together, combinatorial hPTM profiling by ICuRuS suggested that A2a and D1 co-enriched genes are likely suppressed in a cell-type specific manner during development but retain some level of gene activity 33,48,49 .…”

Section: Resultsmentioning

confidence: 89%

Cell-Type Specific Profiling of Histone Post-Translational Modifications in the Adult Mouse Striatum

Carpenter

Fischer

Zhang

et al. 2022

Preprint

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Histone post-translational modifications (hPTMs) regulate gene expression via changes in chromatin accessibility and transcription factor recruitment. At a given locus, the coordinated enrichment of several distinct hPTMs regulate gene expression in response to external stimuli. However, neuronal hPTMs have been primarily characterized in bulk brain tissue and/or tissue pooled across subjects. This obscures both cell-type and individual variability, features essential to understand individual susceptibility to psychiatric disease. To address this limitation, we optimized a hybrid protocol, ICuRuS, to profile both activating and repressive hPTMs in neuronal subtypes from a single mouse. We report here profiling of striatal medium spiny neuron (MSN) subtypes, genetically defined by expression of Adenosine 2a Receptor (A2a) or Dopamine Receptor D1 (D1), which differentially regulate reward processing and pathophysiology. Using ICuRuS, we defined genome-wide, A2a- or D1-specific combinatorial hPTM profiles, and discovered regulatory epigenomic features at genes implicated in neurobiological function and disease.

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Key transcription factors mediating cocaine-induced plasticity in the nucleus accumbens

Cited by 61 publications

References 169 publications

Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction

Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction

Asymmetry in the Central Nervous System: A Clinical Neuroscience Perspective

Cell-Type Specific Profiling of Histone Post-Translational Modifications in the Adult Mouse Striatum

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