Epigenetic Priming in Drug Addiction

Mews, Philipp; Walker, Deena M.; Nestler, Eric J.

doi:10.1101/sqb.2018.83.037663

Cited by 27 publications

(21 citation statements)

References 49 publications

(56 reference statements)

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“…To this end, we first confirmed the presence of crosssensitization between WIN and cocaine only in adolescent (and not in adult) rats. Our previous studies on other "gateway" drugs, such as nicotine and alcohol (41,42), suggested that drugpriming properties are mediated by epigenetic mechanisms (e.g., HDACs and histone acetylation) in line with the epigeneticpriming hypothesis in addiction (43). In agreement with this hypothesis, we found that WIN preexposure resulted in cocaineinduced global histone hyperacetylation in the adolescent PFC.…”

Section: Discussionsupporting

confidence: 89%

Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine

Scherma

Qvist

Asok

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological evidence demonstrating that cannabinoids can also alter the brain’s initial molecular and epigenetic response to cocaine. Here, we utilized a multiomics approach (epigenomics, transcriptomics, proteomics, and phosphoproteomics) to characterize how the rat brain responds to its first encounter with cocaine, with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN). We find that in adolescent (but not in adult) rats, preexposure to WIN results in cross-sensitization to cocaine, which correlates with histone hyperacetylation and decreased levels of HDAC6 in the prefrontal cortex (PFC). In the PFC, we also find that WIN preexposure blunts the typical mRNA response to cocaine and instead results in alternative splicing and chromatin accessibility events, involving genes such as Npas2. Moreover, preexposure to WIN enhances the effects of cocaine on protein phosphorylation, including ERK/MAPK-targets like gephyrin, and modulates the synaptic AMPAR/GluR composition both in the PFC and the nucleus accumbens (NAcc). PFC–NAcc gene network topological analyses, following cocaine exposure, reveal distinct top nodes in the WIN preexposed group, which include PACAP/ADCYAP1. These preclinical data demonstrate that adolescent cannabinoid exposure reprograms the initial behavioral, molecular, and epigenetic response to cocaine.

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Section: Discussionsupporting

confidence: 89%

Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine

Scherma

Qvist

Asok

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Indeed, this is what we found (Suppl Figure 7G,H). Many of the genes associated with Factor 4 are immediate early genes (Suppl Table 4) and have been implicated in regulating responses of Drd1 neurons in nucleus accumbens to cocaine (cFos, Fosb, Ppp1r1b, Arc; (Mews et al, 2018). Together, these data suggest that Crym OE in meA reprograms expression of reward-associated transcripts, which leads to sex-differences in responses to cocaine.…”

Section: R Y M O E I N a D U L T M E A M I M I C S Transcriptional mentioning

confidence: 87%

Adolescent Social Isolation Reprograms the Medial Amygdala: Transcriptome and Sex Differences in Reward

Walker

Zhou

Ramakrishnan

et al. 2020

Preprint

Self Cite

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Adolescence is a sensitive window for reward-and stress-associated behavior. Although stress during this period causes long-term changes in behavior in males, how females respond is relatively unknown. Here we show that social isolation stress in adolescence, but not adulthood, induces persistent but opposite effects on anxiety-and cocaine-related behaviors in male vs. female mice, and that these effects are reflected in transcriptional profiles within the adult medial amygdala (meA). By integrating differential gene expression with co-expression network analyses, we identified crystallin mu (Crym), a thyroid-binding protein, as a key driver of these transcriptional profiles. Manipulation of Crym specifically within adult meA neurons recapitulates the behavioral and transcriptional effects of social isolation and re-opens a window of plasticity that is otherwise closed. Our results establish that meA is essential for sex-specific responses to stressful and rewarding stimuli through transcriptional programming that occurs during adolescence. INTRODUCTION:In many mammals, sex differences in behavior are required for the perpetuation of the species and are expressed as differences in mating and reproductive strategies. Individual variations in reproductive strategies are known to be dependent on e n v i r o n m e n t a l f a c t o r s a n d r e l y o n programming mediated by experiencedependent plasticity (Bergan et al., 2014). Stressful and rewarding stimuli are two key factors that may be especially important for encoding these strategies to optimize sexual behaviors and maximize reproductive success . However, very little is known about the brain region-specific m o l e c u l a r p r o c e s s e s u n d e r l y i n g t h e programming of such strategies.Adolescence is a sensitive period for programming reward-associated behaviors particularly in males (Sisk, 2016;Walker et al., 2019) and a time of heightened responsiveness to rewarding and stressful Statistical Analysis of Behavioral DataAll behaviors were analyzed using a 2-way ANOVA or a Kruskall-Wallis non-parametric test depending on the significance of a Levene's test for homogeneity of variance. If an interaction was identified, a Tukey post-hoc analysis was conducted to determine specific differences between groups. If an effect was identified via Kruskall-Wallis, follow-up Mann-Whitney tests were run to determine specific differences between groups. Chi-square tests were used to determine differences in the distribution of behavioral phenotypes within a group (marble burying and CPP). Pearson's Chi Squared tests were used to account for the lack of representation of all categories across groups. All analyses were conducted using SPSS Statistical Software, V25 (IBM, Armonk, NY). Cocaine Injections and Tissue Collection for RNA-seqOn P80, animals were divided into 8 groups of males and 8 groups of females: GH + chronic cocaine/saline; SI + chronic cocaine /saline; GH + acute cocaine/saline; SI + acute cocaine/saline. In total, 200 animals were utlilized. F...

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“…Rick Huganir discussed the molecular mechanisms underlying the effects of loss-of-function mutations in SYNGAP1 known to cause intellectual disability. Eric Nestler emphasized the use of new unbiased transcriptional approaches leading to the identification of "chromatin scars," which can produce lasting change in gene expression in brain reward regions, including nucleus accumbens, tracking the history of cocaine self-administration in mice (Mews et al 2019). Rob Malenka showed that activating serotonergic dorsal raphe neurons could reverse social deficits in the 16p11.2 model (Klawonn and Malenka 2019), and Pico Caroni showed how the plasticity of inhibitory neurons underlies specific learning processes and reported that in 22q11 deletion syndrome model mice, D2 receptor antagonists transiently rescue baseline and activation-induced parvalbumin plasticity in adult mice.…”

Section: Curiosity-driven Science Connects With the Clinicmentioning

confidence: 99%

Summary: Order and Disorder in Brains and Behavior

Kepecs

2018

Cold Spring Harb Symp Quant Biol

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System explored the tremendous recent progress in neuroscience and how these advances may be used to improve brain health and address psychiatric and neurological disorders. The Symposium explored a vast array of topics from cell types to cognition. My summary focuses on a few emerging themes. Innovative techniques were ever-present, opening up new experimental possibilities. The commoditization of many state-of-the-art technologies is pushing neuroscience beyond its artisanal ways. Another important theme was "circuits in the middle": Numerous presentations dissected cell type-specific circuits that connect different levels of analysis from molecules to behavior. These new technologies have enabled curiosity-driven investigations in animals to connect more directly with preclinical and clinical studies of human brain disorders. Numerous emerging approaches were presented in human neuroscience, bolstering the hope that circuit-specific manipulations will soon provide improved treatments for brain disorders.The seat of the soul and the control of voluntary movement-in fact, of nervous functions in general-are to be sought in the heart. The brain is an organ of minor importance… .-Aristotle, De motu animalium

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Epigenetic Priming in Drug Addiction

Cited by 27 publications

References 49 publications

Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine

Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine

Adolescent Social Isolation Reprograms the Medial Amygdala: Transcriptome and Sex Differences in Reward

Summary: Order and Disorder in Brains and Behavior

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