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Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, with aberrant transcription across several limbic brain regions, most notably in the nucleus accumbens (NAc). Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in the NAc have not yet been investigated. In this study, we examined long-lasting changes to histone modifications in the NAc of male and female mice exposed to ELS. Dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes (DOT1L and KDM2B) that control this modification are enriched in D2-type medium spiny neurons and are shown to be crucial for the expression of ELS-induced stress susceptibility. We mapped the site-specific regulation of this histone mark genome wide to reveal the transcriptional networks it modulates. Finally, systemic delivery of a small molecule inhibitor of DOT1L reversed ELS-induced behavioral deficits, indicating the clinical relevance of this epigenetic mechanism. Early life stress (ELS) promotes susceptibility to the effects of chronic stress in adulthood. Kronman et al. show that ELS alters H3K79me2 in D2 medium spiny neurons in the nucleus accumbens and that this underlies the susceptibility to the effects of subsequent stress.

Cocaine addiction is characterized by dysfunction in reward-related brain circuits, leading to maladaptive motivation to seek and take the drug. There are currently no clinically available pharmacotherapies to treat cocaine addiction. Through a broad screen of innate immune mediators, we identify granulocyte-colony stimulating factor (G-CSF) as a potent mediator of cocaine-induced adaptations. Here we report that G-CSF potentiates cocaine-induced increases in neural activity in the nucleus accumbens (NAc) and prefrontal cortex. In addition, G-CSF injections potentiate cocaine place preference and enhance motivation to self-administer cocaine, while not affecting responses to natural rewards. Infusion of G-CSF neutralizing antibody into NAc blocks the ability of G-CSF to modulate cocaine’s behavioral effects, providing a direct link between central G-CSF action in NAc and cocaine reward. These results demonstrate that manipulating G-CSF is sufficient to alter the motivation for cocaine, but not natural rewards, providing a pharmacotherapeutic avenue to manipulate addictive behaviors without abuse potential. Cocaine addiction is accompanied by dysfunction in neural circuits related to reward, but it is unclear how these adaptations occur. Here, authors identify granulocyte-colony stimulating factor as a potent mediator of cocaine-induced adaptations, and show that it can alter the motivation for cocaine.

Learned associations between the rewarding effects of drugs and the context in which they are experienced are critical for context-induced relapse. While context re-exposure triggers the recall of such drug-related associative memories it is unclear whether this relies on the reactivation of and plasticity in neuronal populations previously engaged in their acquisition. Here, using the immediate early gene Arc , we captured a discrete population of nucleus accumbens (NAc) cells activated during the encoding of cocaine-context memory in mice and showed that this neuronal ensemble is later reactivated upon context-induced recall. Furthermore, we show that ensembles recruited at early vs. late stages of memory encoding are largely distinct and contribute differentially to memory retrieval. Single nuclei RNA-sequencing of these ensembles identified plasticity-related transcriptional programs that segregate cocaine-recruited NAc engram-like cells beyond cell-type composition and revealed molecular features unique to distinct stages of memory processing. These findings suggest that activity-dependent transcription upon initial engram allocation further stamps cells for persistent plasticity programs and thereby supports memory traces at the single-cell level. This study also provides insights into the mechanisms supporting pathological memory formation associated with cocaine exposure. Cocaine-context associations rely on nucleus accumbens neuronal ensembles with engram-like properties unique to distinct stages of memory encoding. Here the authors show that ensemble reactivation parallels recall and selectively engages transcriptional plasticity programs.

Epigenetic consequences of exposure to psychostimulants are substantial but the relationship of these changes to compulsive drug taking and abstinence is not clear. Here, we used a paradigm that helped to segregate rats that reduce or stop their methamphetamine (METH) intake (nonaddicted) from those that continue to take the drug compulsively (addicted) in the presence of footshocks. We used that model to investigate potential alterations in global DNA hydroxymethylation in the nucleus accumbens (NAc) because neuroplastic changes in the NAc may participate in the development and maintenance of drug-taking behaviors. We found that METH-addicted rats did indeed show differential DNA hydroxymethylation in comparison with both control and nonaddicted rats. Nonaddicted rats also showed differences from control rats. Differential DNA hydroxymethylation observed in addicted rats occurred mostly at intergenic sites located on long and short interspersed elements. Interestingly, differentially hydroxymethylated regions in genes encoding voltage (Kv1.1, Kv1.2, Kvb1 and Kv2.2)- and calcium ( Kcnma1, Kcnn1 and Kcnn2 )-gated potassium channels observed in the NAc of nonaddicted rats were accompanied by increased mRNA levels of these potassium channels when compared with mRNA expression in METH-addicted rats. These observations indicate that changes in differentially hydroxymethylated regions and increased expression of specific potassium channels in the NAc may promote abstinence from drug-taking behaviors. Thus, activation of specific subclasses of voltage- and/or calcium-gated potassium channels may provide an important approach to the beneficial treatment for METH addiction.

Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome, in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, male Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an fixed-ratio 1 schedule. However, microbiome-depleted rats exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinence and altered transcriptional regulation in the nucleus accumbens. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target.

Background: Anxiety is an emotional response that, under normal conditions, promotes adaptive safety and survival behaviors through appropriate resolution of approach/avoidance conflicts, but, when inappropriate to the level of threat, contributes to several psychiatric disorders. Despite accumulating evidence for both the ventral hippocampus (vHipp) and the mesocorticolimbic dopamine system in encoding anxiety-relevant information and motivating exploratory behaviors, surprisingly little is known about how dopamine signaling selectively affects vHipp representations of emotionally-salient stimuli to guide approach/avoidance arbitration. To address these shortcomings, we here study dopaminoceptive neurons in mouse vHipp – which can be segregated based on their expression of either the dopamine D1 or D2 receptor – to delineate a model for dopamine neuromodulation within vHipp in coordinating decision-making processes and appropriate behavioral selection.Methods: We capitalized on D1-Cre and D2-Cre transgenic mice to visualize, record and manipulate vHipp D1 and D2 cells. These reporter lines were used for anatomy, single-nuclei RNA-sequencing, ex vivo slice electrophysiology, and cell-type-specific in vivo calcium imaging, chemogenetics and optogenetics. Genetically-encoded fluorescent dopamine sensors were used to record dopamine release in vHipp.Results: At the histological level, D1- and D2-expressing cells exhibit a precise topographical organization across vHipp subfields, which we further dissected using RNA-sequencing of single, sorted nuclei from D1 and D2 cells to identify separate sub-types of dopaminoceptive interneurons and principal cells in this region, which appear especially enriched in the caudo-ventral tip of the ventral CA1 and subiculum. Functionally, we found that anxiogenic environments and approach/avoidance conflicts trigger largely similar patterns of calcium activity in D1 versus D2 vHipp neurons in concert with dopamine release in in this region, which can in turn pharmacologically modulate the electrophysiological properties of these cell types. Bidirectional chemogenetic and optogenetic manipulation of D1 or D2 vHipp neurons’ activity however causally demonstrated their opposite roles in mediating approach/avoidance behaviors in both innate and learned anxiety-inducing situations. Intriguingly, vHipp dopaminoceptive mechanisms also contribute to cocaine-related behaviors, suggesting drug-induced plasticity in this circuit as well.Conclusions: Together, we propose that dopamine dynamics in vHipp operate as a feedback loop that bidirectionally tracks anxiety levels to gate exploratory behaviors through differential recruitment of vHipp D1 and D2 neurons, which in turn arbitrate opposite approach/avoidance and anxiety-like responses. This work paves the way for further studies of dopamine signal processing in limbic regions, and underscores the complexity of the circuit and neuromodulatory mechanisms that govern affective states.

MiR-124 is a highly expressed miRNA in the brain and regulates genes involved in neuronal function. We report that miR-124 post-transcriptionally regulates PARP-1. We have identified a highly conserved binding site of miR-124 in the 3′-untranslated region (3′UTR) of Parp-1 mRNA. We demonstrate that miR-124 directly binds to the Parp-1 3′UTR and mutations in the seed sequences abrogate binding between the two RNA molecules. Luciferase reporter assay revealed that miR-124 post-transcriptionally regulates Parp-1 3′UTR activity in a dopaminergic neuronal cell model. Interestingly, the binding region of miR-124 in Parp-1 3′UTR overlapped with the target sequence of miR-125b, another post-transcriptional regulator of Parp-1 . Our results from titration and pull-down studies revealed that miR-124 binds to Parp-1 3′UTR with greater affinity and confers a dominant post-transcriptional inhibition compared to miR-125b. Interestingly, acute or chronic cocaine exposure downregulated miR-124 levels concomitant with upregulation of PARP-1 protein in dopaminergic-like neuronal cells in culture. Levels of miR-124 were also downregulated upon acute or chronic cocaine exposure in the mouse nucleus accumbens (NAc)-a key reward region of brain. Time-course studies revealed that cocaine treatment persistently downregulated miR-124 in NAc. Consistent with this finding, miR-124 expression was also significantly reduced in the NAc of animals conditioned for cocaine place preference. Collectively, these studies identify Parp-1 as a direct target of miR-124 in neuronal cells, establish miR-124 as a cocaine-regulated miRNA in the mouse NAc, and highlight a novel pathway underlying the molecular effects of cocaine.

The persistent and experience-dependent nature of drug addiction may result in part from epigenetic alterations, including non-coding micro-RNAs (miRNAs), which are both critical for neuronal function and modulated by cocaine in the striatum. Two major striatal cell populations, the striato-nigral and striato-pallidal projection neurons, express, respectively, the D1 (D1-SPNs) and D2 (D2-SPNs) dopamine receptor, and display distinct but complementary functions in drug-evoked responses. However, a cell-type-specific role for miRNAs action has yet to be clarified. Here, we evaluated the expression of a subset of miRNAs proposed to modulate cocaine effects in the nucleus accumbens (NAc) and dorsal striatum (DS) upon sustained cocaine exposure in mice and showed that these selected miRNAs were preferentially upregulated in the NAc. We focused on miR-1 considering the important role of some of its predicted mRNA targets, Fosb and Npas4, in the effects of cocaine. We validated these targets in vitro and in vivo. We explored the potential of miR-1 to regulate cocaine-induced behavior by overexpressing it in specific striatal cell populations. In DS D1-SPNs miR-1 overexpression downregulated Fosb and Npas4 and reduced cocaine-induced CPP reinstatement, but increased cue-induced cocaine seeking. In DS D2-SPNs miR-1 overexpression reduced the motivation to self-administer cocaine. Our results indicate a role of miR1 and its target genes, Fosb and Npas4, in these behaviors and highlight a precise cell-type- and region-specific modulatory role of miR-1, illustrating the importance of cell-specific investigations.

Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, and show aberrant transcription across several limbic brain regions. The nucleus accumbens (NAc) in particular shows unique susceptible versus resilient phenotypes at the transcriptional, neuroanatomical, and physiological levels. Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in NAc have not yet been investigated. Here, we examined long-lasting changes in histone modifications induced in NAc by ELS and studied their underlying mechanisms in mediating heightened lifelong stress susceptibility in male and female mice. We identify dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes that control this modification, selectively in D2-type medium spiny neurons, as crucial for the expression of ELS-induced stress susceptibility. We also map the site-specific regulation of this histone mark genome-wide, and reveal the transcriptional networks it modulates. Finally, we demonstrate the potential clinical relevance of this epigenetic mechanism by showing that systemic delivery of a small molecule inhibitor of H3K79me2 deposition reverses ELS-induced behavioral deficits.

A Correction to this paper has been published: https://doi.org/10.1038/s41593-021-00848-y.