Male and female behavioral variability and morphine response in C57BL/6J, DBA/2J, and their BXD progeny following chronic stress exposure.

Drug addiction is a multifactorial syndrome in which genetic predispositions and exposure to environmental stressors constitute major risk factors for the early onset, escalation, and relapse of addictive behaviors. While it is well known that stress plays a key role in drug addiction, the genetic factors that make certain individuals particularly sensitive to stress and, thereby, more vulnerable to becoming addicted are unknown. In an effort to test a complex set of gene x environment interactions-specifically gene x chronic stress-here we leveraged a systems genetics resource: BXD recombinant inbred mice (BXD5, BXD8, BXD14, BXD22, BXD29, and BXD32) and their parental mouse lines, C57BL/6J and DBA/2J.

Cell-Type-Specific Regulation of Cocaine Reward by the E2F3a Transcription Factor in Nucleus Accumbens.

The development of drug addiction is characterized by molecular changes in brain reward regions that lead to the transition from recreational to compulsive drug use. These neurobiological processes in brain reward regions, such as the nucleus accumbens (NAc), are orchestrated in large part by transcriptional regulation. Our group recently identified the transcription factor E2F3a as a novel regulator of cocaine's rewarding effects and gene expression regulation in the NAc of male mice.

Mono-methylation of lysine 27 at histone 3 confers lifelong susceptibility to stress.

Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice susceptible to early life stress (ELS) or chronic social defeat stress (CSDS) displayed increased H3K27me1 enrichment in the nucleus accumbens (NAc), a key brain-reward region.

Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need.

Drugs of abuse are thought to promote addiction in part by "hijacking" brain reward systems, but the underlying mechanisms remain undefined. Using whole-brain FOS mapping and in vivo single-neuron calcium imaging, we found that drugs of abuse augment dopaminoceptive ensemble activity in the nucleus accumbens (NAc) and disorganize overlapping ensemble responses to natural rewards in a cell type-specific manner. Combining FOS-Seq, CRISPR-perturbation, and single-nucleus RNA sequencing, we identified as a molecular substrate that regulates cell type-specific signal transduction in NAc while enabling drugs to suppress natural reward consumption.

Circuit-Wide Gene Network Analysis Reveals Sex-Specific Roles for Phosphodiesterase 1b in Cocaine Addiction.

Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms that underlie long-lasting maladaptive plasticity and addiction-like behaviors. Here, we leverage a large RNA sequencing dataset to generate gene coexpression networks across six interconnected regions of the brain's reward circuitry from mice that underwent saline or cocaine self-administration.

Transcriptional characterization of cocaine withdrawal versus extinction within nucleus accumbens.

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.

Male and female variability in response to chronic stress and morphine in C57BL/6J, DBA/2J, and their BXD progeny.

Drug addiction is a multifactorial syndrome in which genetic predispositions and exposure to environmental stressors constitute major risk factors for the early onset, escalation, and relapse of addictive behaviors. While it is well known that stress plays a key role in drug addiction, the genetic factors that make certain individuals particularly sensitive to stress and thereby more vulnerable to becoming addicted are unknown. In an effort to test a complex set of gene x environment interactions-specifically -here we leveraged a systems genetics resource: BXD recombinant inbred mice (BXD5, BXD8, BXD14, BXD22, BXD29, and BXD32) and their parental mouse lines, C57BL/6J and DBA/2J.

tRNA epitranscriptomic alterations associated with opioid-induced reward-seeking and long-term opioid withdrawal in male mice.

DNA cytosine methylation has been documented as a potential epigenetic mechanism of transcriptional regulation underlying opioid use disorder. However, methylation of RNA cytosine residues, which would drive another level of biological influence as an epitranscriptomic mechanism of gene and protein regulation has not been studied in the context of addiction. Here, we probed whether chronic morphine exposure could alter tRNA cytosine methylation (mC) and resulting expression levels in the medial prefrontal cortex (mPFC), a brain region crucial for reward processing and executive function that exhibits opioid-induced molecular restructuring.

Shared and divergent transcriptomic regulation in nucleus accumbens D1 and D2 medium spiny neurons by cocaine and morphine.

Substance use disorders (SUDs) induce widespread molecular dysregulation in the nucleus accumbens (NAc), a brain region pivotal for coordinating motivation and reward. These molecular changes are thought to support lasting neural and behavioral disturbances that promote drug-seeking in addiction. However, different drug classes exert unique influences on neural circuits, cell types, physiology, and gene expression despite the overlapping symptomatology of SUDs.

Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need.

Addiction prioritizes drug use over innate needs by "hijacking" brain circuits that direct motivation, but how this develops remains unclear. Using whole-brain FOS mapping and single-neuron calcium imaging, we find that drugs of abuse augment ensemble activity in the nucleus accumbens (NAc) and disorganize overlapping ensemble responses to natural rewards in a cell-type-specific manner. Combining "FOS-Seq", CRISPR-perturbations, and snRNA-seq, we identify as a shared molecular substrate that regulates cell-type-specific signal transductions in NAc while enabling drugs to suppress natural reward responses.

Manipulating ΔFOSB in D1-Type Medium Spiny Neurons of the Nucleus Accumbens Reshapes Whole-Brain Functional Connectivity.

Background: The transcription factor ΔFOSB, acting in the nucleus accumbens, has been shown to control transcriptional and behavioral responses to opioids and other drugs of abuse. However, circuit-level consequences of ΔFOSB induction on the rest of the brain, which are required for its regulation of complex behavior, remain unknown.

Methods: We used an epigenetic approach in mice to suppress or activate the endogenous Fosb gene and thereby decrease or increase, respectively, levels of ΔFOSB selectively in D1-type medium spiny neurons of the nucleus accumbens and tested whether these modifications affect the organization of functional connectivity (FC) in the brain.

Monomethylation of Lysine 27 at Histone 3 Confers Lifelong Susceptibility to Stress.

Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling, and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice exposed to early life stress (ELS) or to chronic social defeat stress (CSDS) in adulthood displayed increased enrichment of H3K27me1, and transient decreases in H3K27me2, in the nucleus accumbens (NAc), a key brain-reward region.

Cell Type-Specific Whole-Genome Landscape of ΔFOSB Binding in the Nucleus Accumbens After Chronic Cocaine Exposure.

Background: The ability of neurons to respond to external stimuli involves adaptations of gene expression. Induction of the transcription factor ΔFOSB in the nucleus accumbens, a key brain reward region, is important for the development of drug addiction. However, a comprehensive map of ΔFOSB's gene targets has not yet been generated.

Transcriptional control of nucleus accumbens neuronal excitability by retinoid X receptor alpha tunes sensitivity to drug rewards.

The complex nature of the transcriptional networks underlying addictive behaviors suggests intricate cooperation between diverse gene regulation mechanisms that go beyond canonical activity-dependent pathways. Here, we implicate in this process a nuclear receptor transcription factor, retinoid X receptor alpha (RXRα), which we initially identified bioinformatically as associated with addiction-like behaviors. In the nucleus accumbens (NAc) of male and female mice, we show that although its own expression remains unaltered after cocaine exposure, RXRα controls plasticity- and addiction-relevant transcriptional programs in both dopamine receptor D1- and D2-expressing medium spiny neurons, which in turn modulate intrinsic excitability and synaptic activity of these NAc cell types.

Transcriptional signatures of heroin intake and seeking throughout the brain reward circuit.

Opioid use disorder (OUD) looms as one of the most severe medical crises currently facing society. More effective therapeutics for OUD requires in-depth understanding of molecular changes supporting drug-taking and relapse. Recent efforts have helped advance these aims, but studies have been limited in number and scope.

The long noncoding RNA FEDORA is a cell type- and sex-specific regulator of depression.

Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify marked baseline sex differences in the expression of long noncoding RNAs (lncRNAs), a class of regulatory transcripts, in human postmortem brain tissue that are profoundly lost in depression. One such human lncRNA, RP11-298D21.

CREB Binding at the Zfp189 Promoter Within Medium Spiny Neuron Subtypes Differentially Regulates Behavioral and Physiological Adaptations Over the Course of Cocaine Use.

Background: Over the course of chronic drug use, brain transcriptional neuroadaptation is thought to contribute to a change in drug use behavior over time. The function of the transcription factor CREB (cAMP response element binding protein) within the nucleus accumbens (NAc) has been well documented in opposing the rewarding properties of many classes of drugs, yet the gene targets through which CREB causally manifests these lasting neuroadaptations remain unknown. Here, we identify zinc finger protein 189 (Zfp189) as a CREB target gene that is transcriptionally responsive to acute and chronic cocaine use within the NAc of mice.

Dynamic processing of hunger and thirst by common mesolimbic neural ensembles.

The nucleus accumbens (NAc) is a canonical reward center that regulates feeding and drinking but it is not known whether these behaviors are mediated by same or different neurons. We employed two-photon calcium imaging in awake, behaving mice and found that during the appetitive phase, both hunger and thirst are sensed by a nearly identical population of individual D1 and D2 neurons in the NAc that respond monophasically to food cues in fasted animals and water cues in dehydrated animals. During the consummatory phase, we identified three distinct neuronal clusters that are temporally correlated with action initiation, consumption, and cessation shared by feeding and drinking.

Crystallin Mu in Medial Amygdala Mediates the Effect of Social Experience on Cocaine Seeking in Males but Not in Females.

Background: Social experiences influence susceptibility to substance use disorder. The adolescent period is associated with the development of social reward and is exceptionally sensitive to disruptions to reward-associated behaviors by social experiences. Social isolation (SI) during adolescence alters anxiety- and reward-related behaviors in adult males, but little is known about females.

Blood miR-144-3p: a novel diagnostic and therapeutic tool for depression.

Major depressive disorder (MDD) is the leading cause of disability worldwide. There is an urgent need for objective biomarkers to diagnose this highly heterogeneous syndrome, assign treatment, and evaluate treatment response and prognosis. MicroRNAs (miRNAs) are short non-coding RNAs, which are detected in body fluids that have emerged as potential biomarkers of many disease conditions.

Sperm Transcriptional State Associated with Paternal Transmission of Stress Phenotypes.

Paternal stress can induce long-lasting changes in germ cells potentially propagating heritable changes across generations. To date, no studies have investigated differences in transmission patterns between stress-resilient and stress-susceptible mice. We tested the hypothesis that transcriptional alterations in sperm during chronic social defeat stress (CSDS) transmit increased susceptibility to stress phenotypes to the next generation.