Biology subjects

Nestler, E. J.

Publications and source records attributed to Nestler, E. J..

53 records · Page 3Linked to original sources

bioRxiv2022

Cell-Type-Specific Epigenetic Priming of Gene Expression in Nucleus Accumbens by Cocaine

A hallmark of addiction is the ability of drugs of abuse to trigger relapse after periods of prolonged abstinence. Here, we describe a novel epigenetic mechanism whereby chronic cocaine exposure causes lasting chromatin and downstream transcriptional modifications in the nucleus accumbens (NAc), a critical brain region controlling motivation. We link prolonged withdrawal from cocaine to the depletion of the histone variant H2A.Z, coupled to increased genome accessibility and latent priming of gene transcription, in D1 dopamine receptor-expressing medium spiny neurons (D1 MSNs) that relates to aberrant gene expression upon drug relapse. The histone chaperone ANP32E removes H2A.Z from chromatin, and we demonstrate that D1 MSN-selective Anp32e knockdown prevents cocaine-induced H2A.Z depletion and blocks cocaines rewarding actions. By contrast, very different effects of cocaine exposure, withdrawal, and relapse were found for D2-MSNs. These findings establish histone variant exchange as an important mechanism and clinical target engaged by drugs of abuse to corrupt brain function and behavior.

molecular biology↗

bioRxiv2022

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 novel nuclear receptor transcription factor, Retinoid X Receptor Alpha (RXR), which we identified bioinformatically as associated with addiction-like behaviors. In the nucleus accumbens (NAc) of male and female mice, we show that, while its own expression remains unaltered after cocaine exposure, RXR 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. Behaviorally, bidirectional viral and pharmacological manipulation of RXR regulates drug reward sensitivity in both non-operant and operant paradigms. Together, this study demonstrates a key role for NAc RXR in promoting drug addiction, and paves the way for future studies of rexinoid signaling in psychiatric disease states.

neuroscience↗

bioRxiv2022

Chronic social stress induces isolated deficits in reward anticipation on a neuroeconomic foraging task

Measuring reward anticipation distinct from other aspects of reward value, including costs required to obtain a reward or the intrinsic hedonic value of consuming the reward itself, can be difficult to disentangle. Here, we show that mice trained on a self-paced neuroeconomic foraging task convey reward anticipation via differentially invigorated travel times between uniquely flavored feeding sites separate from willingness to wait, consummatory behaviors, or place preferences measured within the same trial. Following exposure to chronic social defeat stress, we found that only stress-susceptible but not stress-resilient mice revealed deficits in this metric after consuming but not after rejecting a reward on the previous trial, indicating that blunted anticipation in these animals is state-dependent, or punctuated by recent reward receipt. After increasing economic pressure and task demands, locomotion was globally invigorated and, in turn, masked stress-related deficits in reward anticipation. These findings suggest that the ability to detect changes in specific aspects of motivational deficits associated with depression and other stress-related disorders depends on an interaction between the state of an individual and environmental circumstances.

animal behavior and cognition↗

bioRxiv2022

Region-specific CREB function regulates distinct forms of regret associated with resilience versus susceptibility to chronic stress

Regret describes recognizing that alternative actions could have led to better outcomes. This can transform into behavioral consequences, altering subsequent valuations, but remains unclear if regret derives from a generalized computation for mistake appraisal or instead is made up of dissociable action-specific processes. Using a novel neuroeconomic decision-making paradigm, we found mice were differentially sensitive to fundamentally distinct types of missed opportunities following exposure to chronic social defeat stress or manipulations of CREB, a key transcription factor implicated in chronic stress action. Bias to make compensatory decisions after rejecting high-value offers (regret type I) was unique to stress-susceptible mice. Bias following the converse operation, accepting low-value offers (regret type II), was enhanced in stress-resilient and absent in stress-susceptible mice. CREB function in either the medial prefrontal cortex or nucleus accumbens was required to suppress regret type I but differentially affected regret type II. We provide insight into how adaptive versus maladaptive stress-response traits may be related to fundamentally distinct forms of counterfactual thinking and could steer psychotherapy for mood disorders such as depression toward unveiling circuit-specific computations through a careful description of decision narrative.

neuroscience↗

bioRxiv2021

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 dramatic baseline sex differences in expression of long noncoding RNAs (lncRNAs) in human postmortem brain tissue that are profoundly lost in depression. One such lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and upregulated in several cortical regions of depressed females but not males. We found that virally-expressing FEDORA selectively either in neurons or in oligodendrocytes of prefrontal cortex promoted depression-like behavioral abnormalities in female mice only, changes associated with cell-type-specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic significance for depressed women. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.

neuroscience↗

bioRxiv2021

DeepRegFinder: Deep Learning-Based Regulatory Elements Finder

MotivationEnhancers and promoters are important classes of DNA regulatory elements that control gene expression. Identifying them at the genomic scale is a critical and challenging task in bioinformatics. The most successful method so far is to train machine learning models on known enhancer and promoter sites and predict them at other genomic regions using ChIP-seq and related data. ResultsWe have developed a highly customizable program called DeepRegFinder which automates data processing, model training and genome-wide prediction of enhancers and promoters using convolutional and recurrent neural networks. Our program further classifies the enhancers and promoters into active and poised states to facilitate downstream analysis. Based on mean average precision scores of different classes across multiple cell types, our method significantly outperforms the existing algorithms. Availabilityhttps://github.com/shenlab-sinai/DeepRegFinder

bioinformatics↗

bioRxiv2020

miR-218 in adolescence predicts and mediates vulnerability to stress

Adolescence is a period of increased vulnerability to psychiatric disorders including depression. Discovering novel biomarkers to identify individuals who are at high risk is very much needed. Our previous work shows that the microRNA miR-218 mediates susceptibility to stress and depression in adulthood, by targeting the Netrin-1 guidance cue receptor gene Dcc (Deleted in colorectal cancer) in the medial prefrontal cortex (mPFC). Here we investigated whether miR-218 regulates Dcc expression in adolescence and could serve as an early predictor of lifetime stress vulnerability. miR-218 expression in the mPFC increases from early adolescence to adulthood and correlates negatively with Dcc levels. In blood, postnatal miR-218 expression parallels changes occurring in the mPFC. Notably, circulating miR-218 levels in adolescence associate with vulnerability to social defeat stress in adulthood, with high levels associated with social avoidance severity. Indeed, downregulation of miR-218 in the mPFC in adolescence promotes resilience to stress in adulthood, indicating that adolescent miR-218 expression may serve both as a marker of risk and as a target for early interventions.

neuroscience↗

bioRxiv2020

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

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.

neuroscience↗

bioRxiv2020

Cocaine triggers glial-mediated synaptogenesis

Synaptogenesis is essential in forming new neurocircuits during development, and this is mediated in part by astrocyte-released thrombospondins (TSPs) and activation of their neuronal receptor, 2{delta}-1. Here, we show that this developmental synaptogenic mechanism is utilized during cocaine experience to induce spinogenesis and the generation of AMPA receptor-silent glutamatergic synapses in the adult nucleus accumbens (NAc). Specifically, cocaine administration activates NAc astrocytes, and preventing this activation blocks cocaine-induced generation of silent synapses. Furthermore, knockout of TSP2, or pharmacological inhibition or viral-mediated knockdown of 2{delta}-1, prevents cocaine-induced generation of silent synapses. Moreover, disrupting TSP2-2{delta}-1-mediated spinogenesis and silent synapse generation in the NAc occludes cue-induced cocaine seeking after withdrawal from cocaine self-administration and cue-induced reinstatement of cocaine seeking after drug extinction. These results establish that silent synapses are generated by an astrocyte-mediated synaptogenic mechanism in response to cocaine experience and embed critical cue-associated memory traces that promote cocaine relapse.

neuroscience↗

bioRxiv2019

Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior

Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have a wide variety of negative effects on patients, their families, and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, repeated domination of subordinate social targets is reinforcing. Here, we show that orexin neurons originating from the lateral hypothalamus activate a small population of GABAergic interneurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2) to promote aggression and conditioned place preference (CPP) for aggression-paired contexts. Our study suggests that the orexin system is a potential target for the development of novel therapies aimed at reducing aggressive behaviors and provides the first functional evidence of a local inhibitory circuit within the LHb.

neuroscience↗

bioRxiv2019

Epigenetic signatures of chronic social stress in stress-susceptible animals

Exposure of mice to chronic social defeat stress (CSDS) produces depressive- and anxiety-like behaviors and widespread transcriptomic changes in several brain regions in susceptible animals. Here we present the first study of genome-wide cytosine methylation patterns of mice susceptible to CSDS using whole-genome bisulfite sequencing on DNA from the nucleus accumbens, a critical region for CSDS effects on behavior. We found extensive evidence for differential methylation following exposure to CSDS in susceptible animals, with a greater proportion of CG hypermethylation than hypomethylation in CSDS-susceptible mice compared to non-stressed controls; non-CG methylation shows the opposite trend. Several genes previously implicated in the effects of CSDS are among those with the greatest number of differentially methylated sites, including estrogen receptor alpha (Esr1), the deleted in colorectal cancer (Dcc) gene and Cacna1c, which has been associated with a range of psychiatric conditions. Informatic analysis of DM sites revealed a gene network with {beta}-catenin as the hub gene of a network that included the {beta}-catenin-related WNT/frizzled signaling pathway as well as both Esr1 and Dcc. Finally, we found considerable overlap between DM genes associated with CSDS in susceptible animals and those associated with human neuroticism in a genome-wide association study. Analysis of these overlapping genes revealed WNT signaling as the top pathway, which features {beta}-catenin as the primary hub gene. These findings reveal a striking convergence between the molecular pathways identified through either transcriptional or epigenomic analyses of the mouse model of susceptibility to chronic stress and the genomic architecture of increased stress susceptibility reflected in neuroticism in humans.

neuroscience↗

bioRxiv2019

Early life stress alters transcriptomic patterning across reward circuitry in male and female mice

Abuse, neglect, and other forms of early life stress (ELS) significantly increase risk for psychiatric disorders including depression. In this study, we show that ELS in a postnatal sensitive period increases sensitivity to adult stress in female mice, consistent with our earlier findings in male mice. We used RNA-sequencing in the ventral tegmental area, nucleus accumbens, and prefrontal cortex of male and female mice to show that adult stress is distinctly represented in the brains transcriptome depending on ELS history. We identify: 1) biological pathways disrupted after ELS and associated with increased behavioral stress sensitivity, 2) putative transcriptional regulators of the effect of ELS on adult stress response, and 3) subsets of primed genes specifically associated with latent behavioral changes. We also provide transcriptomic evidence that ELS increases sensitivity to future stress through enhancement of known programs of cortical plasticity.

neuroscience↗

bioRxiv2019

MiR-218: A Molecular Switch and Potential Biomarker of Susceptibility to Stress

Low miR-218 expression in the medial prefrontal cortex (mPFC) is a consistent trait of depression. Here we assessed whether miR-218 in the mPFC confers resilience or susceptibility to depression-like behaviors in adult mice, using the chronic social defeat stress (CSDS) model of depression. We also investigated whether stress-induced variations of miR-218 expression in the mPFC can be detected in blood. We find that downregulation of miR-218 in the mPFC increases susceptibility to a single session of social defeat, whereas overexpression of miR-218 selectively in mPFC pyramidal neurons promotes resilience to CSDS and prevents stress-induced morphological alterations to those neurons. After CSDS, susceptible mice have low levels of miR-218 in the blood as compared to control or resilient groups. We show further that up-and downregulation of miR-218 levels specifically in the mPFC correlates with miR-218 expression in blood. Our results suggest that miR-218 in the adult mPFC might function as a molecular switch that determines susceptibility versus resilience to chronic stress, and that stress-induced variations in mPFC levels of miR-218 could be detected in blood. We propose that blood expression of miR-218 might serve as potential readout of vulnerability to stress and as a proxy of mPFC function.

neuroscience↗

bioRxiv2018

Multi-OMIC analysis of brain and serum from chronically-stressed mice reveals network disruptions in purine metabolism, fatty acid beta-oxidation, and antioxidant activity that are reversed by antidepressant treatment

Major depressive disorder (MDD) is a complex condition with unclear pathophysiology. Molecular disruptions within the periphery and limbic brain regions contribute to depression symptomatology. Here, we utilized a mouse chronic stress model of MDD and performed metabolomic, lipidomic, and proteomic profiling on serum plus several brain regions (ventral hippocampus, nucleus accumbens, and prefrontal cortex) of susceptible, resilient, and unstressed control mice. Proteomic analysis identified three serum proteins reduced in susceptible animals; lipidomic analysis detected differences in lipid species between resilient and susceptible animals in serum and brain; and metabolomic analysis revealed pathway dysfunctions of purine metabolism, beta oxidation, and antioxidants, which were differentially associated with stress susceptibility vs resilience by brain region. Antidepressant treatment ameliorated MDD-like behaviors and affected key metabolites within outlined networks, most dramatically in the ventral hippocampus. This work presents a resource for chronic stress-induced, tissue-specific changes in proteins, lipids, and metabolites and illuminates how molecular dysfunctions contribute to individual differences in stress sensitivity.

neuroscience↗

bioRxiv2018

Biology and Bias in Cell Type-Specific RNAseq of Nucleus Accumbens Medium Spiny Neurons

Isolation of cell populations is untangling complex biological interactions, but studies comparing methodologies lack in vivo complexity and draw limited conclusions about the types of transcripts identified by each technique. Furthermore, few studies compare FACS-based techniques to ribosomal affinity purification, and none do so genome-wide. We addressed this gap by systematically comparing nuclear-FACS, whole cell-FACS, and RiboTag affinity purification in the context of D1 or D2 dopamine receptor-expressing medium spiny neuron (MSN) subtypes of the nucleus accumbens (NAc), a key brain reward region. We find that nuclear-FACS-seq generates a substantially longer list of differentially expressed genes between these cell types, and a significantly larger number of neuropsychiatric GWAS hits than the other two methods. RiboTag-seq has much lower coverage of the transcriptome than the other methods, but very efficiently distinguishes D1- and D2-MSNs. We also demonstrate differences between D1- and D2-MSNs with respect to RNA localization, suggesting fundamental cell type differences in mechanisms of transcriptional regulation and subcellular transport of RNAs. Together, these findings guide the field in selecting the RNAseq method that best suits the scientific questions under investigation.

neuroscience↗

bioRxiv2018

Zfp189 Mediates Stress Resilience Through a CREB-Regulated Transcriptional Network in Prefrontal Cortex

Stress resilience involves numerous brain-wide transcriptional changes. Determining the organization and orchestration of these transcriptional events may reveal novel antidepressant targets, but this remains unexplored. Here, we characterize the resilient transcriptome with co-expression analysis and identify a single transcriptionally-active uniquely-resilient gene network. Zfp189, a previously unstudied zinc finger protein, is the top network key driver and its overexpression in prefrontal cortical (PFC) neurons preferentially activates this network, alters neuronal activity and promotes behavioral resilience. CREB, which binds Zfp189, is the top upstream regulator of this network. To probe CREB-Zfp189 interactions as a network regulatory mechanism, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB selectively to the Zfp189 promoter. This single molecular interaction in PFC neurons recapitulates the pro-resilient Zfp189-dependent downstream effects on gene network activity, electrophysiology and behavior. These findings reveal an essential role for Zfp189 and a CREB-Zfp189 regulatory axis in mediating a central transcriptional network of resilience.

neuroscience↗

bioRxiv2017

Generation and validation of a floxed FosB mouse line

Expression of the FosB gene has been studied extensively in many fields using a variety of tools. However, previous techniques have had a variety of caveats, from potential off-target effects (e.g., overexpression of FosB, {Delta}FosB, or a dominant negative mutant of JunD, termed {Delta}JunD) or confounding developmental effects (e.g., the constitutive FosB knockout mouse). Therefore, we sought to create a floxed FosB mouse line that will allow true silencing of the FosB gene with both spatial and temporal control. Here, we detail the cloning strategy, production, and validation of the floxed FosB mouse. We demonstrate methodology for breeding and genotyping, and show that viral-mediated expression of Cre recombinase in a targeted, discrete brain region ablates expression of the FosB gene in floxed but not wild type mice. Thus, the floxed FosB mouse presented here represents an important new tool for the continued investigation of this critical gene.

genetics↗