Eric J Nestler

Icahn School of Medicine at Mount Sinai, Borough of Manhattan, New York, United States

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Publications (521)4526.21 Total impact

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    ABSTRACT: Previous research has demonstrated antidepressant-like effects in rodents upon intracerebral inhibition of histone deacetylases (HDACs). Such effects have been reported for local HDAC inhibition in the nucleus accumbens, hippocampus, and amygdala. However, the effect of HDAC inhibition within the medial prefrontal cortex, which is integral to depression-related symptoms and their treatment, remains unknown. Here we show that local infusion of the highly selective HDAC inhibitor, MS-275, into medial prefrontal cortex exerts robust antidepressant-like effects in the chronic social defeat stress paradigm in mice. These findings provide further impetus for the assessment of HDAC inhibitors for the treatment of depression. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 04/2015; DOI:10.1016/j.neuroscience.2015.04.030 · 3.33 Impact Factor
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    ABSTRACT: Ten-eleven translocation (TET) enzymes mediate the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is enriched in brain, and its ultimate DNA demethylation. However, the influence of TET and 5hmC on gene transcription in brain remains elusive. We found that ten-eleven translocation protein 1 (TET1) was downregulated in mouse nucleus accumbens (NAc), a key brain reward structure, by repeated cocaine administration, which enhanced behavioral responses to cocaine. We then identified 5hmC induction in putative enhancers and coding regions of genes that have pivotal roles in drug addiction. Such induction of 5hmC, which occurred similarly following TET1 knockdown alone, correlated with increased expression of these genes as well as with their alternative splicing in response to cocaine administration. In addition, 5hmC alterations at certain loci persisted for at least 1 month after cocaine exposure. Together, these reveal a previously unknown epigenetic mechanism of cocaine action and provide new insight into how 5hmC regulates transcription in brain in vivo.
    Nature Neuroscience 03/2015; DOI:10.1038/nn.3976 · 14.98 Impact Factor
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    ABSTRACT: Neuropathic and inflammatory pain promote a large number of persisting adaptations at the cellular and molecular level, allowing even transient tissue or nerve damage to elicit changes in cells that contribute to the development of chronic pain and associated symptoms. There is evidence that injury-induced changes in chromatin structure drive stable changes in gene expression and neural function, which may cause several symptoms, including allodynia, hyperalgesia, anxiety, and depression. Recent findings on epigenetic changes in the spinal cord and brain during chronic pain may guide fundamental advances in new treatments. Here, we provide a brief overview of epigenetic regulation in the nervous system and then discuss the still-limited literature that directly implicates epigenetic modifications in chronic pain syndromes. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Trends in Neurosciences 03/2015; DOI:10.1016/j.tins.2015.02.001 · 12.90 Impact Factor
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    ABSTRACT: Previous studies have shown that chronic cocaine administration induces SIRT1, a Class III histone deacetylase, in the nucleus accumbens (NAc), a key brain reward region, and that such induction influences the gene regulation and place conditioning effects of cocaine. To determine the mechanisms by which SIRT1 mediates cocaine-induced plasticity in NAc, we used chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), 1 d after 7 daily cocaine (20 mg/kg) or saline injections, to map SIRT1 binding genome-wide in mouse NAc. Our unbiased results revealed two modes of SIRT1 action. First, despite its induction in NAc, chronic cocaine causes depletion of SIRT1 from most affected gene promoters in concert with enrichment of H4K16ac (itself a deacetylation target of SIRT1), which is associated with increased expression of these genes. Second, we deduced the forkhead transcription factor (FOXO) family to be a downstream mechanism through which SIRT1 regulates cocaine action. We proceeded to demonstrate that SIRT1 induction causes the deacetylation and activation of FOXO3a in NAc, which leads to the induction of several known FOXO3a gene targets in other systems. Finally, we directly establish a role for FOXO3a in promoting cocaine-elicited behavioral responses by use of viral-mediated gene transfer: we show that overexpressing FOXO3a in NAc enhances cocaine place conditioning. The discovery of these two actions of SIRT1 in NAc in the context of behavioral adaptations to cocaine represents an important step forward in advancing our understanding of the molecular adaptations underlying cocaine action. Copyright © 2015 the authors 0270-6474/15/353100-12$15.00/0.
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) has a crucial role in modulating neural and behavioral plasticity to drugs of abuse. We found a persistent downregulation of exon-specific Bdnf expression in the ventral tegmental area (VTA) in response to chronic opiate exposure, which was mediated by specific epigenetic modifications at the corresponding Bdnf gene promoters. Exposure to chronic morphine increased stalling of RNA polymerase II at these Bdnf promoters in VTA and altered permissive and repressive histone modifications and occupancy of their regulatory proteins at the specific promoters. Furthermore, we found that morphine suppressed binding of phospho-CREB (cAMP response element binding protein) to Bdnf promoters in VTA, which resulted from enrichment of trimethylated H3K27 at the promoters, and that decreased NURR1 (nuclear receptor related-1) expression also contributed to Bdnf repression and associated behavioral plasticity to morphine. Our findings suggest previously unknown epigenetic mechanisms of morphine-induced molecular and behavioral neuroadaptations.
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    ABSTRACT: Drug addiction involves long-term behavioral abnormalities and gene expression changes throughout the mesolimbic dopamine system. Epigenetic mechanisms establish/maintain alterations in gene expression in the brain, providing the impetus for investigations characterizing how epigenetic processes mediate the effects of drugs of abuse. This review focuses on evidence that epigenetic events, specifically histone modifications, regulate gene expression changes throughout the reward circuitry. Drugs of abuse induce changes in histone modifications throughout the reward circuitry by altering histone-modifying enzymes, manipulation of which reveals a role for histone modification in addiction-related behaviors. There is a complex interplay between these enzymes, resulting in a histone signature of the addicted phenotype. Insights gained from these studies are key to identifying novel targets for diagnosis and therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Current Opinion in Neurobiology 12/2014; 30C:112-121. DOI:10.1016/j.conb.2014.11.002 · 6.77 Impact Factor
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    ABSTRACT: β-catenin is a multi-functional protein that has an important role in the mature central nervous system; its dysfunction has been implicated in several neuropsychiatric disorders, including depression. Here we show that in mice β-catenin mediates pro-resilient and anxiolytic effects in the nucleus accumbens, a key brain reward region, an effect mediated by D2-type medium spiny neurons. Using genome-wide β-catenin enrichment mapping, we identify Dicer1-important in small RNA (for example, microRNA) biogenesis-as a β-catenin target gene that mediates resilience. Small RNA profiling after excising β-catenin from nucleus accumbens in the context of chronic stress reveals β-catenin-dependent microRNA regulation associated with resilience. Together, these findings establish β-catenin as a critical regulator in the development of behavioural resilience, activating a network that includes Dicer1 and downstream microRNAs. We thus present a foundation for the development of novel therapeutic targets to promote stress resilience.
    Nature 11/2014; 516(7529). DOI:10.1038/nature13976 · 42.35 Impact Factor
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    ABSTRACT: Over the past decade, rapid advances in epigenomics research have extensively characterized critical roles for chromatin regulatory events during normal periods of eukaryotic cell development and plasticity, as well as part of aberrant processes implicated in human disease. Application of such approaches to studies of the CNS, however, is more recent. Here we provide a comprehensive overview of available tools for analyzing neuroepigenomics data, as well as a discussion of pending challenges specific to the field of neuroscience. Integration of numerous unbiased genome-wide and proteomic approaches will be necessary to fully understand the neuroepigenome and the extraordinarily complex nature of the human brain. This will be critical to the development of future diagnostic and therapeutic strategies aimed at alleviating the vast array of heterogeneous and genetically distinct disorders of the CNS.
    Nature Neuroscience 11/2014; 17(11):1476-1490. DOI:10.1038/nn.3816 · 14.98 Impact Factor
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    ABSTRACT: Background The high rate of comorbidity between depression and cocaine addiction suggests shared molecular mechanisms and anatomical pathways. Limbic structures, such as the Nucleus Accumbens (NAc), play a crucial role in both disorders, yet how different cell types within these structures contribute to the pathogenesis remains elusive. Downregulation of p11 (S100A10) specifically in the NAc elicits depressive-like behaviors in mice but its role in drug addiction is unknown. Methods We combine mouse genetics and viral strategies to determine how the titration of p11 levels within the entire NAc affects the rewarding actions of cocaine on behavior (6 to 8 mice per group) and molecular correlates (3 experiments, 5 to 8 mice per group). Finally, the manipulation of p11 expression in distinct NAc dopaminoceptive neuronal subsets distinguished cell-type specific effects of p11 on cocaine reward (5 to 8 mice per group) Results We demonstrate that p11 knockout mice have enhanced cocaine conditioned place preference (CPP), which is reproduced by the focal downregulation of p11 in the NAc of wild-type mice. In wild-type mice, cocaine reduced p11 expression in the NAc, while p11 overexpression exclusively in the NAc reduced cocaine CPP. Finally, we identify dopamine receptor-1 (D1) expressing medium spiny neurons (MSNs) as key mediators of p11’s effects on cocaine reward. Conclusions Our data provide evidence that disruption of p11 homeostasis in the NAc particularly in D1-expressing MSNs may underlie pathophysiological mechanisms of cocaine rewarding action. Treatments to counter maladaptation of p11 levels may provide novel therapeutic opportunities for cocaine addiction.
    Biological psychiatry 11/2014; 76(10). DOI:10.1016/j.biopsych.2014.02.012 · 9.47 Impact Factor
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    ABSTRACT: Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. We investigated the mechanism linking chromatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo. We found that histone methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery. This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior.
    Nature Neuroscience 10/2014; DOI:10.1038/nn.3871 · 14.98 Impact Factor
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    ABSTRACT: Previous work has implicated the transcription factor, ΔFosB, acting in the nucleus accumbens, in mediating the pro-rewarding effects of drugs of abuse such as cocaine as well as in mediating resilience to chronic social stress. However, the transgenic and viral gene transfer models used to establish these ΔFosB phenotypes express, in addition to ΔFosB, an alternative translation product of ΔFosB mRNA, termed Δ2ΔFosB, which lacks the N-terminal 78 aa present in ΔFosB. To study the possible contribution of Δ2ΔFosB to these drug and stress phenotypes, we prepared a viral vector that overexpresses a point mutant form of ΔFosB mRNA which cannot undergo alternative translation as well as a vector that overexpresses Δ2ΔFosB alone. Our results show that the mutant form of ΔFosB, when overexpressed in the nucleus accumbens, reproduces the enhancement of reward and of resilience seen with our earlier models, with no effects seen for Δ2ΔFosB. Overexpression of full length FosB, the other major product of the FosB gene, also has no effect. These findings confirm the unique role of ΔFosB in nucleus accumbens in controlling responses to drugs of abuse and stress.
    Neuroscience 10/2014; 284. DOI:10.1016/j.neuroscience.2014.10.002 · 3.33 Impact Factor
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    ABSTRACT: Background Anhedonia, or diminished interest or pleasure in rewarding activities, characterizes depression and reflects deficits in brain reward circuitries. Social stress induces anhedonia and increases depression risk, although the effect of social stress on brain reward function remains incompletely understood. Methods We assessed: 1) brain reward function in rats (using the intracranial self-stimulation procedure) and protein levels of brain-derived neurotrophic factor (BDNF) and related signaling molecules in response to chronic social defeat; 2) brain reward function during social defeat and chronic treatment with the antidepressants fluoxetine (5 mg/kg/day) or desipramine (10 mg/kg/day); and 3) forced swim test behavior after social defeat and fluoxetine treatment. Results Social defeat profoundly and persistently decreased brain reward function, reflecting an enduring anhedonic response, in susceptible rats, while resilient rats showed no long-term brain reward deficits. In the ventral tegmental area (VTA), social defeat, regardless of susceptibility or resilience, decreased and increased BDNF and phosphorylated AKT, respectively, whereas only susceptibility was associated with increased phosphorylated mammalian target of rapamycin (mTOR). Fluoxetine and desipramine reversed lower, but not higher, stress-induced brain reward deficits in susceptible rats. Fluoxetine decreased immobility in the forced swim test, as did social defeat. Conclusions These results suggest that the differential persistent anhedonic response to psychosocial stress may be mediated by VTA signaling molecules independent of BDNF, and indicate that greater stress-induced anhedonia is associated with antidepressant treatment resistance. Consideration of these behavioral and neurobiological factors associated with resistance to stress and antidepressant action may promote the discovery of novel targets to treat stress-related mood disorders.
    Biological psychiatry 10/2014; 76(7). DOI:10.1016/j.biopsych.2014.01.013 · 9.47 Impact Factor
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    ABSTRACT: Background Chronic social defeat stress (CSDS) produces persistent behavioral adaptations in mice. In many behavioral assays, it can be difficult to determine if these adaptations reflect core signs of depression. We designed studies to characterize the effects of CSDS on sensitivity to reward, since anhedonia (reduced sensitivity to reward) is a defining characteristic of depressive disorders in humans. We also examined the effects of striatal ΔFosB overexpression or the N-methyl-D-aspartate antagonist ketamine, both of which promote resilience, on CSDS-induced alterations in reward function and social interaction. Methods We used intracranial self-stimulation (ICSS) to quantify CSDS-induced changes in reward function. Mice were implanted with lateral hypothalamic (LH) electrodes and ICSS thresholds were measured following each of 10 daily CSDS sessions, and during a 5-day recovery period. We also examined if acute administration of ketamine (2.5-20 mg/kg, intraperitoneal) reverses CSDS-induced effects on reward or, in separate mice, social interaction. Results CSDS increased ICSS thresholds, indicating decreases in the rewarding impact of LH stimulation (anhedonia). This effect was attenuated in mice overexpressing ∆FosB in striatum, consistent with pro-resilient actions of this transcription factor. High but not low doses of ketamine administered after completion of the CSDS regimen attenuated social avoidance in defeated mice, although this effect was transient. Ketamine did not block CSDS-induced anhedonia in the ICSS test. Conclusions Our findings demonstrate that CSDS triggers persistent anhedonia, and confirm that ΔFosB overexpression produces stress resilience. They also indicate that acute ketamine fails to attenuate CSDS-induced anhedonia despite reducing other depression-related behavioral abnormalities.
    Biological psychiatry 10/2014; 76(7). DOI:10.1016/j.biopsych.2013.12.014 · 9.47 Impact Factor
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    ABSTRACT: Psychiatric disorders are complex multifactorial disorders involving chronic alterations in neural circuit structure and function. While genetic factors play a role in the etiology of disorders such as depression, addiction, and schizophrenia, relatively high rates of discordance among identical twins clearly point to the importance of additional factors. Environmental factors, such as stress, play a major role in the psychiatric disorders by inducing stable changes in gene expression, neural circuit function, and ultimately behavior. Insults at the developmental stage and in adulthood appear to induce distinct maladaptations. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Indeed, transcriptional dysregulation and associated aberrant epigenetic regulation is a unifying theme in psychiatric disorders. Aspects of depression can be modeled in animals by inducing disease-like states through environmental manipulations, and these studies can provide a more general understanding of epigenetic mechanisms in psychiatric disorders. Understanding how environmental factors recruit the epigenetic machinery in animal models is providing new insights into disease mechanisms in humans.
    Dialogues in clinical neuroscience 09/2014; 16(3):281-95.
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    ABSTRACT: Environmental enrichment produces protective addiction and depression phenotypes in rats. ΔFosB is a transcription factor that regulates reward in the brain and is induced by psychological stress as well as drugs of abuse. However, the role played by ΔFosB in the protective phenotypes of environmental enrichment has not been well studied. Here, we demonstrate that ΔFosB is differentially regulated in rats reared in an isolated condition (IC) compared to those in an enriched condition (EC) in response to restraint stress or cocaine. Chronic stress or chronic cocaine treatment each elevates ΔFosB protein levels in the nucleus accumbens (NAc) of IC rats, but not of EC rats due to an already elevated basal accumulation of ΔFosB seen under EC conditions. Viral-mediated overexpression of ΔFosB in the NAc shell of pair-housed rats (i.e., independent of environmental enrichment/isolation) increases operant responding for sucrose when motivated by hunger, but decreases responding in satiated animals. Moreover, ΔFosB overexpression decreases cocaine self-administration, enhances extinction of cocaine seeking, and decreases cocaine-induced reinstatement of intravenous cocaine self-administration; all behavioral findings consistent with the enrichment phenotype. In contrast, however, ΔFosB overexpression did not alter responses of pair-housed rats in several tests of anxiety- and depression-related behavior. Thus, ΔFosB in the NAc the shell mimics the protective addiction phenotype, but not the protective depression phenotype of environmental enrichment.
    Frontiers in Behavioral Neuroscience 08/2014; 8:297. DOI:10.3389/fnbeh.2014.00297 · 4.16 Impact Factor
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    ABSTRACT: Stable changes in neuronal gene expression have been studied as mediators of addicted states. Of particular interest is the transcription factor ΔFosB, a truncated and stable FosB gene product whose expression in nucleus accumbens (NAc), a key reward region, is induced by chronic exposure to virtually all drugs of abuse and regulates their psychomotor and rewarding effects. Phosphorylation at Ser(27) contributes to ΔFosB's stability and accumulation following repeated exposure to drugs, and our recent work demonstrates that the protein kinase CaMKIIα phosphorylates ΔFosB at Ser(27) and regulates its stability in vivo. Here, we identify two additional sites on ΔFosB that are phosphorylated in vitro by CaMKIIα, Thr(149) and Thr(180), and demonstrate their regulation in vivo by chronic cocaine. We show that phosphomimetic mutation of Thr(149) (T149D) dramatically increases AP-1 transcriptional activity while alanine mutation does not affect transcriptional activity when compared with wild-type (WT) ΔFosB. Using in vivo viral-mediated gene transfer of ΔFosB-T149D or ΔFosB-T149A in mouse NAc, we determined that overexpression of ΔFosB-T149D in NAc leads to greater locomotor activity in response to an initial low dose of cocaine than does WT ΔFosB, while overexpression of ΔFosB-T149A does not produce the psychomotor sensitization to chronic low-dose cocaine seen after overexpression of WT ΔFosB and abrogates the sensitization seen in control animals at higher cocaine doses. We further demonstrate that mutation of Thr(149) does not affect the stability of ΔFosB overexpressed in mouse NAc, suggesting that the behavioral effects of these mutations are driven by their altered transcriptional properties.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2014; 34(34):11461-9. DOI:10.1523/JNEUROSCI.1611-14.2014 · 6.75 Impact Factor
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    ABSTRACT: Rationale Schizophrenia remains among the most prevalent neuropsychiatric disorders, and current treatment options are accompanied by unwanted side effects. New treatments that better address core features of the disease with minimal side effects are needed. Objectives As a new therapeutic approach, 1-(4-fluoro-phenyl)-4-((6bR, 10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) is currently in human clinical trials for the treatment of schizophrenia. Here, we characterize the preclinical functional activity of ITI-007. Results ITI-007 is a potent 5-HT2A receptor ligand (Ki = 0.5 nM) with strong affinity for dopamine (DA) D2 receptors (Ki = 32 nM) and the serotonin transporter (SERT) (Ki = 62 nM) but negligible binding to receptors (e.g., H1 histaminergic, 5-HT2C, and muscarinic) associated with cognitive and metabolic side effects of antipsychotic drugs. In vivo it is a 5-HT2A antagonist, blocking (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced headtwitch in mice with an inhibitory dose 50 (ID50) = 0.09 mg/kg, per oral (p.o.), and has dual properties at D2 receptors, acting as a postsynaptic D2 receptor antagonist to block D-amphetamine hydrochloride (D-AMPH) hyperlocomotion (ID50 = 0.95 mg/kg, p.o.), yet acting as a partial agonist at presynaptic striatal D2 receptors in assays measuring striatal DA neurotransmission. Further, in microdialysis studies, this compound significantly and preferentially enhances mesocortical DA release. At doses relevant for antipsychotic activity in rodents, ITI-007 has no demonstrable cataleptogenic activity. ITI-007 indirectly modulates glutamatergic neurotransmission by increasing phosphorylation of GluN2B-type N-methyl-d-aspartate (NMDA) receptors and preferentially increases phosphorylation of glycogen synthase kinase 3β (GSK-3β) in mesolimbic/mesocortical dopamine systems. Conclusion The combination of in vitro and in vivo activities of this compound support its development for the treatment of schizophrenia and other psychiatric and neurologic disorders.
    Psychopharmacology 08/2014; 232(3). DOI:10.1007/s00213-014-3704-1 · 3.99 Impact Factor
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    ABSTRACT: Drugs of abuse modulate the function and activity of the mesolimbic dopamine circuit. To identify novel mediators of drug-induced neuroadaptations in the ventral tegmental area (VTA), we performed RNA sequencing analysis on VTA samples from mice administered repeated saline, morphine, or cocaine injections. One gene that was similarly upregulated by both drugs was serum- and glucocorticoid-inducible kinase 1 (SGK1). SGK1 activity, as measured by phosphorylation of its substrate N-myc downstream-regulated gene (NDRG), was also increased robustly by chronic drug treatment. Increased NDRG phosphorylation was evident 1 but not 24 hours after the last drug injection. SGK1 phosphorylation itself was similarly modulated. To determine the role of increased SGK1 activity on drug-related behaviors, we overexpressed constitutively-active (CA) SGK1 in the VTA. SGK1-CA expression reduced locomotor sensitization elicited by repeated cocaine, but surprisingly had the opposite effect and promoted locomotor sensitization to morphine, without affecting the initial locomotor responses to either drug. SGK1-CA expression did not significantly affect morphine or cocaine conditioned place preference (CPP), although there was a trend towards increased CPP with both drugs. Further characterizing the role of this kinase in drug-induced changes in VTA may lead to improved understanding of neuroadaptations critical to drug dependence and addiction. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 08/2014; DOI:10.1111/jnc.12925 · 4.24 Impact Factor
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    ABSTRACT: Repeated Δ(9)-tetrahydrocannabinol (THC) administration produces cannabinoid type 1 receptor (CB1R) desensitization and downregulation, as well as tolerance to its in vivo pharmacological effects. However, the magnitude of CB1R desensitization varies by brain region, with CB1Rs in the striatum and its output nuclei undergoing less desensitization than other regions. A growing body of data indicates that regional differences in CB1R desensitization are produced, in part, by THC-mediated induction of the stable transcription factor, ΔFosB, and subsequent regulation of CB1Rs. The purpose of the present study was to determine whether THC-mediated induction of ΔFosB in the striatum inhibits CB1R desensitization in the striatum and output nuclei. This hypothesis was tested using bitransgenic mice with inducible expression of ΔFosB or ΔcJun, a dominant negative inhibitor of AP-1-mediated transcription, in specific forebrain regions. Mice were treated repeatedly with escalating doses of THC or vehicle for 6.5 days, and CB1R-mediated G-protein activation was assessed using CP55,940-stimulated [(35)S]GTPγS autoradiography. Overexpression of ΔFosB in striatal dopamine type 1 receptor-containing (D1R) medium spiny neurons (MSNs) attenuated CB1R desensitization in the substantia nigra, ventral tegmental area (VTA) and amygdala. Expression of ΔcJun in striatal D1R- and dopamine type 2 receptor (D2R)-containing MSNs enhanced CB1R desensitization in the caudate-putamen and attenuated desensitization in the hippocampus and VTA. THC-mediated in vivo pharmacological effects were then assessed in ΔcJun-expressing mice. Tolerance to THC-mediated hypomotility was enhanced in ΔcJun-expressing mice. These data reveal that ΔFosB and possibly other AP-1 binding proteins regulate CB1R signaling and adaptation in the striatum and limbic system.
    Biochemical Pharmacology 08/2014; 91(3). DOI:10.1016/j.bcp.2014.07.024 · 4.65 Impact Factor
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    ABSTRACT: The Fosb gene encodes subunits of the activator protein-1 transcription factor complex. Two mature mRNAs, Fosb and ΔFosb, encoding full-length FOSB and ΔFOSB proteins respectively, are formed by alternative splicing of Fosb mRNA. Fosb products are expressed in several brain regions. Moreover, Fosb-null mice exhibit depressive-like behaviors and adult-onset spontaneous epilepsy, demonstrating important roles in neurological and psychiatric disorders. Study of Fosb products has focused almost exclusively on neurons; their function in glial cells remains to be explored. In this study, we found that microglia express equivalent levels of Fosb and ΔFosb mRNAs to hippocampal neurons and, using microarray analysis, we identified six microglial genes whose expression is dependent on Fosb products. Of these genes, we focused on C5ar1 and C5ar2, which encode receptors for complement C5a. In isolated Fosb-null microglia, chemotactic responsiveness toward the truncated form of C5a was significantly lower than that in wild-type cells. Fosb-null mice were significantly resistant to kainate-induced seizures compared with wild-type mice. C5ar1 mRNA levels and C5aR1 immunoreactivity were increased in wild-type hippocampus 24 hours after kainate administration; however, such induction was significantly reduced in Fosb-null hippocampus. Furthermore, microglial activation after kainate administration was significantly diminished in Fosb-null hippocampus, as shown by significant reductions in CD68 immunoreactivity, morphological change and reduced levels of Il6 and Tnf mRNAs, although no change in the number of Iba-1-positive cells was observed. These findings demonstrate that, under excitotoxicity, Fosb products contribute to a neuroinflammatory response in the hippocampus through regulation of microglial C5ar1 and C5ar2 expression. GLIA 2014
    Glia 08/2014; 62(8). DOI:10.1002/glia.22680 · 5.47 Impact Factor

Publication Stats

52k Citations
4,526.21 Total Impact Points


  • 2008–2015
    • Icahn School of Medicine at Mount Sinai
      • • Department of Pharmacology and Systems Therapeutics
      • • Department of Psychiatry
      Borough of Manhattan, New York, United States
  • 2013
    • University of Crete
      • Division of Basic Sciences
      Retimo, Crete, Greece
  • 2006–2013
    • Stanford University
      • Department of Psychiatry and Behavioral Sciences
      Palo Alto, CA, United States
  • 2012
    • James J. Peters VA Medical Center
      New York, New York, United States
  • 2011
    • Mount Sinai Medical Center
      New York City, New York, United States
    • Mount Sinai Hospital
      New York, New York, United States
  • 2000–2011
    • University of Texas Southwestern Medical Center
      • Department of Psychiatry
      Dallas, TX, United States
    • Karolinska Institutet
      • Institutionen för neurovetenskap
      Solna, Stockholm, Sweden
  • 2010
    • University of Pennsylvania
      • Department of Animal Biology
      Philadelphia, PA, United States
  • 2000–2008
    • University of Texas at Dallas
      Richardson, Texas, United States
  • 2005–2006
    • Harvard University
      Cambridge, Massachusetts, United States
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 2003–2005
    • Harvard Medical School
      • Department of Psychiatry
      Boston, MA, United States
  • 1985–2003
    • Yale-New Haven Hospital
      • • Department of Laboratory Medicine
      • • Department of Pathology
      New Haven, Connecticut, United States
  • 1981–2003
    • Yale University
      • Department of Psychiatry
      New Haven, CT, United States
  • 2002
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 1981–2001
    • The Rockefeller University
      • Laboratory of Molecular and Cellular Neuroscience
      New York City, NY, United States
  • 1997
    • The Scripps Research Institute
      • Committee on the Neurobiology of Addictive Disorders
      La Jolla, California, United States
    • Loyola University Maryland
      Baltimore, Maryland, United States
  • 1996
    • Community Health Center, Connecticut
      मिडलटाउन, Connecticut, United States
    • Massachusetts General Hospital
      • Department of Psychiatry
      Boston, MA, United States
  • 1990
    • New York Medical College
      • Department of Biochemistry and Molecular Biology
      New York, New York, United States