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ABSTRACT: Although it is a widely studied psychiatric syndrome, major depressive disorder remains a poorly understood illness, especially with regard to the disconnect between treatment initiation and the delayed onset of clinical improvement. We have recently validated chronic social defeat stress in mice as a model in which a depression-like phenotype is reversed by chronic, but not acute, antidepressant administration. Here, we use chromatin immunoprecipitation (ChIP)-chip assays--ChIP followed by genome wide promoter array analyses--to study the effects of chronic defeat stress on chromatin regulation in the mouse nucleus accumbens (NAc), a key brain reward region implicated in depression. Our results demonstrate that chronic defeat stress causes widespread and long-lasting changes in gene regulation, including alterations in repressive histone methylation and in phospho-CREB (cAMP response element-binding protein) binding, in the NAc. We then show similarities and differences in this regulation to that observed in another mouse model of depression, prolonged adult social isolation. In the social defeat model, we observed further that many of the stress-induced changes in gene expression are reversed by chronic imipramine treatment, and that resilient mice-those resistant to the deleterious effects of defeat stress-show patterns of chromatin regulation in the NAc that overlap dramatically with those seen with imipramine treatment. These findings provide new insight into the molecular basis of depression-like symptoms and the mechanisms by which antidepressants exert their delayed clinical efficacy. They also raise the novel idea that certain individuals resistant to stress may naturally mount antidepressant-like adaptations in response to chronic stress.
Journal of Neuroscience 07/2009; 29(24):7820-32. · 7.11 Impact Factor
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William Renthal, Arvind Kumar,
Guanghua Xiao,
Matthew Wilkinson,
Herbert E Covington,
Ian Maze,
Devanjan Sikder,
Alfred J Robison,
Quincey LaPlant,
David M Dietz,
Scott J Russo,
Vincent Vialou,
Sumana Chakravarty,
Thomas J Kodadek,
Ashley Stack,
Mohamed Kabbaj,
Eric J Nestler
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ABSTRACT: Changes in gene expression contribute to the long-lasting regulation of the brain's reward circuitry seen in drug addiction; however, the specific genes regulated and the transcriptional mechanisms underlying such regulation remain poorly understood. Here, we used chromatin immunoprecipitation coupled with promoter microarray analysis to characterize genome-wide chromatin changes in the mouse nucleus accumbens, a crucial brain reward region, after repeated cocaine administration. Our findings reveal several interesting principles of gene regulation by cocaine and of the role of DeltaFosB and CREB, two prominent cocaine-induced transcription factors, in this brain region. The findings also provide comprehensive insight into the molecular pathways regulated by cocaine-including a new role for sirtuins (Sirt1 and Sirt2)-which are induced in the nucleus accumbens by cocaine and, in turn, dramatically enhance the behavioral effects of the drug.
Neuron 06/2009; 62(3):335-48. · 14.74 Impact Factor
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Scott J Russo,
Matthew B Wilkinson,
Michelle S Mazei-Robison,
David M Dietz,
Ian Maze,
Vaishnav Krishnan,
William Renthal,
Ami Graham,
Shari G Birnbaum,
Thomas A Green, [......],
Alan Lesselyong,
Linda I Perrotti,
Carlos A Bolaños, Arvind Kumar,
Michael S Clark,
John F Neumaier,
Rachael L Neve,
Asha L Bhakar,
Philip A Barker,
Eric J Nestler
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ABSTRACT: Although chronic cocaine-induced changes in dendritic spines on nucleus accumbens (NAc) neurons have been correlated with behavioral sensitization, the molecular pathways governing these structural changes, and their resulting behavioral effects, are poorly understood. The transcription factor, nuclear factor kappa B (NFkappaB), is rapidly activated by diverse stimuli and regulates expression of many genes known to maintain cell structure. Therefore, we evaluated the role of NFkappaB in regulating cocaine-induced dendritic spine changes on medium spiny neurons of the NAc and the rewarding effects of cocaine. We show that chronic cocaine induces NFkappaB-dependent transcription in the NAc of NFkappaB-Lac transgenic mice. This induction of NFkappaB activity is accompanied by increased expression of several NFkappaB genes, the promoters of which show chromatin modifications after chronic cocaine exposure consistent with their transcriptional activation. To study the functional significance of this induction, we used viral-mediated gene transfer to express either a constitutively active or dominant-negative mutant of Inhibitor of kappa B kinase (IKKca or IKKdn), which normally activates NFkappaB signaling, in the NAc. We found that activation of NFkappaB by IKKca increases the number of dendritic spines on NAc neurons, whereas inhibition of NFkappaB by IKKdn decreases basal dendritic spine number and blocks the increase in dendritic spines after chronic cocaine. Moreover, inhibition of NFkappaB blocks the rewarding effects of cocaine and the ability of previous cocaine exposure to increase an animal's preference for cocaine. Together, these studies establish a direct role for NFkappaB pathways in the NAc to regulate structural and behavioral plasticity to cocaine.
Journal of Neuroscience 04/2009; 29(11):3529-37. · 7.11 Impact Factor
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Quincey LaPlant,
Sumana Chakravarty,
Vincent Vialou,
Shibani Mukherjee,
Ja Wook Koo,
Geetha Kalahasti,
Kathryn R Bradbury,
Shameeke V Taylor,
Ian Maze, Arvind Kumar,
Ami Graham,
Shari G Birnbaum,
Vaishnav Krishnan,
Hoang-Trang Truong,
Rachael L Neve,
Eric J Nestler,
Scott J Russo
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ABSTRACT: The molecular mechanisms of stress-induced depressive behaviors have been characterized extensively in male rodents; however, much less is known about female subjects, despite the fact that human depression is far more prevalent in women.
To gain insight into these mechanisms, we performed microarray analysis in nucleus accumbens (NAc), a key brain reward region implicated in depression, in ovariectomized (OVX) and gonadally intact female mice after chronic unpredictable stress and measured stress-induced depression-like behavior in the forced swim test (FST). Male mice were studied in the FST for comparison.
We find that stress regulation of genes in NAc of gonadally intact female mice is blunted in OVX mice. This pattern of gene regulation is consistent with behavioral findings on the FST: the pro-depression-like effect of stress in intact female mice is absent in OVX female and gonadally intact male mice. We identified, among many genes regulated by stress, several nuclear factor kappaB (NFkappaB) subunits-a pro-survival transcription factor involved in cellular responses to stress-as being highly upregulated in NAc of OVX mice. Given the role of NFkappaB during stress, we hypothesized that upregulation of NFkappaB by OVX decreases susceptibility to stress. Indeed, we show that inhibition of NFkappaB in NAc of OVX animals increases susceptibility to stress-induced depressive behaviors, whereas activation of NFkappaB in NAc of intact female subjects blocks susceptibility.
These results suggest a hormonal mechanism of NFkappaB regulation that contributes to stress-induced depressive behaviors in female subjects and might represent a mechanism for gender differences in prevalence rates of these disorders in humans.
Biological psychiatry 03/2009; 65(10):874-80. · 8.93 Impact Factor
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Deanna L Wallace,
Ming-Hu Han,
Danielle L Graham,
Thomas A Green,
Vincent Vialou,
Sergio D Iñiguez,
Jun-Li Cao,
Anne Kirk,
Sumana Chakravarty, Arvind Kumar,
Vaishnav Krishnan,
Rachael L Neve,
Don C Cooper,
Carlos A Bolaños,
Michel Barrot,
Colleen A McClung,
Eric J Nestler
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ABSTRACT: Here, we characterized behavioral abnormalities induced by prolonged social isolation in adult rodents. Social isolation induced both anxiety- and anhedonia-like symptoms and decreased cAMP response element-binding protein (CREB) activity in the nucleus accumbens shell (NAcSh). All of these abnormalities were reversed by chronic, but not acute, antidepressant treatment. However, although the anxiety phenotype and its reversal by antidepressant treatment were CREB-dependent, the anhedonia-like symptoms were not mediated by CREB in NAcSh. We found that decreased CREB activity in NAcSh correlated with increased expression of certain K(+) channels and reduced electrical excitability of NAcSh neurons, which was sufficient to induce anxiety-like behaviors and was reversed by chronic antidepressant treatment. Together, our results describe a model that distinguishes anxiety- and depression-like behavioral phenotypes, establish a selective role of decreased CREB activity in NAcSh in anxiety-like behavior, and provide a mechanism by which antidepressant treatment alleviates anxiety symptoms after social isolation.
Nature Neuroscience 02/2009; 12(2):200-9. · 15.53 Impact Factor
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ABSTRACT: It is becoming increasingly clear that epigenetic modifications are critical factors in the regulation of gene expression. With regard to the nervous system, epigenetic alterations play a role in a diverse set of processes and have been implicated in a variety of disorders. Gaining a more complete understanding of the essential components and underlying mechanisms involved in epigenetic regulation could lead to novel treatments for a number of neurological and psychiatric conditions.
Journal of Neuroscience 12/2008; 28(46):11753-9. · 7.11 Impact Factor
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Deanna L Wallace,
Vincent Vialou,
Loretta Rios,
Tiffany L Carle-Florence,
Sumana Chakravarty, Arvind Kumar,
Danielle L Graham,
Thomas A Green,
Anne Kirk,
Sergio D Iñiguez,
Linda I Perrotti,
Michel Barrot,
Ralph J DiLeone,
Eric J Nestler,
Carlos A Bolaños-Guzmán
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ABSTRACT: The transcription factor deltaFosB (DeltaFosB), induced in nucleus accumbens (NAc) by chronic exposure to drugs of abuse, has been shown to mediate sensitized responses to these drugs. However, less is known about a role for DeltaFosB in regulating responses to natural rewards. Here, we demonstrate that two powerful natural reward behaviors, sucrose drinking and sexual behavior, increase levels of DeltaFosB in the NAc. We then use viral-mediated gene transfer to study how such DeltaFosB induction influences behavioral responses to these natural rewards. We demonstrate that overexpression of DeltaFosB in the NAc increases sucrose intake and promotes aspects of sexual behavior. In addition, we show that animals with previous sexual experience, which exhibit increased DeltaFosB levels, also show an increase in sucrose consumption. This work suggests that DeltaFosB is not only induced in the NAc by drugs of abuse, but also by natural rewarding stimuli. Additionally, our findings show that chronic exposure to stimuli that induce DeltaFosB in the NAc can increase consumption of other natural rewards.
Journal of Neuroscience 11/2008; 28(41):10272-7. · 7.11 Impact Factor
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Suprabha Pulipparacharuvil,
William Renthal,
Carly F Hale,
Makoto Taniguchi,
Guanghua Xiao, Arvind Kumar,
Scott J Russo,
Devanjan Sikder,
Colleen M Dewey,
Maya M Davis,
Paul Greengard,
Angus C Nairn,
Eric J Nestler,
Christopher W Cowan
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ABSTRACT: Repeated exposure to cocaine causes sensitized behavioral responses and increased dendritic spines on medium spiny neurons of the nucleus accumbens (NAc). We find that cocaine regulates myocyte enhancer factor 2 (MEF2) transcription factors to control these two processes in vivo. Cocaine suppresses striatal MEF2 activity in part through a mechanism involving cAMP, the regulator of calmodulin signaling (RCS), and calcineurin. We show that reducing MEF2 activity in the NAc in vivo is required for the cocaine-induced increases in dendritic spine density. Surprisingly, we find that increasing MEF2 activity in the NAc, which blocks the cocaine-induced increase in dendritic spine density, enhances sensitized behavioral responses to cocaine. Together, our findings implicate MEF2 as a key regulator of structural synapse plasticity and sensitized responses to cocaine and suggest that reducing MEF2 activity (and increasing spine density) in NAc may be a compensatory mechanism to limit long-lasting maladaptive behavioral responses to cocaine.
Neuron 09/2008; 59(4):621-33. · 14.74 Impact Factor
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ABSTRACT: The molecular mechanisms underlying the transition from recreational drug use to chronic addiction remain poorly understood. One molecule implicated in this process is DeltaFosB, a transcription factor that accumulates in striatum after repeated drug exposure and mediates sensitized behavioral responses to psychostimulants and other drugs of abuse. The downstream transcriptional mechanisms by which DeltaFosB regulates drug-induced behaviors are incompletely understood. We reported previously the chromatin remodeling mechanisms by which DeltaFosB activates the expression of certain genes; however, the mechanisms underlying DeltaFosB-mediated gene repression remain unknown. Here, we identify c-fos, an immediate early gene rapidly induced in striatum after acute psychostimulant exposure, as a novel downstream target that is repressed chronically by DeltaFosB. We show that accumulation of DeltaFosB in striatum after chronic amphetamine treatment desensitizes c-fos mRNA induction to a subsequent drug dose. DeltaFosB desensitizes c-fos expression by recruiting histone deacetylase 1 (HDAC1) to the c-fos gene promoter, which, in turn, deacetylates surrounding histones and attenuates gene activity. Accordingly, local knock-out of HDAC1 in striatum abolishes amphetamine-induced desensitization of the c-fos gene. In concert, chronic amphetamine increases histone H3 methylation on the c-fos promoter, a chromatin modification also known to repress gene activity, as well as expression levels of the H3 histone methyltransferase, KMT1A (lysine methyltransferase 1A, formerly SUV39H1). This study reveals a novel epigenetic pathway through which DeltaFosB mediates distinct transcriptional programs that may ultimately alter behavioral plasticity to chronic amphetamine exposure.
Journal of Neuroscience 07/2008; 28(29):7344-9. · 7.11 Impact Factor
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ABSTRACT: Increased impulsivity caused by addictive drugs is believed to contribute to the maintenance of addiction and has been linked to hypofunction within the orbitofrontal cortex (OFC). Recent data indicate that cocaine "self-administration" induces the transcription factor DeltaFosB in the OFC that alters the effects of investigator-administered cocaine on impulsivity. Here, using viral-mediated gene transfer, the effects of overexpressing DeltaFosB within the OFC were assessed on the cognitive sequelae of chronic cocaine self-administration as measured by the 5-choice serial reaction time task (5CSRT). Cognitive testing occurred in the mornings, and self-administration sessions in the evenings, to enable the progressive assessment of repeated volitional drug intake on performance. Animals self-administering cocaine initially made more omissions and premature or impulsive responses on the 5CSRT but quickly developed tolerance to these disruptive effects. However, withdrawal from cocaine dramatically increased premature responding. When access to cocaine was increased, animals overexpressing DeltaFosB failed to regulate their intake as effectively and were more impulsive during withdrawal. In summary, rats develop tolerance to the cognitive disruption caused by cocaine self-administration and show a deficit in impulse control that is unmasked during withdrawal. Our findings suggest that induction of DeltaFosB within the OFC is one mediator of these effects and, thereby, increases vulnerability to addiction.
Cerebral Cortex 07/2008; 19(2):435-44. · 6.54 Impact Factor
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William Renthal,
Ian Maze,
Vaishnav Krishnan,
Herbert E Covington,
Guanghua Xiao, Arvind Kumar,
Scott J Russo,
Ami Graham,
Nadia Tsankova,
Tod E Kippin,
Kerry A Kerstetter,
Rachael L Neve,
Stephen J Haggarty,
Timothy A McKinsey,
Rhonda Bassel-Duby,
Eric N Olson,
Eric J Nestler
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ABSTRACT: Previous work has identified alterations in histone acetylation in animal models of drug addiction and depression. However, the mechanisms which integrate drugs and stress with changes in chromatin structure remain unclear. Here, we identify the activity-dependent class II histone deacetylase, HDAC5, as a central integrator of these stimuli with changes in chromatin structure and gene expression. Chronic, but not acute, exposure to cocaine or stress decreases HDAC5 function in the nucleus accumbens (NAc), a major brain reward region, which allows for increased histone acetylation and transcription of HDAC5 target genes. This regulation is behaviorally important, as loss of HDAC5 causes hypersensitive responses to chronic, not acute, cocaine or stress. These findings suggest that proper balance of histone acetylation is a crucial factor in the saliency of a given stimulus and that disruption of this balance is involved in the transition from an acute adaptive response to a chronic psychiatric illness.
Neuron 12/2007; 56(3):517-29. · 14.74 Impact Factor
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Vaishnav Krishnan,
Ming-Hu Han,
Danielle L Graham,
Olivier Berton,
William Renthal,
Scott J Russo,
Quincey Laplant,
Ami Graham,
Michael Lutter,
Diane C Lagace, [......],
Rachael L Neve,
Sumana Chakravarty, Arvind Kumar,
Amelia J Eisch,
David W Self,
Francis S Lee,
Carol A Tamminga,
Donald C Cooper,
Howard K Gershenfeld,
Eric J Nestler
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ABSTRACT: While stressful life events are an important cause of psychopathology, most individuals exposed to adversity maintain normal psychological functioning. The molecular mechanisms underlying such resilience are poorly understood. Here, we demonstrate that an inbred population of mice subjected to social defeat can be separated into susceptible and unsusceptible subpopulations that differ along several behavioral and physiological domains. By a combination of molecular and electrophysiological techniques, we identify signature adaptations within the mesolimbic dopamine circuit that are uniquely associated with vulnerability or insusceptibility. We show that molecular recapitulations of three prototypical adaptations associated with the unsusceptible phenotype are each sufficient to promote resistant behavior. Our results validate a multidisciplinary approach to examine the neurobiological mechanisms of variations in stress resistance, and illustrate the importance of plasticity within the brain's reward circuits in actively maintaining an emotional homeostasis.
Cell 11/2007; 131(2):391-404. · 32.40 Impact Factor
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ABSTRACT: The transcription factor DeltaFosB (Delta FosB) accumulates in a region-specific manner in the brain during chronic exposure to stress, drugs of abuse or other chronic stimuli. Once induced, DeltaFosB persists in the brain for at least several weeks following cessation of the chronic stimulus. The biochemical basis of the persistent expression of DeltaFosB has remained unknown. Here, we show that the FosB C-terminus, absent in DeltaFosB as a result of alternative splicing, contains two degron domains. Pulse-chase experiments of C-terminal truncation mutants of full-length FosB indicate that removal of its most C-terminal degron increases its half-life approximately fourfold, and prevents its proteasome-mediated degradation and ubiquitylation, properties similar to DeltaFosB. In addition, removal of a second degron domain, which generates DeltaFosB, further stabilizes FosB approximately twofold, but in a proteasome-independent manner. These data indicate that alternative splicing specifically removes two destabilizing elements from FosB in order to generate a longer-lived transcription factor, DeltaFosB, in response to chronic perturbations to the brain.
European Journal of Neuroscience 06/2007; 25(10):3009-19. · 3.63 Impact Factor
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ABSTRACT: Many neurological and most psychiatric disorders are not due to mutations in a single gene; rather, they involve molecular disturbances entailing multiple genes and signals that control their expression. Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene activity without altering the DNA code, have long-lasting effects within mature neurons. This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.
Nature reviews. Neuroscience 06/2007; 8(5):355-67. · 30.44 Impact Factor
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Scott J Russo,
Carlos A Bolanos,
David E Theobald,
Nathan A DeCarolis,
William Renthal, Arvind Kumar,
Catharine A Winstanley,
Nora E Renthal,
Matthew D Wiley,
David W Self,
David S Russell,
Rachael L Neve,
Amelia J Eisch,
Eric J Nestler
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ABSTRACT: Chronic morphine administration (via subcutaneous pellet) decreases the size of dopamine neurons in the ventral tegmental area (VTA), a key reward region in the brain, yet the molecular basis and functional consequences of this effect are unknown. In this study, we used viral-mediated gene transfer in rat to show that chronic morphine-induced downregulation of the insulin receptor substrate 2 (IRS2)-thymoma viral proto-oncogene (Akt) signaling pathway in the VTA mediates the decrease in dopamine cell size seen after morphine exposure and that this downregulation diminishes morphine reward, as measured by conditioned place preference. We further show that the reduction in size of VTA dopamine neurons persists up to 2 weeks after morphine withdrawal, which parallels the tolerance to morphine's rewarding effects caused by previous chronic morphine exposure. These findings directly implicate the IRS2-Akt signaling pathway as a critical regulator of dopamine cell morphology and opiate reward.
Nature Neuroscience 02/2007; 10(1):93-9. · 15.53 Impact Factor
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ABSTRACT: Previous research has shown that cAMP response element (CRE)-mediated transcription is activated in the nucleus accumbens, a major brain reward region, by a variety of environmental stimuli and contributes to neuroadaptations to these stimuli. CRE-binding protein (CREB) is the most studied activator of CRE transcription and has been implicated in this brain region as a gating mechanism for behavioral responses to emotional stimuli. Little attention, however, has been given to naturally occurring inhibitors of CRE-mediated transcription, such as the inducible cAMP early repressor (ICER), an inhibitory product of the CRE modulator gene. In the present study, we investigated the extent to which ICER is induced in the nucleus accumbens by two types of environmental stimuli, stress and amphetamine, and characterized how induction of ICER in this region affects complex behavior. We show that stress and amphetamine each induces ICER expression and that overexpression of ICER in the nucleus accumbens, using viral-mediated gene transfer, increases behavioral responses to both rewarding and aversive emotional stimuli. For example, ICER overexpression increases sensitivity to amphetamine-stimulated locomotor activity as well as to natural rewards such as sucrose and social grooming. However, ICER overexpression also increases measures of anxiety in the elevated plus maze and neophobia to novel tastes. Finally, ICER produces an antidepressant-like effect in the forced swim test, further indication of an enhanced active response to stress. These results suggest that ICER is an important mechanism for modulating CRE-mediated transcription in the nucleus accumbens.
Journal of Neuroscience 09/2006; 26(32):8235-42. · 7.11 Impact Factor
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ABSTRACT: To better understand the molecular mechanisms of depression and antidepressant action, we administered chronic social defeat stress followed by chronic imipramine (a tricyclic antidepressant) to mice and studied adaptations at the levels of gene expression and chromatin remodeling of five brain-derived neurotrophic factor (Bdnf) splice variant mRNAs (I-V) and their unique promoters in the hippocampus. Defeat stress induced lasting downregulation of Bdnf transcripts III and IV and robustly increased repressive histone methylation at their corresponding promoters. Chronic imipramine reversed this downregulation and increased histone acetylation at these promoters. This hyperacetylation by chronic imipramine was associated with a selective downregulation of histone deacetylase (Hdac) 5. Furthermore, viral-mediated HDAC5 overexpression in the hippocampus blocked imipramine's ability to reverse depression-like behavior. These experiments underscore an important role for histone remodeling in the pathophysiology and treatment of depression and highlight the therapeutic potential for histone methylation and deacetylation inhibitors in depression.
Nature Neuroscience 05/2006; 9(4):519-25. · 15.53 Impact Factor
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Venetia Zachariou,
Carlos A Bolanos,
Dana E Selley,
David Theobald,
Michael P Cassidy,
Max B Kelz,
Tamara Shaw-Lutchman,
Olivier Berton,
Laura J Sim-Selley,
Ralph J Dileone, Arvind Kumar,
Eric J Nestler
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ABSTRACT: The transcription factor DeltaFosB is induced in the nucleus accumbens (NAc) and dorsal striatum by the repeated administration of drugs of abuse. Here, we investigated the role of DeltaFosB in the NAc in behavioral responses to opiates. We achieved overexpression of DeltaFosB by using a bitransgenic mouse line that inducibly expresses the protein in the NAc and dorsal striatum and by using viral-mediated gene transfer to specifically express the protein in the NAc. DeltaFosB overexpression in the NAc increased the sensitivity of the mice to the rewarding effects of morphine and led to exacerbated physical dependence, but also reduced their sensitivity to the analgesic effects of morphine and led to faster development of analgesic tolerance. The opioid peptide dynorphin seemed to be one target through which DeltaFosB produced this behavioral phenotype. Together, these experiments demonstrated that DeltaFosB in the NAc, partly through the repression of dynorphin expression, mediates several major features of opiate addiction.
Nature Neuroscience 03/2006; 9(2):205-11. · 15.53 Impact Factor
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Christine M Colvis,
Jonathan D Pollock,
Richard H Goodman,
Soren Impey,
John Dunn,
Gail Mandel,
Frances A Champagne,
Mark Mayford,
Edward Korzus, Arvind Kumar,
William Renthal,
David E H Theobald,
Eric J Nestler
Journal of Neuroscience 12/2005; 25(45):10379-89. · 7.11 Impact Factor
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Arvind Kumar,
Kwang-Ho Choi,
William Renthal,
Nadia M Tsankova,
David E H Theobald,
Hoang-Trang Truong,
Scott J Russo,
Quincey Laplant,
Teresa S Sasaki,
Kimberly N Whistler,
Rachael L Neve,
David W Self,
Eric J Nestler
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ABSTRACT: Given that cocaine induces neuroadaptations through regulation of gene expression, we investigated whether chromatin remodeling at specific gene promoters may be a key mechanism. We show that cocaine induces specific histone modifications at different gene promoters in striatum, a major neural substrate for cocaine's behavioral effects. At the cFos promoter, H4 hyperacetylation is seen within 30 min of a single cocaine injection, whereas no histone modifications were seen with chronic cocaine, consistent with cocaine's ability to induce cFos acutely, but not chronically. In contrast, at the BDNF and Cdk5 promoters, genes that are induced by chronic, but not acute, cocaine, H3 hyperacetylation was observed with chronic cocaine only. DeltaFosB, a cocaine-induced transcription factor, appears to mediate this regulation of the Cdk5 gene. Furthermore, modulating histone deacetylase activity alters locomotor and rewarding responses to cocaine. Thus, chromatin remodeling is an important regulatory mechanism underlying cocaine-induced neural and behavioral plasticity.
Neuron 11/2005; 48(2):303-14. · 14.74 Impact Factor
