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Eric J Nestler

Publications and source records attributed to Eric J Nestler.

At least 19 recordsLinked to original sources
PubMed2026

E2F3a transcription factor mediates behavioral, cellular, and DNA-protein regulation of cocaine reward in the nucleus accumbens.

Drug addiction is characterized by orchestrated transcriptional changes in brain reward regions, including the nucleus accumbens (NAc). The transcription factor E2F3a has emerged as a novel regulator of cocaine's rewarding effects, yet its sex- and cell-specific mechanisms, as well as its genome-wide targets, remain undetermined. Here, we investigated the motivational and reinforcing roles of E2F3a in cocaine reward using conditioned place preference (CPP) and self-administration, combined with behavioral economics and viral-mediated gene manipulation. Selective overexpression of E2F3a in D1-type medium spiny neurons (MSNs), but not D2-MSNs, increased cocaine CPP in both male and female mice, whereas knockdown produced the opposite effects. Behavioral economics analyses further revealed that E2F3a regulates specific aspects of cocaine reinforcement. Genome-wide mapping revealed increased E2F3a binding to DNA at genes associated with cocaine exposure. Together, these results establish E2F3a as a central substrate of cocaine reward via the recruitment of D1-MSNs and coordinated expression of both proven and new molecular drivers.

Journal Article↗
PubMed2007

Topographical organization of GABAergic neurons within the ventral tegmental area of the rat.

The ventral tegmental area (VTA), the origin of dopaminergic cell bodies that comprise the mesocorticolimibic DA system, is widely implicated in drug and natural reward, cognition, and several psychiatric disorders. In addition to dopaminergic neurons, this region is populated by GABAergic neurons, which both regulate the firing of their dopaminergic counterparts and send projections throughout the brain. Although the dopaminergic neurons of the VTA have been extensively characterized neuroanatomically, much less is known about the GABAergic neurons in this region. Recent data suggest that the rostro-caudal topographic organization of these GABAergic neurons may correspond to their ability to regulate drug reward. In the present study, we used immunohistochemical techniques to examine the frequency and topography of GABAergic neurons throughout the rostro-caudal axis of the VTA and the extent to which they coexpress other proteins, including tyrosine hydroxylase (a marker of DA neurons), cholecystokinin, parvalbumin, calretinin, and calbindin d 28k.

Animals↗
PubMed2006

IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates.

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.

Animals↗
PubMed2006

DeltaFosB in the nucleus accumbens regulates food-reinforced instrumental behavior and motivation.

Alterations in motivation have been implicated in the pathophysiology of several psychiatric disorders, including substance abuse and depression. Repeated exposure to drugs of abuse or stress is known to persistently induce the transcription factor deltaFosB in the nucleus accumbens (NAc) and dorsal striatum, effects hypothesized to contribute to neuroadaptations in dopamine-regulated signaling. Little is known, however, about the specific involvement of deltaFosB in dysregulation of appetitively motivated behaviors. We show here that inducible overexpression of deltaFosB in NAc and dorsal striatum of bitransgenic mice, or specifically in the NAc core of rats by use of viral-mediated gene transfer, enhanced food-reinforced instrumental performance and progressive ratio responding. Very similar behavioral effects were found after previous repeated exposure to cocaine, amphetamine, MDMA [(+)-3,4-methylenedioxymethamphetamine], or nicotine in rats. These results reveal the powerful regulation of motivational processes by deltaFosB, and provide evidence that drug-induced alterations in gene expression via induction of deltaFosB within the NAc core may play a critical role in the impact of motivational influences on instrumental behavior.

Animals↗
PubMed2006

Induction of inducible cAMP early repressor expression in nucleus accumbens by stress or amphetamine increases behavioral responses to emotional stimuli.

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.

Amphetamine↗
PubMed2006

Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors.

BACKGROUND: Indirect evidence suggests that loss of brain-derived neurotrophic factor (BDNF) from forebrain regions contributes to an individual's vulnerability for depression, whereas upregulation of BDNF in these regions is suggested to mediate the therapeutic effect of antidepressants. METHODS: We have tested this hypothesis by generating two independent lines of conditional BDNF knockout mice in which the BDNF gene is deleted selectively in forebrain. RESULTS: We show that male conditional knockouts exhibit hyperactivity but normal depression-related behaviors. In contrast, female conditional knockouts display normal locomotor activity but a striking increase in depression-like behavior. We also demonstrate that loss of BDNF in both male and female mice attenuates the actions of the antidepressant desipramine in the forced swim test. CONCLUSIONS: These gender differences in depression-related behaviors in BDNF conditional knockout mice provide direct evidence for a role of BDNF in depression. The results also support the view that forebrain BDNF may be essential in mediating antidepressant efficacy.

Alleles↗
PubMed2006

Regulation of DeltaFosB stability by phosphorylation.

The transcription factor DeltaFosB (also referred to as FosB2 or FosB[short form]) is an important mediator of the long-term plasticity induced in brain by chronic exposure to several types of psychoactive stimuli, including drugs of abuse, stress, and electroconvulsive seizures. A distinct feature of DeltaFosB is that, once induced, it persists in brain for relatively long periods of time in the absence of further stimulation. The mechanisms underlying this apparent stability, however, have remained unknown. Here, we demonstrate that DeltaFosB is a relatively stable transcription factor, with a half-life of approximately 10 h in cell culture. Furthermore, we show that DeltaFosB is a phosphoprotein in brain and that phosphorylation of a highly conserved serine residue (Ser27) in DeltaFosB protects it from proteasomal degradation. We provide several lines of evidence suggesting that this phosphorylation is mediated by casein kinase 2. These findings constitute the first evidence that DeltaFosB is phosphorylated and demonstrate that phosphorylation contributes to its stability, which is at the core of its ability to mediate long-lasting adaptations in brain.

Animals↗
PubMed2006

Role of cAMP response element-binding protein in the rat locus ceruleus: regulation of neuronal activity and opiate withdrawal behaviors.

The transcription factor cAMP response element-binding protein (CREB) is implicated in mediating the actions of chronic morphine in the locus ceruleus (LC), but direct evidence to support such a role is limited. Here, we investigated the influence of CREB on LC neuronal activity and opiate withdrawal behaviors by selectively manipulating CREB activity in the LC using viral vectors encoding genes for CREBGFP (wild-type CREB tagged with green fluorescent protein), caCREBGFP (a constitutively active CREB mutant), dnCREBGFP (a dominant-negative CREB mutant), or GFP alone as a control. Our results show that in vivo overexpression of CREBGFP in the LC significantly aggravated particular morphine withdrawal behaviors, whereas dnCREBGFP expression attenuated these behaviors. At the cellular level, CREBGFP expression in the LC in vivo and in vitro had no significant effect on neuronal firing at baseline but enhanced the excitatory effect of forskolin (an activator of adenylyl cyclase) on these neurons, which suggests that the cAMP signaling pathway in these neurons was sensitized after CREB expression. Moreover, in vitro studies showed that caCREBGFP-expressing LC neurons fired significantly faster and had a more depolarized resting membrane potential compared with GFP-expressing control cells. Conversely, LC neuronal activity was decreased by dnCREBGFP, and the neurons were hyperpolarized by this treatment. Together, these data provide direct evidence that CREB plays an important role in controlling the electrical excitability of LC neurons and that morphine-induced increases in CREB activity contribute to the behavioral and neural adaptations associated with opiate dependence and withdrawal.

Action Potentials↗
PubMed2006

The mesolimbic dopamine reward circuit in depression.

The neural circuitry that mediates mood under normal and abnormal conditions remains incompletely understood. Most attention in the field has focused on hippocampal and frontal cortical regions for their role in depression and antidepressant action. While these regions no doubt play important roles in these phenomena, there is compelling evidence that other brain regions are also involved. Here we focus on the potential role of the nucleus accumbens (NAc; ventral striatum) and its dopaminergic input from the ventral tegmental area (VTA), which form the mesolimbic dopamine system, in depression. The mesolimbic dopamine system is most often associated with the rewarding effects of food, sex, and drugs of abuse. Given the prominence of anhedonia, reduced motivation, and decreased energy level in most individuals with depression, we propose that the NAc and VTA contribute importantly to the pathophysiology and symptomatology of depression and may even be involved in its etiology. We review recent studies showing that manipulations of key proteins (e.g. CREB, dynorphin, BDNF, MCH, or Clock) within the VTA-NAc circuit of rodents produce unique behavioral phenotypes, some of which are directly relevant to depression. Studies of these and other proteins in the mesolimbic dopamine system have established novel approaches to modeling key symptoms of depression in animals, and could enable the development of antidepressant medications with fundamentally new mechanisms of action.

Animals↗
PubMed2006

CREB modulates excitability of nucleus accumbens neurons.

Drugs of abuse cause activation of the cyclic AMP response element binding protein (CREB) in the nucleus accumbens (NAc). Expression of active CREB in rat NAc medium spiny neurons (MSNs) increased their excitability, whereas dominant-negative CREB had the opposite effect. Decreasing excitability of NAc MSNs in vivo by overexpression of potassium channels enhanced locomotor responses to cocaine, suggesting that the increased NAc MSN excitability caused by CREB helped to limit behavioral sensitivity to cocaine.

Animals↗
PubMed2006

Adenylyl cyclase type 5 (AC5) is an essential mediator of morphine action.

Opioid drugs produce their pharmacological effects by activating inhibitory guanine nucleotide-binding regulatory protein-linked mu, delta, and kappa opioid receptors. One major effector for these receptors is adenylyl cyclase, which is inhibited upon receptor activation. However, little is known about which of the ten known forms of adenylyl cyclase are involved in mediating opioid actions. Here we show that all of the major behavioral effects of morphine, including locomotor activation, analgesia, tolerance, reward, and physical dependence and withdrawal symptoms, are attenuated in mice lacking adenylyl cyclase type 5 (AC5), a form of adenylyl cyclase that is highly enriched in striatum. Furthermore, the behavioral effects of selective mu or delta opioid receptor agonists are lost in AC5-/- mice, whereas the behavioral effects of selective kappa opioid receptor agonists are unaffected. These behavioral data are consistent with the observation that the ability of a mu or delta opioid receptor agonist to suppress adenylyl cyclase activity was absent in striatum of AC5-/- mice. Together, these results establish AC5 as an important component of mu and delta opioid receptor signal transduction mechanisms in vivo and provide further support for the importance of the cAMP pathway as a critical mediator of opioid action.

Adenylyl Cyclases↗
PubMed2006

Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action.

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.

Acetylation↗
PubMed2006

Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.

Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.

Aggression↗
PubMed2006

An essential role for DeltaFosB in the nucleus accumbens in morphine action.

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.

Animals↗
PubMed2006

New approaches to antidepressant drug discovery: beyond monoamines.

All available antidepressant medications are based on serendipitous discoveries of the clinical efficacy of two classes of antidepressants more than 50 years ago. These tricyclic and monoamine oxidase inhibitor antidepressants were subsequently found to promote serotonin or noradrenaline function in the brain. Newer agents are more specific but have the same core mechanisms of action in promoting these monoamine neurotransmitters. This is unfortunate, because only approximately 50% of individuals with depression show full remission in response to these mechanisms. This review summarizes the obstacles that have hindered the development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategies.

Animals↗
PubMed2006

Phosphorylation of DARPP-32 at Threonine-34 is required for cocaine action.

Mice lacking DARPP-32, a striatal-enriched phosphoprotein, show abnormal behavioral and biochemical responses to cocaine, but the role of individual phosphorylation sites in DARPP-32 in these responses is unknown. We show here that mutation of Thr-34 in DARPP-32 mimicked the behavioral phenotype of the constitutive DARPP-32 knockout in cocaine-induced place conditioning, locomotor activity, and sensitization paradigms. In contrast, mutations of Thr75 did not affect conditioned place preference or the acute locomotor response to cocaine, but DARPP-32 Thr-75 mutants showed no locomotor sensitization in response to repeated cocaine administration. Consistent with these behavioral findings, we found that cocaine regulation of gene expression in striatum, including the acute induction of the immediate early genes c-fos and arc (activity-regulated cytoskeletal-associated gene), was abolished in DARPP-32 Thr-34 mutants, but not in Thr-75 mutants. Similarly, induction of the transcription factor DeltaFosB in the ventral striatum (nucleus accumbens) by chronic cocaine was diminished by the Thr-34, but not the Thr-75, mutation. These findings highlight distinct roles of the Thr-34 and Thr-75 phosphorylation sites of DARPP-32 in mediating short- and long-term behavioral and biochemical actions of cocaine.

Animals↗
PubMed2006

Neural mechanisms of addiction: the role of reward-related learning and memory.

Addiction is a state of compulsive drug use; despite treatment and other attempts to control drug taking, addiction tends to persist. Clinical and laboratory observations have converged on the hypothesis that addiction represents the pathological usurpation of neural processes that normally serve reward-related learning. The major substrates of persistent compulsive drug use are hypothesized to be molecular and cellular mechanisms that underlie long-term associative memories in several forebrain circuits (involving the ventral and dorsal striatum and prefrontal cortex) that receive input from midbrain dopamine neurons. Here we review progress in identifying candidate mechanisms of addiction.

Animals↗