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E J Nestler

Publications and source records attributed to E J Nestler.

At least 19 recordsLinked to original sources
PubMed2002

Regulating DeltaFosB expression in adult Tet-Off-DeltaFosB transgenic mice alters bone formation and bone mass.

The DeltaFosB isoforms are naturally occurring AP-1 family members that increase bone volume via a cell-autonomous effect on osteoblastic bone formation. Mice overexpressing DeltaFosB demonstrate a very high level of bone formation, resulting in a progressive osteosclerosis. Despite the linkage of bone formation and resorption in physiological systems, no alteration in bone resorption was detected in mice overexpressing DeltaFosB. To determine whether altering DeltaFosB expression can regulate bone formation independently of bone resorption in adult mice, we used the Tet-Off-inducible transgene system to induce or block transgenic DeltaFosB overexpression and thereby regulate bone formation in vivo. Overexpression of DeltaFosB after skeletal maturity increased trabecular bone volume by increasing bone formation, again without altering bone resorption, indicating that developmental DeltaFosB overexpression is not required for the osteosclerotic phenotype. Similarly, switching off DeltaFosB overexpression after osteosclerosis had developed led to a marked decrease in bone formation and loss of bone mass such that trabecular bone volume approached normal levels. Despite this dramatic reduction, no alteration in bone resorption was detected. These results clearly demonstrate that DeltaFosB regulates bone formation and bone mass in adult mice with no effect on bone resorption.

Animals↗
PubMed2001

Elevated levels of DeltaFosB and RGS9 in striatum in Parkinson's disease.

INTRODUCTION: In the present study, we determined whether certain proteins known to mediate dopamine signaling in striatum show abnormal levels in Parkinson's disease. METHODS: Protein levels were assayed by western blotting in samples of caudate nucleus and putamen obtained at autopsy from patients with Parkinson's disease and from control subjects. Levels of several markers of dopaminergic function were also assayed. RESULTS: Levels of the transcription factor DeltaFosB and of the G protein modulatory protein RGS9 were both increased in caudate and putamen from patients with Parkinson's disease. Levels of several other proteins were not affected. Interestingly, levels of both DeltaFosB and RGS9 correlated inversely with putamen levels of dopamine, dopamine metabolites, and the dopamine transporter. CONCLUSIONS: These findings are consistent with observations in laboratory animals, which have demonstrated elevated levels of DeltaFosB in striatum after denervation of the midbrain dopamine system, and confirm that similar adaptations in DeltaFosB and RGS9 occur in humans with Parkinson's disease. Knowledge of these adaptations can help us understand the changes in striatal function associated with Parkinson's disease and assist in the development of novel treatments.

Blotting, Western↗
PubMed2001

Psychogenomics: opportunities for understanding addiction.

The term psychogenomics is used here to describe the process of applying the powerful tools of genomics and proteomics to achieve a better understanding of the biological substrates of normal behavior and of diseases of the brain that manifest themselves as behavioral abnormalities. Applying psychogenomics to the study of drug addiction will lead to the identification of genes and their protein products that control the reward pathways of the brain and their adaptations to drugs of abuse, as well as variations in these genes that confer genetic risk for addiction and related disorders. The ultimate goal is to use this information to develop more effective treatments for these disorders as well as objective diagnostic tools, preventive measures, and eventually cures.

Animals↗
PubMed2001

DeltaFosB: a sustained molecular switch for addiction.

The longevity of some of the behavioral abnormalities that characterize drug addiction has suggested that regulation of neural gene expression may be involved in the process by which drugs of abuse cause a state of addiction. Increasing evidence suggests that the transcription factor DeltaFosB represents one mechanism by which drugs of abuse produce relatively stable changes in the brain that contribute to the addiction phenotype. DeltaFosB, a member of the Fos family of transcription factors, accumulates within a subset of neurons of the nucleus accumbens and dorsal striatum (brain regions important for addiction) after repeated administration of many kinds of drugs of abuse. Similar accumulation of DeltaFosB occurs after compulsive running, which suggests that DeltaFosB may accumulate in response to many types of compulsive behaviors. Importantly, DeltaFosB persists in neurons for relatively long periods of time because of its extraordinary stability. Therefore, DeltaFosB represents a molecular mechanism that could initiate and then sustain changes in gene expression that persist long after drug exposure ceases. Studies in inducible transgenic mice that overexpress either DeltaFosB or a dominant negative inhibitor of the protein provide direct evidence that DeltaFosB causes increased sensitivity to the behavioral effects of drugs of abuse and, possibly, increased drug seeking behavior. This work supports the view that DeltaFosB functions as a type of sustained "molecular switch" that gradually converts acute drug responses into relatively stable adaptations that contribute to the long-term neural and behavioral plasticity that underlies addiction.

Animals↗
PubMed2001

Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens.

Drugs of abuse regulate the transcription factor cAMP response element-binding protein (CREB) in striatal regions, including the nucleus accumbens (NAc). To explore how regulation of CREB in the NAc affects behavior, we used herpes simplex virus (HSV) vectors to elevate CREB expression in this region or to overexpress a dominant-negative mutant CREB (mCREB) that blocks CREB function. Rats treated with HSV-mCREB in place conditioning studies spent more time in environments associated with cocaine, indicating increased cocaine reward. Conversely, rats treated with HSV-CREB spent less time in cocaine-associated environments, indicating increased cocaine aversion. Studies in which drug-environment pairings were varied to coincide with either the early or late effects of cocaine suggest that CREB-associated place aversions reflect increased cocaine withdrawal. Because cocaine withdrawal can be accompanied by symptoms of depression, we examined how altered CREB function in the NAc affects behavior in the forced swim test (FST). Elevated CREB expression increased immobility in the FST, an effect that is opposite to that caused by standard antidepressants and is consistent with a link between CREB and dysphoria. Conversely, overexpression of mCREB decreased immobility, an effect similar to that caused by antidepressants. Moreover, the kappa opioid receptor antagonist nor-Binaltorphimine decreased immobility in HSV-CREB- and HSV-mCREB-treated rats, suggesting that CREB-mediated induction of dynorphin (an endogenous kappa receptor ligand) contributes to immobility behavior in the FST. Exposure to the FST itself dramatically increased CREB function in the NAc. These findings raise the possibility that CREB-mediated transcription within the NAc regulates dysphoric states.

Animals↗
PubMed2001

Differential behavioral responses to cocaine are associated with dynamics of mesolimbic dopamine proteins in Lewis and Fischer 344 rats.

Differential behavioral and biochemical responses to drugs of abuse may reflect genetic makeup as suggested by studies of inbred Lewis (LEW) and Fischer 344 (F344) rats. We investigated locomotor activity, stereotypy signs, and levels of specific proteins in the nucleus accumbens (NAc) and ventral tegmental area (VTA) in these strains at baseline and following chronic administration of cocaine (30 mg/kg/day for 14 days). Using Western blot analysis, we replicated our previous findings of baseline strain differences and found lower levels of DeltaFosB immunoreactivity in NAc of F344 vs. LEW rats. F344 rats showed greater baseline locomotor activity, sniffing, and grooming compared to LEW rats. Chronic cocaine increased DeltaFosB levels in NAc in both strains, whereas adaptations in other proteins were induced in F344 rats only. These included reduced levels of tyrosine hydroxylase (TH) in NAc and increased TH and glial fibrillary acidic protein (GFAP) immunoreactivity in VTA. Chronic cocaine led to greater increases in overall stereotypy in F344 vs. LEW rats and decreased exploratory behaviors in LEW rats. Opposing effects by strain were seen in locomotor activity. Whereas F344 rats showed higher initial activity levels that decreased with cocaine exposure (tolerance), LEW rats showed increased activity over days (sensitization) with no strain differences seen at 14 days. Further, conditioned locomotor activation to vehicle injections was greater in F344 vs. LEW rats. These results suggest that behavioral responsiveness to chronic cocaine exposure may reflect dynamics of mesolimbic dopamine protein levels and demonstrate the role of genetic background in responsiveness to cocaine.

Animals↗
PubMed2001

Dopamine receptor regulating factor, DRRF: a zinc finger transcription factor.

Dopamine receptor genes are under complex transcription control, determining their unique regional distribution in the brain. We describe here a zinc finger type transcription factor, designated dopamine receptor regulating factor (DRRF), which binds to GC and GT boxes in the D1A and D2 dopamine receptor promoters and effectively displaces Sp1 and Sp3 from these sequences. Consequently, DRRF can modulate the activity of these dopamine receptor promoters. Highest DRRF mRNA levels are found in brain with a specific regional distribution including olfactory bulb and tubercle, nucleus accumbens, striatum, hippocampus, amygdala, and frontal cortex. Many of these brain regions also express abundant levels of various dopamine receptors. In vivo, DRRF itself can be regulated by manipulations of dopaminergic transmission. Mice treated with drugs that increase extracellular striatal dopamine levels (cocaine), block dopamine receptors (haloperidol), or destroy dopamine terminals (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) show significant alterations in DRRF mRNA. The latter observations provide a basis for dopamine receptor regulation after these manipulations. We conclude that DRRF is important for modulating dopaminergic transmission in the brain.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala.

At least two temporally and mechanistically distinct forms of memory are conserved across many species: short-term memory that persists minutes to hours after training and long-term memory (LTM) that persists days or longer. In general, repeated training trials presented with intervening rest intervals (spaced training) is more effective than massed training (the same number of training trials presented with no or short intervening rest intervals) in producing LTM. LTM requires de novo protein synthesis, and cAMP response element-binding protein (CREB) may be one of the transcription factors regulating the synthesis of new proteins necessary for the formation of LTM. Here we show that rats given massed fear conditioning training show no or weak LTM, as measured by fear-potentiated startle, compared with rats given the same amount of training but presented in a spaced manner. Increasing CREB levels specifically in the basolateral amygdala via viral vector-mediated gene transfer significantly increases LTM after massed fear training. The enhancing effect of CREB overexpression on LTM formation is shown to be specific in terms of biochemistry, anatomy, time course, and the training procedure used. These results suggest that CREB activity in the amygdala serves as a molecular switch for the formation of LTM in fear conditioning.

Amygdala↗
PubMed2001

Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5.

Cocaine enhances dopamine-mediated neurotransmission by blocking dopamine re-uptake at axon terminals. Most dopamine-containing nerve terminals innervate medium spiny neurons in the striatum of the brain. Cocaine addiction is thought to stem, in part, from neural adaptations that act to maintain equilibrium by countering the effects of repeated drug administration. Chronic exposure to cocaine upregulates several transcription factors that alter gene expression and which could mediate such compensatory neural and behavioural changes. One such transcription factor is DeltaFosB, a protein that persists in striatum long after the end of cocaine exposure. Here we identify cyclin-dependent kinase 5 (Cdk5) as a downstream target gene of DeltaFosB by use of DNA array analysis of striatal material from inducible transgenic mice. Overexpression of DeltaFosB, or chronic cocaine administration, raised levels of Cdk5 messenger RNA, protein, and activity in the striatum. Moreover, injection of Cdk5 inhibitors into the striatum potentiated behavioural effects of repeated cocaine administration. Our results suggest that changes in Cdk5 levels mediated by DeltaFosB, and resulting alterations in signalling involving D1 dopamine receptors, contribute to adaptive changes in the brain related to cocaine addiction.

Animals↗
PubMed2001

Learning about addiction from the genome.

Drug addiction can be defined as the compulsive seeking and taking of a drug despite adverse consequences. Although addiction involves many psychological and social factors, it also represents a biological process: the effects of repeated drug exposure on a vulnerable brain. The sequencing of the human and other mammalian genomes will help us to understand the biology of addiction by enabling us to identify both genes that contribute to individual risk for addiction and those through which drugs cause addiction. We illustrate this potential impact by searching a draft sequence of the human genome for genes related to desensitization of receptors that mediate the actions of drugs of abuse on the nervous system.

Databases, Factual↗
PubMed2001

Regulation of GFRalpha-1 and GFRalpha-2 mRNAs in rat brain by electroconvulsive seizure.

The influence of both acute and chronic electroconvulsive seizure (ECS) or antidepressant drug treatments on expression of mRNAs encoding glial cell line-derived neurotrophic factor (GDNF) and its receptors, GFRalpha-1, GFRalpha-2, and c-Ret proto-oncogene (RET) in the rat hippocampus was examined by in situ hybridization. Two hours after acute ECS, levels of GFRalpha-1 mRNA in the dentate gyrus were significantly increased. This increase peaked to nearly 3-fold at 6 h after acute ECS and returned to basal levels 24 h after treatment. Chronic (once daily for 10 days) ECS significantly increased the expression of GFRalpha-1 mRNA nearly 5-fold after the last treatment. Levels of GFRalpha-2 mRNA in the dentate gyrus were also significantly increased by acute and chronic ECS, although this effect was less than that observed for GFRalpha-1. Maximum induction of GFRalpha-2 was 30% and 70% compared to sham in response to acute or chronic ECS, respectively. Levels of GDNF and RET mRNAs were not significantly changed following either acute or chronic ECS treatment at the time points examined. Chronic (14 days) administration of different classes of antidepressant drugs, including tranylcypromine, desipramine, or fluoxetine, did not significantly affect the GDNF, GFRalpha-1, GFRalpha-2, or RET mRNA levels in CA1, CA3, and dentate gyrus areas of hippocampus. The results demonstrate that acute ECS increases the expression of GFRalpha-1 and GFRalpha-2 and that these effects are enhanced by chronic ECS. The results also imply that regulation of the binding components of GDNF receptor complex may mediate the adaptive responses of the GDNF system to acute and chronic stimulation.

Animals↗
PubMed2001

Molecular basis of long-term plasticity underlying addiction.

Studies of human addicts and behavioural studies in rodent models of addiction indicate that key behavioural abnormalities associated with addiction are extremely long lived. So, chronic drug exposure causes stable changes in the brain at the molecular and cellular levels that underlie these behavioural abnormalities. There has been considerable progress in identifying the mechanisms that contribute to long-lived neural and behavioural plasticity related to addiction, including drug-induced changes in gene transcription, in RNA and protein processing, and in synaptic structure. Although the specific changes identified so far are not sufficiently long lasting to account for the nearly permanent changes in behaviour associated with addiction, recent work has pointed to the types of mechanism that could be involved.

Animals↗
PubMed2001

Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal.

Somatic symptoms and aversion of opiate withdrawal, regulated by noradrenergic signaling, were attenuated in mice with a CNS-wide conditional ablation of neurotrophin-3. This occurred in conjunction with altered cAMP-mediated excitation and reduced upregulation of tyrosine hydroxylase in A6 (locus coeruleus) without loss of neurons. Transgene-derived NT-3 expressed by noradrenergic neurons of conditional mutants restored opiate withdrawal symptoms. Endogenous NT-3 expression, strikingly absent in noradrenergic neurons of postnatal and adult brain, is present in afferent sources of the dorsal medulla and is upregulated after chronic morphine exposure in noradrenergic projection areas of the ventral forebrain. NT-3 expressed by non-catecholaminergic neurons may modulate opiate withdrawal and noradrenergic signalling.

Aging↗
PubMed2001

Induction of nuclear factor-kappaB in nucleus accumbens by chronic cocaine administration.

DeltaFosB is a Fos family transcription factor that is induced by chronic exposure to cocaine and other drugs of abuse in the nucleus accumbens and related striatal regions, brain regions that are important for the behavioral effects of these drugs. To better understand the mechanisms by which DeltaFosB contributes to the effects of chronic drug treatment, we used DNA microarray analysis to identify genes that are regulated in the nucleus accumbens upon DeltaFosB expression in inducible bitransgenic mice. One of the most highly regulated genes was that encoding a subunit of another transcription factor, nuclear factor-kappaB (NF-kappaB). Subsequent experiments confirmed the induction of NF-kappaB in the nucleus accumbens of mice overexpressing DeltaFosB as well as in wild-type mice treated chronically, but not acutely, with cocaine. These results establish NF-kappaB as a putative target for DeltaFosB and implicate NF-kappaB signaling pathways in the long-term adaptations of nucleus accumbens neurons to cocaine.

Animals↗
PubMed2001

Molecular neurobiology of addiction.

Addiction can be viewed as a form of drug-induced neural plasticity. One of the best established molecular mechanisms of addiction is the upregulation of the cAMP second messenger pathway, which occurs in many neuronal cell types in response to chronic administration of opiates or other drugs of abuse. This upregulation and the resulting activation of the transcription factor CREB appear to mediate aspects of tolerance and dependence. In contrast, induction of another transcription factor, termed delta FosB, exerts the opposite effect and may contribute to sensitized responses to drug exposure. Knowledge of these mechanisms could lead to more effective treatments for addictive disorders.

Acute Disease↗
PubMed2001

Molecular and functional analysis of hyperpolarization-activated pacemaker channels in the hippocampus after entorhinal cortex lesion.

Differential display of hippocampal tissue after entorhinal cortex lesion (ECL) revealed decreases in mRNA encoding the neuronal hyperpolarization-activated, cyclic nucleotide-gated channel HCN1. In situ hybridization confirmed that hippocampal transcripts of HCN1, but not HCN2/3/4, are down-regulated after ECL. Expression recovered at approximately 21 days after lesion (dal). Immunohistochemistry demonstrated a corresponding regulation of HCN1 protein expression in CA1-CA3 dendrites, hilar mossy cells and interneurons, and granule cells. Patch-clamp recordings in the early phase after lesion from mossy cells and hilar interneurons revealed an increase in the fast time constant of current activation and a profound negative shift in voltage activation of Ih. Whereas current activation recovered at 30 dal, the voltage activation remained hyperpolarized in mossy cells and hilar interneurons. Granule cells, however, were devoid of any detectable somatic Ih currents. Hence, denervation of the hippocampus decreases HCN1 and concomitantly the Ih activity in hilar neurons, and the recovery of h-current activation kinetics occurs parallel to postlesion sprouting.

Animals↗
PubMed2000

Induction of cyclin-dependent kinase 5 in the hippocampus by chronic electroconvulsive seizures: role of [Delta]FosB.

The transcription factor DeltaFosB is induced in the hippocampus and other brain regions by repeated electroconvulsive seizures (ECS), an effective antidepressant treatment. The unusually high stability of this protein makes it an attractive candidate to mediate some of the long-lasting changes in the brain caused by ECS treatment. To understand how DeltaFosB might alter brain function, we examined the gene expression profiles in the hippocampus of inducible transgenic mice that express DeltaFosB in this brain region by the use of cDNA expression arrays that contain 588 genes. Of the 430 genes detected, 20 genes were consistently upregulated, and 14 genes were downregulated, by >50%. One of the upregulated genes is cyclin-dependent kinase 5 (cdk5). On the basis of its purported role in regulating neuronal structure, we studied directly whether cdk5 is a true target for DeltaFosB. Upregulation of cdk5 immunoreactivity in the hippocampus was confirmed by Western blotting in the DeltaFosB-expressing transgenic mice as well as in rats treated chronically with ECS. Chronic ECS treatment also increased, in the hippocampus, the phosphorylation state of tau, a microtubule-associated protein that is a known substrate for cdk5. A 1.6 kb fragment of the cdk5 promoter was cloned, and activity of the promoter was found to be increased after overexpression of DeltaFosB in cell culture. Moreover, mutation of the single consensus activator protein-1 site contained within the cdk5 promoter fragment completely abolished activation of the promoter by DeltaFosB. Together, these results suggest that cdk5 is one target by which DeltaFosB produces some of its physiological effects in the hippocampus and thereby mediates certain long-term consequences of chronic ECS treatment.

Animals↗