neuro
Role of ΔFosB in the Nucleus Accumbens
Role of ΔFosB in the Nucleus Accumbens ΔFosB is a member of the Fos family of transcription factors. With repeated exposure to drugs of abuse or to stress, isoforms of ΔFosB accumulate due to their very high level of stability and eventually become the predominant Fos-like protein in these neurons. This phenomenon is observed in response to chronic administration of virtually any drug of abuse. It is also observed after high levels of consumption of natural rewards (exercise, sucrose, high fat diet, sex). As well, it is observed in response to several types of chronic stress. However, different neuronal cell types are involved: drugs and natural rewards induce ΔFosB in a single subtype of nucleus accumbens neuron, while stress induces the protein more broadly in this brain region.

These ΔFosB responses are interesting because they provide a molecular mechanism (based in the stability of the protein) by which drugs of abuse, natural rewards, and stress can induce long-lasting changes in gene expression.

Role of ΔFosB in Addiction

Studies with inducible transgenic mice and viral vectors, combined with an array of behavioral models, has taught us that induction of ΔFosB in the nucleus accumbens increases an animal's sensitivity to the locomotor-activating and rewarding effects of drugs of abuse. ΔFosB may also increase incentive motivation, or drive, for the drugs. In addition, ΔFosB increases an animal's drive for natural rewards as well. These findings support our hypothesis that ΔFosB functions as a sustained molecular switch which first helps initiate and then maintains a state of addiction for a relatively prolonged period of time.

Role of ΔFosB in Depression

More recently, we have shown that induction of ΔFosB in nucleus accumbens in response to chronic stress represents a positive, adaptive mechanism to help the animal cope with the stress. In the social defeat paradigm, for example, animalsthat are resilient to the deleterious effects of defeat stress show greater induction of ΔFosB than vulnerable animals. Moreover, chronic administration of antidepressant medications induces ΔFosB in nucleus accumbens and the behavioral effects of these treatments can be blocked by blockade of ΔFosB activity in this brain region. Together, these data demonstrate that ΔFosB is a novel mechanism of resilience and a potentially important mediator of antidepressant action.

In Search of Target Genes for ΔFosB: Studies of Chromatin Structure

We are searching for target genes of ΔFosB using several approaches. We are identifying genes whose mRNA's are up- or downregulated in nucleus accumbens by use of gene expression arrays of mice that inducibly overexpress ΔFosB or a dominant negative antagonist. In parallel, we are using chromatin immunoprecipitation (ChIP) followed by promotor array analysis (ChIP-chip) or high throughput sequencing (ChIP-Seq) to identify genes bound significantly by endogenous ΔFosB after chronic exposure to drugs of abuse or stress. Related ChIP-chip and ChIP-Seq work is identifying genes that also show general markers of gene activation (e.g., histone acetylation, certain types of histone methylation) or gene repression (e.g., other types of histone methylation, DNA methylation) after chronic drug or stress exposure. By overlapping such diverse gene sets, we are identifying gene regulation by drugs of abuse and stress in unprecedented ways.

Among the many target genes for ΔFosB in nucleus accumbens are several which encode proteins that regulate neuronal structure and growth. Indeed, we now know that ΔFosB, and several of its targets (e.g., CDK5, NFkB), mediate the ability of cocaine and certain other drugs of abuse as well as stress to increase the dendritic arborization of nucleus accumbens neurons. (See Neurotrophic Mechanisms in Drug Addiction.)

Studies of ΔFosB in Other Brain Regions

While the most dramatic induction of ΔFosB by drugs and stress occurs in the nucleus accumbens, lower levels of induction are seen in several other limbic brain regions, in particular, areas of prefrontal cortex. We are therefore examining the influence of ΔFosB in these other regions in animal models of addiction and depression, as well as searching for target genes in these brain areas.

Comparisons with CREB

Interesting comparisons and contrasts with CREB are evident. Both ΔFosB and CREB are induced by stress and by drugs of abuse, yet they exert opposite effects on behavior. CREB reduces behavioral responses to emotional stimuli and induces a depression-like state in the extreme, whereas ΔFosB sensitizes reward and induces antidepressant-like responses. Also, the CREB signal is relatively short-lived, while the ΔFosB signal is long-lived. The two transcription factors thereby mediate very different aspects of drug- and stress-induced behavioral syndromes. Interestingly, the summation of the CREB and ΔFosB phenotype would suggest a biphasic pattern during drug withdrawal, early anhedonia or dysphoria followed by a more prolonged sensitized state. Such a biphasic pattern is indeed seen in many human addicts. (See CREB and Chromatin Regulation in the Nucleus Accumbens.)




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nestler lab
Laboratory of Molecular Psychiatry