CREB and Chromatin Remodeling in the Nucleus Accumbens
A role for CREB in emotional regulation first came from studies of the locus coeruleus, the major noradrenergic nucleus in brain, where we showed that chronic opiate administration induced the CREB pathway to mediate physical aspects of opiate dependence and withdrawal. Since that time, we and others have shown that CREB is activated in several other brain regions by chronic exposure to opiates, where it mediates distinct aspects of opiate tolerance and dependence, depending on the brain region involved.

Role of CREB in Addiction

Interestingly, CREB is activated within the nucleus accumbens not only by opiates, but also by stimulant drugs of abuse such as cocaine and amphetamine. Studies with inducible transgenic mice and viral vectors, combined with an array of behavioral models, has taught us that CREB in this brain region decreases an animal's sensitivity to the rewarding effects of these drugs of abuse, an indication of tolerance. In addition, CREB activation causes a negative emotional state, suggesting that it could mediate depression-like symptoms seen during drug withdrawal.

Role of CREB in Depression and Anxiety

These findings with drugs of abuse led us to investigate whether CREB is also induced in nucleus accumbens by stress. Indeed it is and increasing evidence now demonstrates that such activation mediates a depression-like state in several animal models. This negative emotional state is mediated in part via CREB's induction of the opioid peptide dynorphin in this brain region. Unlike most opioid peptides, dynorphin induces a negative emotional state in part by feeding back and suppressing the activity of dopamine neurons.

In contrast, inhibition of CREB activity in the nucleus accumbens, which is induced after prolonged periods of social isolation, causes a profound state of anxiety. Together, these observations have suggested that CREB functions as a rheostat of reward. High CREB states (chronic exposure to drugs of abuse or to active forms of stress) are associated with depression and low emotional reactivity, while low CREB states (long-term social isolation) are associated with excessive emotional reactivity including anxiety. Interestingly, antidepressant treatments can normalize both high and low CREB states.

Studies of CREB Family Proteins

CREB is just one of several related transcription factors, which include ICER (inducible cAMP early repressor) and several ATFs (activating transcription factors). We have systematically defined distinct roles for several in addiction- and depression/anxiety-related behaviors, with some inducing high CREB states, while others inducing low CREB states due to their functions as endogenous dominant negative CREB inhibitors. We are also using DNA microarray chips to identify additional genes through which CREB produces a negative emotional state at the level of the nucleus accumbens.

Studies of Chromatin Remodeling: Identification of CREB Target Genes

Chromatin structure provides a unique window into the state of activation or repression of genes in the brain in vivo and as such we have been exploring drug and stress regulation of chromatin in nucleus accumbens in addiction and depression models.

We have used chromatin immunoprecipitation (ChIP) followed by gene promoter arrays (ChIP-chip) or by high throughput sequencing (ChIP-Seq) to identify genes in nucleus accumbens that show changes in markers of transcriptional activation or repression. Examples of activation markers include acetylation of histone H3 and H4 and methylation of H3 at certain lysine residues (e.g., Lys4). Examples of repression markers include methylation of H3 at other lysine residues (e.g., Lys9 or 27) or methylation of the DNA itself. Coupled with ChiP-chip and ChIP-Seq analyses of CREB binding, this approach has made it possible to identify many target genes for CREB, such as dynorphin as mentioned above.

Studies of Chromatin Remodeling: Global Changes in Gene Regulation

In addition to examining histone and DNA modifications at specific genes, we have demonstrated global alterations in these chromatin remodeling events in animal models of addiction and depression. Indeed, we have shown that chronic exposure to drugs of abuse or to stress alters the levels of expression of several of the enzymes that catalyze these modifications, including several specific histone deacetylases (HDACs), histone methyltransferases, histone demethylases, and DNA methyltransferases, in the nucleus accumbens. This has raised the novel possibility that drugs aimed at these modifications may have some medicinal utility. For example, we have found that administration of HDAC (histone deacetylase) inhibitors into nucleus accumbens (or other brain regions or even systemically) exerts antidepressant-like effects.

nestler lab
Laboratory of Molecular Psychiatry