Much research has been done in studying the genetic components of addiction and mental health disorders. Particularly interesting is the study of the gene, DeltaFosB, which has been specifically linked to addiction behaviors and depression. Research has shown, using mice, that an over-expression in DeltaFosB causes increased sensitivity to the behavioral effects of drugs and alcohol, increasing drug seeking behavior. DeltaFosB seems to act as a switch, gradually converting drug responses to stable adaptations contributing to the long-term neural and behavioral functions that underlie addiction.
A new study, conducted at the Icahn School of Medicine at Mount Sinai Health System in New York City, has found that by inducing specific changes in the action of the gene, FosB, within the nucleus accumbens region of the brain, the mice (modeled for human depression, stress and addiction) became more resilient to stress and to cocaine addiction. The nucleus accumbens region has been shown, in former studies, to be linked to both addiction and depression.
Past research shed light on the action between epigenetic regulation and the diseases of drug addiction and depression, in both human patients and mice. Specialized proteins that bind to specific DNA sequences will either turn on or shut off the expression of a given gene.
DNA, found in every cell of the body, contains genes that are wired to carry out various survival functions. The DNA sequences are converted into messages that dictate to cells which proteins to make for the specific function of a given cell. Most genes are not activated at all times. It is the action of transcription factors, or proteins, that manipulate the structure of DNA in a cell, causing some genes to be active and others to be repressed.
Eric J. Nestler, M.D., Ph.D., chair of the department of neuroscience at Mount Sinai, who led the study, states:
“Earlier work in our laboratory found that several transcription factors and downstream epigenetic modifications are altered by exposure to drugs or to stress and that these changes, in turn, control gene expression. But because such epigenetic regulation occurs at hundreds or thousands of genes, until now it had been impossible to determine the difference between the mere presence of an epigenetic modification and its functional relevance to neuropsychiatric disease.”
Lead author on the paper, Elizabeth A. Heller, Ph.D., developed a way to effectively control regulatory aspects of FosB. She designed synthetic transcription factors called Zinc Finger Proteins (ZFPs) to target a single gene out of 20,000 by incorporating them into a virus and infecting that virus into the nucleus accumbens, the reward-related region of the brain. After the virus binded to the FosB gene, now modified by the ZFPs, histones were created that either activated or repressed the gene’s expression.
Expression of the FosB gene is sufficient for drug and stress responsiveness in mice. Specifically, activation of FosB expression is associated with increased drug sensitivity and to stress resilience. “While drug addiction and depression are hereditary diseases that regulate gene expression in the brain, the field has yet to uncover relevant mutations in gene sequences that underlie these disorders,” Heller states.
The data culled from this study provides forward momentum toward developing new and promising methods in battling mental health disorders, including drug and alcohol addiction. The implications are significant. If a gene’s action can be manipulated, this can possibly lead to the development of therapeutic agents to help treat a number of neuropsychiatric disorders, as well as other medical illnesses, even cancer.
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