Researchers have long been aware that the brain can permanently alter its activity in response to repeated exposures to a stimulus. This process underlies everything from the helpful ability to form associations (stove tops with harm, for example) to debilitating changes, such as post-traumatic stress disorder. New work published in a recent edition of Neuron has identified the molecular basis of this process in two significant cases: repeated use of drugs, and chronic stress and anxiety.
The work focused on a structure of the brain called the nucleus accumbens (NAcc). We've discussed the NAcc before, as it plays a role in reward and pleasure evaluation, and is active in the interpretation of everything from the placebo effect to finding a bargain while shopping. In this case, the researchers were interested in the NAcc because it is also thought to be involved in the diminished rewards obtained from a dose of a drug following its chronic use.
The research team was following up on data that had suggested that cells in the NAcc respond to repeated drug use by altering the structure of their chromosomes, leading to long-term changes in gene expression. They focused on a type of protein called a histone deacetylase (or HDAC), which chemically modifies the proteins that package the DNA. One of these proteins, HDAC5, showed an interesting pattern of changes in response to cocaine. After a single dose, its activity was unchanged. But, after repeated doses over the course of several days, HDAC5 became chemically modified, a change that kept it out of the nucleus and away from the chromosomes it normally modifies.
Its absence had a significant effect on the production of other genes in the NAcc, as the researchers identified over 170 genes that had significantly altered expression. It also appears to have a significant effect on the behavioral response to repeated doses of cocaine. Instead of the reward declining with time, mice with mutations in HDAC5 actually derived a greater reward from repeated doses of the drug.
Changes in the NAcc have also been associated with chronic stress and depression, so the researchers looked at how HDAC5 responded to repeated stressful incidents. In this case, the HDAC5 mutant mice showed a more extreme response to repeated stress, displaying behaviors seen in models of depression. In mice with normal copies of the gene, chronic stress caused a drop in the total level of HDAC5 message and protein, rather than altering its location.
The research ties together a number of areas of study, from the brain imaging that identified the NAcc as involved in reward assessment to the biochemistry that confirmed the importance of HDACs in gene regulation. It also shows that two otherwise unrelated stimuli—drug use and chronic stress are unrelated for captive mice, if not humans—can feed into a single effect. In this case, even though the two stimuli do very different things to HDAC5, the end result is the same: less of it in the nucleus, causing changes in gene expression.
Neuron, 2007. DOI: 10.1016/j.neuron.2007.09.032