The air is starting to get crisp, the first few leaves are changing color and you can suddenly buy pumpkin-spice everything – these contextual cues can only mean one thing; you’d better start studying for your midterms! But wait, you haven’t had to worry about exams for years…
Thanks to your hippocampus and epigenetics, environmental factors can trigger strong emotional and behavioral responses, even when they’re no longer useful. For some, it comes as brief moment of back to school panic while you’re working your 9-to-5, but for people with addiction disorders, drug-related context cues can mean the difference between recovery and relapse.
When someone (or some mouse) ingests drugs, the rewarding effects can become strongly associated with the environment that they were in at the time. These maladaptive memories are associated with gene expression changes in the hippocampus, a brain region important to spatial learning, but we still don’t know what regulators organize this trip down memory lane.
A new study from the lab of A.J. Robison (Michigan State University, USA) asked whether ΔFosB, the longer lasting isoform of the activity dependent gene FosB, might act as a molecular cue card. The talented team exposed mice to a novel environment that was paired with injections of either cocaine, or saline, and found that:
- Expression of both FosB and ΔFosB mRNA transcripts is increased in the dorsal and ventral hippocampus of cocaine-injected mice, as measured by qPCR
- Western blots for both FosB isoforms showed increased protein expression in the ventral subregion alone
- The number of ΔFosB-positive cells, as well as their immunofluorescent intensity is increased in the CA1 subregion in both ventral and dorsal samples
- Silencing ΔFosB expression in either the dorsal or ventral hippocampus, by AAV-mediated expression of a dominant negative mutant of its binding partner, impaired the animals ability to develop a preference for contexts associated with cocaine
The researchers also found that the repressive H3K9me2 mark is decreased along the FosB gene in the hippocampus after cocaine exposure. This led to some creative epigenome editing, where they injected a HSV-vector containing a zinc finger that is specific to the FosB promoter and fused with the active domain of the G9a (EHMT2) histone methyltransferase into the hippocampus of mice. Here’s what they found:
- Adding H3K9me2 to the promoter prevents ΔFosB from being induced in response to cocaine
- Injections to either the dorsal or ventral hippocampus prevented the mice from developing a preference for cocaine-paired environments
Taken together, these finding suggest that futuristic epigenome editing therapies may be able to help maladaptive memories go in one ear and out the other!
If you remember to, check out the original article in the Journal of Neuroscience, August 2019