Enhancing Cognition after Stress with Gene Therapy

This is the title of an article from Sapolsky's laboratory. Sapolsky is an amazing off the wall guy. His book "Why Zebras Don't Get Ulcers" is a classic on the biology of stress. He also has written fascinating stuff on aging. In this article he and his coworkers describe a clever trick for diminishing the impairment of memory acquisition and retrieval caused by the adrenal steroid hormones secreted during stress (glucocorticoids, or GCs). Estrogen, known to enhance spatial memory performance, can block the deleterious effects of GCs. The laboratory constructed a chimeric gene ("ER/GR") containing the hormone-binding domain of the GC receptor and the DNA binding domain of the estrogen receptor; as a result, ER/GR transduces deleterious GC signals into beneficial estrogenic ones. A deleterious effect of immobilization stress on spatial memory acquisition and retrieval in male rats was blocked by hippocampal expression of the ER/GR transgene. ER/GR also blocks the suppressive effects of GCs on expression of brain-derived neurotrophic factor (BDNF), a growth factor central to hippocampal-dependent cognition and plasticity, instead producing an estrogenic increase in BDNF expression. These experiments don't mean we are going to be able to use gene therapy to reverse the effects of stress on memory in humans any time soon. The clever tricks for getting transgenes into specific parts of rat brains don't yet exist for us humans.