Editors' ChoiceResponses to Stress

Don’t Bother Me

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Science Translational Medicine  01 Dec 2010:
Vol. 2, Issue 60, pp. 60ec187
DOI: 10.1126/scitranslmed.3001967

Although stress is unavoidable in our lives, it can have myriad negative consequences. Some individuals display maladaptive responses to stress that lead to psychiatric disorders, which typically involve dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis—a set of interactions between the hypothalamus, pituitary gland, and adrenal glands, with the neuropeptide corticotrophin-releasing factor (CRF) serving as the final common pathway out of the brain. In contrast, other individuals seem to inexplicably tolerate events that appear overwhelmingly stressful in nature. This observation has fueled the search for biological factors that confer resilience to stress.

Early-life stress is known to involve altered patterns of methylation of DNA, leading to permanently altered gene expression in the brain and anxiety-related behavior in adulthood. A new study by Elliot and colleagues addresses DNA methylation in stress responses in adulthood and suggests a role for DNA methylation in resilience to stress. Focusing on the Crf locus, they first found that inhibiting DNA methyltransferase in immortalized hypothalamic N42 cells led to increases in both basal and cyclic adenosine 5'-monophosphate (cAMP)–stimulated Crf mRNA expression. Conversely, in vitro methylation led to opposing effects. To evaluate the effects of stress on methylation at the Crf locus, adult mice were subjected to social defeat, which is a well-established protocol to induce anxiety-like behaviors. Mice who exhibited these behaviors showed decreased methylation of the Crf promoter and increased Crf mRNA in the hypothalamus—effects that were attenuated with post-exposure treatment with imipramine, which is an antidepressant medication. In contrast to the susceptible mice, resilient mice neither exhibited these behaviors nor showed changes at the Crf locus. In addition, mice with lentiviral-mediated knockdown of Crf levels after social defeat showed less anxiety-like social avoidance than mice injected with control virus. These findings suggest that the effects of stress on mood and behavior may stem from altered DNA methylation patterns in the HPA axis. Importantly, the way forward for serious stress-exposed persons may emerge from the study of both animal models and those in our community who manifest uncommon resilience in the face of uncommon stress.

E. Elliott et al., Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice. Nat. Neurosci. 13, 1351–1353 (2010). [Abstract]

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