These findings may eventually help with identifying the risk for anxiety disorders and with tailored treatments based on the biological state of the developing brain.These findings may eventually help with identirying the risk for anxiety disorders and with tailored treatments based on the biological state of the developing brain.

Anxiety disorders are the most commonly occurring psychiatric disorders in adolescence, a time of dynamic changes in brain development, specifically in terms of gene expression, endocannabinoid signaling, and frontolimbic circuitry.  The reasons for the elevated incidence are unclear, and many treatments for anxiety disorders are informed by research involving adult participants.

Noting the need to elucidate mechanisms behind the increased risk in order to inform targeted treatments, researchers at Weill Cornell Medical College of Cornell University in New York and the University of California, San Francisco investigated whether “genetic alterations in endocannabinoid signaling related to a common polymorphism in fatty acid amide hydrolase (FAAH), which alters endocannabinoid anandamide (AEA) levels, would impact the development of frontolimbic circuitry implicated in anxiety disorders.”

Findings of their cross-species study involving humans and mice are scheduled to be reported in a new issue of the Proceedings of the National Academy of Sciences of the United States of America. Using data from the Pediatric Imaging, Neurocognition, and Genetics (PING) study, the investigators examined genotyping and diffusion tensor imaging data from 1050 participants–approximately equal numbers of males and females–between the ages of 3 and 21 years. A subset of the PING participants completed the self-reported Screen for Child Anxiety-Related Emotional Disorders, which assesses for various anxiety disorders and school phobia.

In a parallel study, they used anterograde tract tracing in “knock-in” mice–ones that have been genetically manipulated to enable experimental comparisons to humans, in this case, with the FAAH variation. For control purposes, they also included a group of wild-type (WT) mice whose DNA remained unaltered. Previous experiments by the authors showed that “WT mice express the human ancestral C385 allele, and replacement with the variant A385 allele resulted in knock-in mice having lower levels of FAAH protein and higher levels of AEA than WT mice.” They used the elevated plus maze (EPM) task to assess anxiety-like behavior in the mice.

In both humans and mice, the results identify gene-by-development interactions of the same polymorphism in FAAH. “The impact of FAAH genetic variation on frontolimbic circuitry and anxiety in mice and humans emerges during adolescence as anandamide levels decrease, but not before,” the authors reported. Effects of the FAAH genotype on frontolimbic connectivity emerge around the age of 12 years and are accompanied by anxiety-related changes, and similar findings were observed in the knock-in mice during their period of adolescence.

With further research, these findings may eventually help with the identification of risk for anxiety disorders and with tailored treatments based on the “biological state of the developing brain as a function of developmental changes in gene expression and neural circuit maturation,” according to the authors. “Although any single common polymorphism is unlikely to be sufficient for personalizing treatments, this work may contribute to efforts to target treatments that rely on endocannabinoid signaling,” such as FAAH inhibitors, they concluded.


Gee DG, Fetcho RN, Jing D, et al. Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species. Proc Natl Acad Sci USA. 2016; Mar 22. doi: 10.1073/pnas.1600013113.