Individual differences in frontolimbic circuitry and Anxiety emerge with adolescent changes in endocannabinoid signaling across species Academic Article uri icon


MeSH Major

  • Endocannabinoids
  • Frontal Lobe
  • Limbic Lobe
  • Nerve Net
  • Signal Transduction


  • Anxiety disorders peak in incidence during adolescence, a developmental window that is marked by dynamic changes in gene expression, endocannabinoid signaling, and frontolimbic circuitry. We tested 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. In a pediatric imaging sample of over 1,000 3- to 21-y-olds, we show effects of the FAAH genotype specific to frontolimbic connectivity that emerge by ∼12 y of age and are paralleled by changes in anxiety-related behavior. Using a knock-in mouse model of the FAAH polymorphism that controls for genetic and environmental backgrounds, we confirm phenotypic differences in frontoamygdala circuitry and anxiety-related behavior by postnatal day 45 (P45), when AEA levels begin to decrease, and also, at P75 but not before. These results, which converge across species and level of analysis, highlight the importance of underlying developmental neurobiology in the emergence of genetic effects on brain circuitry and function. Moreover, the results have important implications for the identification of risk for disease and precise targeting of treatments to the biological state of the developing brain as a function of developmental changes in gene expression and neural circuit maturation.

publication date

  • April 19, 2016



  • Academic Article



  • eng

PubMed Central ID

  • PMC4843434

Digital Object Identifier (DOI)

  • 10.1073/pnas.1600013113

PubMed ID

  • 27001846

Additional Document Info

start page

  • 4500

end page

  • 5


  • 113


  • 16