title: Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species.
abstract: 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.
authors.affiliation: Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065; Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
authors.forename: Dylan G
authors.initials: DG
authors.lastname: Gee
authors.affiliation: Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065;
authors.forename: Robert N
authors.initials: RN
authors.lastname: Fetcho
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
authors.forename: Deqiang
authors.initials: D
authors.lastname: Jing
authors.affiliation: Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065;
authors.forename: Anfei
authors.initials: A
authors.lastname: Li
authors.affiliation: Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065; Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
authors.forename: Charles E
authors.initials: CE
authors.lastname: Glatt
authors.affiliation: Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065;
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Drysdale
authors.affiliation: Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065; Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
authors.forename: Alexandra O
authors.initials: AO
authors.lastname: Cohen
authors.affiliation: Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065; Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
authors.forename: Danielle V
authors.initials: DV
authors.lastname: Dellarco
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
authors.forename: Rui R
authors.initials: RR
authors.lastname: Yang
authors.affiliation: Departments of Neurosciences, Radiology, and Psychiatry, University of California, San Diego, CA 92093; Department of Cognitive Science, University of California, San Diego, CA 92093;
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
authors.affiliation: Department of Cognitive Science, University of California, San Diego, CA 92093;
authors.forename: Terry L
authors.initials: TL
authors.lastname: Jernigan
authors.affiliation: Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065; Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065; Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10065 fslee@med.cornell.edu bjc2002@med.cornell.edu.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Lee
authors.affiliation: Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065; Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065; fslee@med.cornell.edu bjc2002@med.cornell.edu.
authors.forename: B J
authors.initials: BJ
authors.lastname: Casey
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D063388:Endocannabinoids / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D065726:Limbic Lobe / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009415:Nerve Net / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013045:Species Specificity
chemical_list: D063388:Endocannabinoids
keywords: FAAH; anxiety; cross-species; frontolimbic; gene × development