Skip to main content

Main menu

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
    • Front Matter Portal
    • Journal Club
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses
  • Submit
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Accessibility Statement
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Home
Home
  • Log in
  • My Cart

Advanced Search

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
    • Front Matter Portal
    • Journal Club
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses
  • Submit
Research Article

Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species

Dylan G. Gee, Robert N. Fetcho, Deqiang Jing, Anfei Li, Charles E. Glatt, Andrew T. Drysdale, Alexandra O. Cohen, Danielle V. Dellarco, Rui R. Yang, Anders M. Dale, Terry L. Jernigan, Francis S. Lee, B.J. Casey, and the PING Consortium
  1. aSackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065;
  2. bDepartment of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
  3. cDepartments of Neurosciences, Radiology, and Psychiatry, University of California, San Diego, CA 92093;
  4. dDepartment of Cognitive Science, University of California, San Diego, CA 92093;
  5. eDepartment of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10065

See allHide authors and affiliations

PNAS April 19, 2016 113 (16) 4500-4505; first published March 21, 2016; https://doi.org/10.1073/pnas.1600013113
Dylan G. Gee
aSackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065;
bDepartment of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert N. Fetcho
aSackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Deqiang Jing
bDepartment of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anfei Li
aSackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Charles E. Glatt
aSackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065;
bDepartment of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew T. Drysdale
aSackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alexandra O. Cohen
aSackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065;
bDepartment of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Danielle V. Dellarco
aSackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065;
bDepartment of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rui R. Yang
bDepartment of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anders M. Dale
cDepartments of Neurosciences, Radiology, and Psychiatry, University of California, San Diego, CA 92093;
dDepartment of Cognitive Science, University of California, San Diego, CA 92093;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Terry L. Jernigan
dDepartment of Cognitive Science, University of California, San Diego, CA 92093;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Francis S. Lee
aSackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065;
bDepartment of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
eDepartment of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10065
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: fslee@med.cornell.edu bjc2002@med.cornell.edu
B.J. Casey
aSackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, NY 10065;
bDepartment of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY 10065;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: fslee@med.cornell.edu bjc2002@med.cornell.edu
  1. Edited by Michael I. Posner, University of Oregon, Eugene, OR, and approved February 17, 2016 (received for review January 2, 2016)

  • Article
  • Figures & SI
  • Info & Metrics
  • PDF
Loading

Article Figures & SI

Figures

  • Tables
  • Fig. 1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 1.

    Developmental expression of components of the endocannabinoid system in the brain. Predicted relative concentrations (AEA) and enzymatic activities (FAAH) based on measurement in a rodent system (10). The endocannabinoid system peaks and then wanes in adolescence, which may contribute to changes in risk for anxiety during this developmental stage. FAAH and AEA fluctuate reciprocally across development. Early adolescence is marked by a decrease in FAAH and an increase in AEA levels, whereas FAAH levels increase and AEA levels decrease toward later adolescence (10, 33). CB1 receptor expression peaks with the onset of adolescence (8, 9, 32, 33). The predicted effects of FAAH C385A across development are presented as dotted lines. Adapted from ref. 4, with permission from Elsevier.

  • Fig. 2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 2.

    Phenotypic differences in frontolimbic circuitry resulting from FAAH polymorphism emerge during adolescence in human and mouse. (A, Left) Posthoc analyses revealed a significant genotypic effect on UF FA in participants 12 y of age and older [n = 509; 249 females; F(1,491) = 14.02; P = 0.0002] but not in those under 12 y of age [n = 541; 259 females; F(1,523) = 0.513; P = 0.474]. (A, Right) Mask in Montreal Neurological Institute standard space where UF ascends from the temporal lobe used as the seed region for probabilistic tractography in humans (upper left); UF tract mask is derived from probabilistic tractography averaged across human participants (n = 1,050). (B, Left) Consistent with the findings in humans, a significant genotype by age group interaction [F(2,36) = 58.72; P < 0.0001] in IL afferent fibers to BLA emerged, such that knock-in mice (AA: n = 7 per age) had higher fiber density than WT mice (CC: n = 7 per age) during adolescence at age P45 (P < 0.0001) and adulthood at P75 (P < 0.0001). (B, Right) Drawing of anatomical boundaries and anterograde tracer targeted to IL and labeling afferents in BLA. CeA, central amygdala; MeA, medial amygdala; PL, prelimbic; *P < 0.05.

  • Fig. S1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. S1.

    FAAH genotype by age interaction for FA in the UF. FA of the UF showed a significant increase with age [F(1,1,031) = 305.985; P < 2.2 × 1016; plotted as a function of age in A allele carriers (n = 420; 208 females) and C homozygotes (n = 630; 310 females)]. A significant age by genotype interaction [age by genotype interaction: F(1,1,031) = 5.893; P = 0.0154] revealed that the main effect of genotype [F(1,1,031) = 17.858; P = 2.59 × 10−5] emerged during adolescence.

  • Fig. S2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. S2.

    Trend for dose dependence association between FAAH genotype and frontolimbic circuitry emerging during adolescence. There was a trend toward a linear effect of number of A alleles on UF FA among participants 12 y of age and older [F(2,491) = 2.03; P = 0.154; AA: n = 41; 15 females; AC: n = 182; 90 females; CC: n = 286; 144 females]. However, there was no effect of number of A alleles on UF FA among participants under 12 y of age [F(2,523) = 1.92; P = 0.167; AA: n = 29; 11 females; AC: n = 168; 92 females; CC: n = 344; 166 females]. Data are presented as means ± SEMs.

  • Fig. S3.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. S3.

    No FAAH genotype by age group interaction for FA in the corticospinal tract. (A) Mask in Montreal Neurological Institute standard space of bilateral internal capsules to serve as the seed region for probabilistic tractography. (B) Corticospinal tract mask derived from probabilistic tractography averaged across human participants (n = 1,050). (C) There was a significant effect of age on FA in the corticospinal tract [F(1,1,031) = 531.616; P = 2.0 × 10−16]. However, there was no main effect of genotype [F(1,1,031) = 2.699; P = 0.101] or age by genotype interaction [F(1,1,031) = 0.009; P = 0.927], suggesting specificity of the developmental effects of the FAAH genotype on frontolimbic circuitry. Data are presented as means ± SEMs.

  • Fig. 3.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 3.

    Phenotypic differences in anxiety resulting from FAAH polymorphism emerge during adolescence in human and mouse. (A) A significant gene by development interaction [F(1,198) = 6.2269; P = 0.0134] on anxiety revealed that A allele carriers (n = 54; 19 females) had lower anxiety than C homozygotes (n = 63; 30 females) during adolescence [F(1,102) = 8.96; P = 0.00346] but not during childhood [F(1,83) = 3.82; P = 0.054; A allele carriers: n = 32; 21 females; C homozygotes: n = 65; 28 females]. These findings parallel the adolescent emergence of stronger frontolimbic connectivity among A allele carriers. (B) Consistent with the finding in humans, a significant genotype by age group interaction [F(1,45) = 4.922; P = 0.0316] revealed that FAAHA/A mice (P23: n = 9; P45: n = 9; P65–P75: n = 10) showed less anxiety-like behavior than FAAHC/C mice (P23: n = 6; P45: n = 8; P65–P75: n = 7) during adolescence and adulthood, but not during childhood, as measured by percentage of time spent in the open arms of the EPM. *P < 0.05.

  • Fig. S4.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. S4.

    No FAAH genotype by age group interaction for total distance traveled in the EPM. Despite a genotype by age group interaction for percentage of time spent in the open arms, there was no genotype by age group interaction for total distance traveled in the EPM [F(1,45) = 2.59; P = 0.114]. Data are presented as means ± SEMs.

  • Fig. 4.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 4.

    Developmentally informed vertically integrated translational approach to genetic variation and treatment targets across development. We have used developmentally informed parallel human and mouse studies to identify the relevance and impact of the FAAH C385A polymorphism on brain biochemistry, neurocircuitry, behavior, and symptoms (i.e., vertical integration across multiple levels of analysis) during development and identified a previously unidentified gene by development interaction.

  • Fig. S5.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. S5.

    PHA-L injections in IL cortex of mice. (A) Representative site of IL injection of PHA-L; PHA-L–like positive neurons and neuropil deposits are well-defined in IL, and PHA-L–like immunoreactive positive neurons (red) are counterstained with DAPI. This assessment of injection accuracy was carried out for all seven mice per genotype per age, and all of the injections were within the IL and did not overlap with neighboring regions, such as the prelimbic prefrontal cortex. (B) Bar graph showing numbers of PHA-L–positive cell bodies in IL in different genotypes and ages based on stereological estimation of cell density using the fractionator estimation method. There were no main effects of age [F(1,36) = 0.0273; P = 0.789] or genotype [F(2,36) = 0.453; P = 0.639] and no age by genotype interaction [F(2,36) = 0.309; P = 0.736]. Data are presented as means ± SEMs.

  • Fig. S6.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. S6.

    Dose-dependent association between FAAH genotype and anxiety during adolescence. There was a linear effect of number of A alleles on anxiety among participants 12 y of age and older [F(2,102) = 4.37; P = 0.031; AA: n = 10; 4 females; AC: n = 44; 15 females; CC: n = 63; 30 females]. However, there was no linear effect of number of A alleles on anxiety among participants under 12 y of age [F(2,83) = 0.554; P = 0.459; AA: n = 6; 4 females; AC: n = 26; 17 females; CC: n = 65; 28 females]. Data are presented as means ± SEMs.

Tables

  • Figures
    • View popup
    Table S1.

    Diffusion tensor imaging sample (n = 1,050): Demographic characteristics by genotype

    CharacteristicsUnder 12 y of age12 y of Age and older
    CCACAACCACAA
    n3441682928618241
    Mean age, y (SD)*8.14 (2.27)8.01 (2.39)8.45 (2.53)16.51 (2.64)16.17 (2.55)16.22 (2.49)
    Sex, female/male†166/17892/7611/18144/14290/9215/26
    • ↵* Age did not differ by genotype within the group under 12 y of age [F(2,540) = 0.493; P = 0.611] or 12 y of age and older [F(2,508) = 1.023; P = 0.360].

    • ↵† Sex did not differ by genotype within the group under 12 y of age [χ2(2) = 3.62; P = 0.164] or 12 y of age or older [χ2(2) =2.75; P = 0.253].

    • View popup
    Table S2.

    Anxiety subsample (n = 214): Demographic characteristics and anxiety self-report by genotype

    CharacteristicsUnder 12 y of age12 y of Age and older
    CCACAACCACAA
    n65266634410
    Mean age, y (SD)*10.0 (0.99)9.96 (0.85)9.50 (1.31)14.83 (1.46)14.79 (1.73)15.80 (1.79)
    Sex, female/male†28/3717/94/230/3315/294/6
    Mean anxiety (SD)0.384 (0.25)0.512 (0.24)0.375 (0.15)0.479 (0.23)0.358 (0.27)0.294 (0.21)
    • ↵* Age did not differ by genotype within the group under 12 y of age [F(2,96) = 0.722; P = 0.488] or 12 y of age and older [F(2,116) = 1.759; P = 0.177].

    • ↵† Sex did not differ by genotype within the group under 12 y of age [χ2(2) = 4.36; P = 0.113] or 12 y of age or older [χ2(2) = 1.96; P = 0.375].

    • View popup
    Table S3.

    Coordinates for IL injections

    AgeAP (mm)ML (mm)DV (mm)
    P231.600.352.30
    P451.700.402.50
    P751.700.402.50
    • AP, anterior–posterior; DV, dorsal–ventral; ML, medial–lateral.

Data supplements

  • Supporting Information

    • Download Supporting Information (PDF)
PreviousNext
Back to top
Article Alerts
Email Article

Thank you for your interest in spreading the word on PNAS.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species
(Your Name) has sent you a message from PNAS
(Your Name) thought you would like to see the PNAS web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Variation in frontolimbic development and anxiety
Dylan G. Gee, Robert N. Fetcho, Deqiang Jing, Anfei Li, Charles E. Glatt, Andrew T. Drysdale, Alexandra O. Cohen, Danielle V. Dellarco, Rui R. Yang, Anders M. Dale, Terry L. Jernigan, Francis S. Lee, B.J. Casey, the PING Consortium
Proceedings of the National Academy of Sciences Apr 2016, 113 (16) 4500-4505; DOI: 10.1073/pnas.1600013113

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Variation in frontolimbic development and anxiety
Dylan G. Gee, Robert N. Fetcho, Deqiang Jing, Anfei Li, Charles E. Glatt, Andrew T. Drysdale, Alexandra O. Cohen, Danielle V. Dellarco, Rui R. Yang, Anders M. Dale, Terry L. Jernigan, Francis S. Lee, B.J. Casey, the PING Consortium
Proceedings of the National Academy of Sciences Apr 2016, 113 (16) 4500-4505; DOI: 10.1073/pnas.1600013113
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Mendeley logo Mendeley

Article Classifications

  • Biological Sciences
  • Neuroscience
  • Social Sciences
  • Psychological and Cognitive Sciences
Proceedings of the National Academy of Sciences: 113 (16)
Table of Contents

Submit

Sign up for Article Alerts

Jump to section

  • Article
    • Abstract
    • Results
    • Discussion
    • Conclusions
    • Methods
    • SI Methods
    • PING Consortium
    • Acknowledgments
    • Footnotes
    • References
  • Figures & SI
  • Info & Metrics
  • PDF

You May Also be Interested in

Setting sun over a sun-baked dirt landscape
Core Concept: Popular integrated assessment climate policy models have key caveats
Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Model of the Amazon forest
News Feature: A sea in the Amazon
Did the Caribbean sweep into the western Amazon millions of years ago, shaping the region’s rich biodiversity?
Image credit: Tacio Cordeiro Bicudo (University of São Paulo, São Paulo, Brazil), Victor Sacek (University of São Paulo, São Paulo, Brazil), and Lucy Reading-Ikkanda (artist).
Syrian archaeological site
Journal Club: In Mesopotamia, early cities may have faltered before climate-driven collapse
Settlements 4,200 years ago may have suffered from overpopulation before drought and lower temperatures ultimately made them unsustainable.
Image credit: Andrea Ricci.
Steamboat Geyser eruption.
Eruption of Steamboat Geyser
Mara Reed and Michael Manga explore why Yellowstone's Steamboat Geyser resumed erupting in 2018.
Listen
Past PodcastsSubscribe
Birds nestling on tree branches
Parent–offspring conflict in songbird fledging
Some songbird parents might improve their own fitness by manipulating their offspring into leaving the nest early, at the cost of fledgling survival, a study finds.
Image credit: Gil Eckrich (photographer).

Similar Articles

Site Logo
Powered by HighWire
  • Submit Manuscript
  • Twitter
  • Facebook
  • RSS Feeds
  • Email Alerts

Articles

  • Current Issue
  • Special Feature Articles – Most Recent
  • List of Issues

PNAS Portals

  • Anthropology
  • Chemistry
  • Classics
  • Front Matter
  • Physics
  • Sustainability Science
  • Teaching Resources

Information

  • Authors
  • Editorial Board
  • Reviewers
  • Subscribers
  • Librarians
  • Press
  • Site Map
  • PNAS Updates
  • FAQs
  • Accessibility Statement
  • Rights & Permissions
  • About
  • Contact

Feedback    Privacy/Legal

Copyright © 2021 National Academy of Sciences. Online ISSN 1091-6490