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      FAAH genetic variation enhances fronto-amygdala function in mouse and human

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          Abstract

          Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. Here, we show that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemisty, neurocircuitry, and behavior. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviors. These results suggest a gain-of-function in fear regulation and may indicate for whom and for what anxiety symptoms FAAH inhibitors or exposure-based therapies will be most efficacious, bridging an important translational gap between the mouse and human.

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          Most cited references44

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          Emotional processing in anterior cingulate and medial prefrontal cortex.

          Negative emotional stimuli activate a broad network of brain regions, including the medial prefrontal (mPFC) and anterior cingulate (ACC) cortices. An early influential view dichotomized these regions into dorsal-caudal cognitive and ventral-rostral affective subdivisions. In this review, we examine a wealth of recent research on negative emotions in animals and humans, using the example of fear or anxiety, and conclude that, contrary to the traditional dichotomy, both subdivisions make key contributions to emotional processing. Specifically, dorsal-caudal regions of the ACC and mPFC are involved in appraisal and expression of negative emotion, whereas ventral-rostral portions of the ACC and mPFC have a regulatory role with respect to limbic regions involved in generating emotional responses. Moreover, this new framework is broadly consistent with emerging data on other negative and positive emotions. Published by Elsevier Ltd.
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            R: A Language and Environment for Statistical Computing.

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              Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear.

              Current models of conditioned fear expression and extinction involve the basolateral amygdala (BLA), ventral medial prefrontal cortex (vmPFC), and the hippocampus (HPC). There is some disagreement with respect to the specific roles of these structures, perhaps due to subregional differences within each area. For example, growing evidence suggests that infralimbic (IL) and prelimbic (PL) subregions of vmPFC have opposite influences on fear expression. Moreover, it is the ventral HPC (vHPC), rather than the dorsal HPC, that projects to vmPFC and BLA. To help determine regional specificity, we used small doses of the GABA(A) agonist muscimol to selectively inactivate IL, PL, BLA, or vHPC in an auditory fear conditioning and extinction paradigm. Infusions were performed prior to extinction training, allowing us to assess the effects on both fear expression and subsequent extinction memory. Inactivation of IL had no effect on fear expression, but impaired the within-session acquisition of extinction as well as extinction memory. In contrast, inactivation of PL impaired fear expression, but had no effect on extinction memory. Inactivation of the BLA or vHPC impaired both fear expression and extinction memory. Post-extinction inactivations had no effect in any structure. We suggest a model in which amygdala-dependent fear expression is modulated by inputs from PL and vHPC, whereas extinction memory requires extinction-induced plasticity in IL, BLA, and/or vHPC.
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                Author and article information

                Journal
                101528555
                37539
                Nat Commun
                Nat Commun
                Nature communications
                2041-1723
                25 February 2015
                03 March 2015
                2015
                03 September 2015
                : 6
                : 6395
                Affiliations
                [1 ]Department of Psychiatry, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
                [2 ]Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
                [3 ]Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
                [4 ]The Hotchkiss Brain Institute, Departments of Cell Biology and Anatomy & Psychiatry, University of Calgary, 3330 Hospital Drive NW, Calgary, AB Canada T2N4N1
                [5 ]inGenious Targeting Laboratory, 2200 Smithtown Avenue, Ronkonkoma, NY 11779, USA
                [6 ]Department of Chemical Physiology, The Scripps Research Institute, 10550N. Torrey Pines Rd., La Jolla, CA 92037, United States
                Author notes
                []Correspondence and requests for materials should be addressed to B.J.C. ( bjc2002@ 123456med.cornell.edu ) or F.S.L. ( fslee@ 123456med.cornell.edu )
                [*]

                These authors contributed equally to this work.

                Article
                NIHMS658410
                10.1038/ncomms7395
                4351757
                25731744
                0de877ff-efe4-49b4-9302-3730d0c8e1cc

                Reprints and permissions information is available at www.nature.com/reprints.

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