title: COMT Genetic Reduction Produces Sexually Divergent Effects on Cortical Anatomy and Working Memory in Mice and Humans.
abstract: Genetic variations in catechol-O-methyltransferase (COMT) that modulate cortical dopamine have been associated with pleiotropic behavioral effects in humans and mice. Recent data suggest that some of these effects may vary among sexes. However, the specific brain substrates underlying COMT sexual dimorphisms remain unknown. Here, we report that genetically driven reduction in COMT enzyme activity increased cortical thickness in the prefrontal cortex (PFC) and postero-parieto-temporal cortex of male, but not female adult mice and humans. Dichotomous changes in PFC cytoarchitecture were also observed: reduced COMT increased a measure of neuronal density in males, while reducing it in female mice. Consistent with the neuroanatomical findings, COMT-dependent sex-specific morphological brain changes were paralleled by divergent effects on PFC-dependent working memory in both mice and humans. These findings emphasize a specific sex-gene interaction that can modulate brain morphological substrates with influence on behavioral outcomes in healthy subjects and, potentially, in neuropsychiatric populations.
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Sannino
authors.affiliation: Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Science @UNITN, 38068, Rovereto, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gozzi
authors.affiliation: IBFM Institute of Bioimaging and Molecular Physiology, National Research Council (CNR), 88100, Germaneto (CZ), Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cerasa
authors.affiliation: IRCCS Santa Lucia Foundation, 00142, Rome, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Piras
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Scheggia
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Managò
authors.affiliation: Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Science @UNITN, 38068, Rovereto, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Damiano
authors.affiliation: Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Science @UNITN, 38068, Rovereto, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Galbusera
authors.affiliation: NIMH, NIH, 20892, Bethesda, MD, USA.
authors.forename: Lucy C
authors.initials: LC
authors.lastname: Erickson
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: De Pietri Tonelli
authors.affiliation: Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Science @UNITN, 38068, Rovereto, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Bifone
authors.affiliation: IMT Institute for Advanced Studies, 55100, Lucca, Italy.
authors.forename: Sotirios A
authors.initials: SA
authors.lastname: Tsaftaris
authors.affiliation: IRCCS Santa Lucia Foundation, 00142, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Caltagirone
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, 21205, Baltimore, MD, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: IRCCS Santa Lucia Foundation, 00142, Rome, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Spalletta
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy Dipartimento di Scienze del Farmaco, Università Degli Studi di Padova, 35131 Padova, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Papaleo
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D001245:Association Learning / Q000502:physiology; D001931:Brain Mapping; D002394:Catechol O-Methyltransferase / Q000172:deficiency / Q000235:genetics*; D002540:Cerebral Cortex / Q000033:anatomy & histology* / Q000166:cytology; D005260:Female; D005838:Genotype; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018782:Maze Learning; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012727:Sex Characteristics; D055815:Young Adult
chemical_list: C000624101:Cux1 protein, mouse; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D002394:Catechol O-Methyltransferase; D010751:Phosphopyruvate Hydratase
keywords: cognition; cortical thickness; dopamine; postero-parietal cortex; prefrontal cortex