title: Cognitive impact of genetic variation of the serotonin transporter in primates is associated with differences in brain morphology rather than serotonin neurotransmission.
abstract: A powerful convergence of genetics, neuroimaging and epidemiological research has identified the biological pathways mediating individual differences in complex behavioral processes and the related risk for disease. Orthologous genetic variation in non-human primates (NHPs) represents a unique opportunity to characterize the detailed molecular and cellular mechanisms that bias behaviorally and clinically relevant brain function. We report that a rhesus macaque orthologue of a common polymorphism of the serotonin transporter gene (rh5-HTTLPR) has strikingly similar effects on behavior and brain morphology to those in humans. Specifically, the rh5-HTTLPR (S)hort allele broadly affects cognitive choice behavior and brain morphology without observably affecting the 5-hydroxytryptamine (5-HT) transporter or 5-HT(1A) concentrations in vivo. Collectively, our findings indicate that 5-HTTLPR-associated behavioral effects reflect genotype-dependent biases in cortical development rather than static differences in serotonergic signaling mechanisms. Moreover, these data highlight the vast potential of NHP models in advancing our understanding of human genetic variation affecting behavior and neuropsychiatric disease liability.
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: H P
authors.initials: HP
authors.lastname: Jedema
authors.forename: P J
authors.initials: PJ
authors.lastname: Gianaros
authors.forename: P J
authors.initials: PJ
authors.lastname: Greer
authors.forename: D D
authors.initials: DD
authors.lastname: Kerr
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: J D
authors.initials: JD
authors.lastname: Higley
authors.forename: S J
authors.initials: SJ
authors.lastname: Suomi
authors.forename: A S
authors.initials: AS
authors.lastname: Olsen
authors.forename: J N
authors.initials: JN
authors.lastname: Porter
authors.forename: B J
authors.initials: BJ
authors.lastname: Lopresti
authors.forename: A R
authors.initials: AR
authors.lastname: Hariri
authors.forename: C W
authors.initials: CW
authors.lastname: Bradberry
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D001596:Benzylamines / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects; D001931:Brain Mapping; D002247:Carbon Isotopes / Q000378:metabolism; D002755:Choice Behavior / Q000502:physiology*; D003071:Cognition / Q000502:physiology*; D005838:Genotype; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009483:Neuropsychological Tests; D010879:Piperazines / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011725:Pyridines / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics; D012701:Serotonin / Q000235:genetics / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D009435:Synaptic Transmission / Q000235:genetics*; D013997:Time Factors; D014316:Tritium / Q000378:metabolism
chemical_list: D001596:Benzylamines; D002247:Carbon Isotopes; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; D010879:Piperazines; D011725:Pyridines; D050486:Serotonin Plasma Membrane Transport Proteins; D014316:Tritium; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide