title: Orbitofrontal Neuroadaptations and Cross-Species Synaptic Biomarkers in Heavy-Drinking Macaques.
abstract: Cognitive impairments, uncontrolled drinking, and neuropathological cortical changes characterize alcohol use disorder. Dysfunction of the orbitofrontal cortex (OFC), a critical cortical subregion that controls learning, decision-making, and prediction of reward outcomes, contributes to executive cognitive function deficits in alcoholic individuals. Electrophysiological and quantitative synaptomics techniques were used to test the hypothesis that heavy drinking produces neuroadaptations in the macaque OFC. Integrative bioinformatics and reverse genetic approaches were used to identify and validate synaptic proteins with novel links to heavy drinking in BXD mice. In drinking monkeys, evoked firing of OFC pyramidal neurons was reduced, whereas the amplitude and frequency of postsynaptic currents were enhanced compared with controls. Bath application of alcohol reduced evoked firing in neurons from control monkeys, but not drinking monkeys. Profiling of the OFC synaptome identified alcohol-sensitive proteins that control glutamate release (e.g., SV2A, synaptogyrin-1) and postsynaptic signaling (e.g., GluA1, PRRT2) with no changes in synaptic GABAergic proteins. Western blot analysis confirmed the increase in GluA1 expression in drinking monkeys. An exploratory analysis of the OFC synaptome found cross-species genetic links to alcohol intake in discrete proteins (e.g., C2CD2L, DIRAS2) that discriminated between low- and heavy-drinking monkeys. Validation studies revealed that BXD mouse strains with theDallele at theC2cd2linterval drank less alcohol thanBallele strains. Thus, by profiling of the OFC synaptome, we identified changes in proteins controlling glutamate release and postsynaptic signaling and discovered several proteins related to heavy drinking that have potential as novel targets for treating alcohol use disorder.SIGNIFICANCE STATEMENTClinical research identified cognitive deficits in alcoholic individuals as a risk factor for relapse, and alcoholic individuals display deficits on cognitive tasks that are dependent upon the orbitofrontal cortex (OFC). To identify neurobiological mechanisms that underpin OFC dysfunction, this study used electrophysiology and integrative synaptomics in a translational nonhuman primate model of heavy alcohol consumption. We found adaptations in synaptic proteins that control glutamatergic signaling in chronically drinking monkeys. Our functional genomic exploratory analyses identified proteins with genetic links to alcohol and cocaine intake across mice, monkeys, and humans. Future work is necessary to determine whether targeting these novel targets reduces excessive and harmful levels of alcohol drinking.
authors.affiliation: Departments of Neuroscience.
authors.forename: Sudarat
authors.identifier: 0000-0003-2379-5187
authors.initials: S
authors.lastname: Nimitvilai
authors.affiliation: Cell and Molecular Pharmacology, and.
authors.forename: Joachim D
authors.initials: JD
authors.lastname: Uys
authors.affiliation: Departments of Neuroscience.|Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: John J
authors.initials: JJ
authors.lastname: Woodward
authors.affiliation: Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Randall
authors.affiliation: Cell and Molecular Pharmacology, and.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Ball
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38120, and.
authors.forename: Robert W
authors.identifier: 0000-0001-8924-4447
authors.initials: RW
authors.lastname: Williams
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38120, and.
authors.forename: Byron C
authors.identifier: 0000-0002-4985-6729
authors.initials: BC
authors.lastname: Jones
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38120, and.
authors.forename: Lu
authors.identifier: 0000-0002-6174-3209
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon 97239.
authors.forename: Kathleen A
authors.identifier: 0000-0002-0380-7219
authors.initials: KA
authors.lastname: Grant
authors.affiliation: Departments of Neuroscience, mulholl@musc.edu.|Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Mulholland
mesh_terms: D000222:Adaptation, Physiological; D000437:Alcoholism / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D013569:Synapses / Q000378:metabolism* / Q000473:pathology
chemical_list: D015415:Biomarkers; D009419:Nerve Tissue Proteins
keywords: alcohol; electrophysiology; genetics; orbitofrontal cortex; proteomics