Orbitofrontal neuroadaptations and cross-species synaptic biomarkers in heavy-drinking macaques

Sudarat Nimitvilai, Joachim D. Uys, John J. Woodward, Patrick K. Randall, Lauren E. Ball, Robert Williams, Byron Jones, Lu Lu, Kathleen A. Grant, Patrick J. Mulholland

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 the D allele at the C2cd2l interval drank less alcohol than B allele 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.

Original languageEnglish (US)
Pages (from-to)3646-3660
Number of pages15
JournalJournal of Neuroscience
Volume37
Issue number13
DOIs
StatePublished - Mar 29 2017

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Macaca
Drinking
Biomarkers
Prefrontal Cortex
Haplorhini
Alcohols
Proteins
Synaptogyrins
Glutamic Acid
Alleles
Genetic Crosses
Reverse Genetics
Synaptic Potentials
Pyramidal Cells
Validation Studies
Executive Function
Computational Biology
Baths
Reward
Cognition

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Nimitvilai, S., Uys, J. D., Woodward, J. J., Randall, P. K., Ball, L. E., Williams, R., ... Mulholland, P. J. (2017). Orbitofrontal neuroadaptations and cross-species synaptic biomarkers in heavy-drinking macaques. Journal of Neuroscience, 37(13), 3646-3660. https://doi.org/10.1523/JNEUROSCI.0133-17.2017

Orbitofrontal neuroadaptations and cross-species synaptic biomarkers in heavy-drinking macaques. / Nimitvilai, Sudarat; Uys, Joachim D.; Woodward, John J.; Randall, Patrick K.; Ball, Lauren E.; Williams, Robert; Jones, Byron; Lu, Lu; Grant, Kathleen A.; Mulholland, Patrick J.

In: Journal of Neuroscience, Vol. 37, No. 13, 29.03.2017, p. 3646-3660.

Research output: Contribution to journalArticle

Nimitvilai, S, Uys, JD, Woodward, JJ, Randall, PK, Ball, LE, Williams, R, Jones, B, Lu, L, Grant, KA & Mulholland, PJ 2017, 'Orbitofrontal neuroadaptations and cross-species synaptic biomarkers in heavy-drinking macaques', Journal of Neuroscience, vol. 37, no. 13, pp. 3646-3660. https://doi.org/10.1523/JNEUROSCI.0133-17.2017
Nimitvilai, Sudarat ; Uys, Joachim D. ; Woodward, John J. ; Randall, Patrick K. ; Ball, Lauren E. ; Williams, Robert ; Jones, Byron ; Lu, Lu ; Grant, Kathleen A. ; Mulholland, Patrick J. / Orbitofrontal neuroadaptations and cross-species synaptic biomarkers in heavy-drinking macaques. In: Journal of Neuroscience. 2017 ; Vol. 37, No. 13. pp. 3646-3660.
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