title: Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections.
abstract: Glutamatergic projections from the medial prefrontal cortex (mPFC) to nucleus accumbens (NAc) contribute to cocaine relapse. Here we show that silent synapse-based remodeling of the two major mPFC-to-NAc projections differentially regulated the progressive increase in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving). Specifically, cocaine self-administration in rats generated AMPA receptor-silent glutamatergic synapses within both infralimbic (IL) and prelimbic mPFC (PrL) to NAc projections, measured after 1 day of withdrawal. After 45 days of withdrawal, IL-to-NAc silent synapses became unsilenced/matured by recruiting calcium-permeable (CP) AMPARs, whereas PrL-to-NAc silent synapses matured by recruiting non-CP-AMPARs, resulting in differential remodeling of these projections. Optogenetic reversal of silent synapse-based remodeling of IL-to-NAc and PrL-to-NAc projections potentiated and inhibited, respectively, incubation of cocaine craving on withdrawal day 45. Thus, pro- and antirelapse circuitry remodeling is induced in parallel after cocaine self-administration. These results may provide substrates for utilizing endogenous antirelapse mechanisms to reduce cocaine relapse.
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Yao-Ying
authors.initials: YY
authors.lastname: Ma
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98103, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Xiusong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Changyong
authors.initials: C
authors.lastname: Guo
authors.affiliation: School of Life Science, Northeastern Normal University, Jilin, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: School of Life Science, Northeastern Normal University, Jilin, China.
authors.forename: Ranji
authors.initials: R
authors.lastname: Cui
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lan
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Judith J
authors.initials: JJ
authors.lastname: Balcita-Pedicino
authors.affiliation: Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Marina E
authors.initials: ME
authors.lastname: Wolf
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Sesack
authors.affiliation: Behavioral Neuroscience Branch, Intramural Research Program, NIDA, NIH, Baltimore, MD 21224, USA.
authors.forename: Yavin
authors.initials: Y
authors.lastname: Shaham
authors.affiliation: Molecular Neurobiology and Cluster of Excellence "Nanoscale Microscopy and Molecular Physiology of the Brain," European Neuroscience Institute, 37077 Göttingen, Germany.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Schlüter
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address: huangy3@upmc.edu.
authors.forename: Yanhua H
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address: yandong@pitt.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
mesh_terms: D000818:Animals; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D066249:Craving / Q000502:physiology*; D058999:Drug-Seeking Behavior / Q000502:physiology; D004594:Electrophysiology; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology*; D062308:Optogenetics; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects / Q000502:physiology*