Cortical GluN2B deletion attenuates punished suppression of food reward-seeking
- 343 Downloads
Compulsive behavior, which is a hallmark of psychiatric disorders such as addiction and obsessive-compulsive disorder, engages corticostriatal circuits. Previous studies indicate a role for corticostriatal N-methyl-d-aspartate receptors (NMDARs) in mediating compulsive-like responding for drugs of abuse, but the specific receptor subunits controlling reward-seeking in the face of punishment remain unclear.
The current study assessed the involvement of corticostriatal GluN2B-containing NMDARs in measures of persistent and punished food reward-seeking.
Mice with genetic deletion of GluN2B in one of three distinct neuronal populations, cortical principal neurons, forebrain interneurons, or striatal medium spiny neurons, were tested for (1) sustained food reward-seeking when reward was absent, (2) reward-seeking under a progressive ratio schedule of reinforcement, and (3) persistent reward-seeking after a footshock punishment.
Mutant mice with genetic deletion of GluN2B in cortical principal neurons demonstrated attenuated suppression of reward-seeking during punishment. These mice performed normally on other behavioral measures, including an assay for pain sensitivity. Mutants with interneuronal or striatal GluN2B deletions were normal on all behavioral assays.
Current findings offer novel evidence that loss of GluN2B-containing NMDARs expressed on principal neurons in the cortex results in reduced punished food reward-seeking. These data support the involvement of GluN2B subunit in cortical circuits regulating cognitive flexibility in a variety of settings, with implications for understanding the basis of inflexible behavior in neuropsychiatric disorders including obsessive-compulsive disorders (OCD) and addictions.
KeywordsAddiction NMDA Prefrontal cortex Motivation Striatum Interneuron Alcohol Drug
We are grateful to Munisa Bachu, Shaun Flynn, and Adrina Kocharian for technical assistance and to Dr. Jonathan Brigman for the cartoons of the behavioral procedures. This research was supported by the NIAAA Intramural Research Program and NIMH grant K22MH099164.
- Brigman JL, Wright T, Talani G, Prasad-Mulcare S, Jinde S, Seabold GK, Mathur P, Davis MI, Bock R, Gustin RM (2010) Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J Neurosci 30:4590–4600PubMedCentralCrossRefPubMedGoogle Scholar
- Burgos-Robles A, Vidal-Gonzalez I, Santini E, Quirk GJ (2007) Consolidation of fear extinction requires NMDA receptor-dependent bursting in the ventromedial prefrontal cortex. Neuron 53(6):871–880Google Scholar
- Davies DA, Greba Q, Howland JG (2013) GluN2B-containing NMDA receptors and AMPA receptors in medial prefrontal cortex are necessary for odor span in rats. Front Behav Neurosci 7Google Scholar
- Hamilton DA, Brigman JL (2015) Behavioral flexibility in rats and mice: contributions of distinct frontocortical regions. Genes Brain BehavGoogle Scholar
- Pelloux Y, Murray JE, Everitt BJ (2013) Differential roles of the prefrontal cortical subregions and basolateral amygdala in compulsive cocaine seeking and relapse after voluntary abstinence in rats. Eur J NeurosciGoogle Scholar
- Seif T, Simms JA, Lei K, Wegner S, Bonci A, Messing RO, Hopf FW (2015) D-serine and D-cycloserine reduce compulsive alcohol intake in rats. NeuropsychopharmacologyGoogle Scholar
- Woodward JJ (2000) Ethanol and NMDA receptor signaling. Critical Reviews™ in Neurobiology 14Google Scholar