, 1998; van Duuren et al., mTOR inhibitor 2007a). We show

that NMDARs affect discriminatory coding of OFC neurons especially during stimulus presentation and decision making and shape plasticity of discriminatory firing across learning trials. NMDAR blockade leads to hypersynchronous phase locking in the theta, beta, and high-frequency bands and destroys the functional relationship between theta-band phase-locking and discriminative power by virtue of firing rate. Unilateral blockade of NMDA receptors does not affect behavioral performance during task acquisition but hampers changes in reaction time after reversal of task contingencies. We recorded 623 isolated single units from four rats in 20 counterbalanced sessions (number of sessions for drug/control = 10/10) using a modified microdrive that held 12 tetrodes arranged concentrically around a microdialysis probe (Figure 1). Histological verification indicated

that most recordings were from ventral and lateral orbitofrontal (VO/LO) and agranular insular (AI) cortex with some spread into dorsolateral orbitofrontal (DLO) cortex (Figure 1A). For each rat, recordings were obtained under both drug and control conditions. However, within a single session, only one condition was applied. In drug sessions, we used continuous reverse microdialysis to apply a 0.5 mM ATM/ATR inhibitor clinical trial solution of D-2-amino-5-phosphonopentanoate (D-AP5), a competitive NMDAR blocker, dissolved in aCSF. old A separate autoradiography experiment with 3H-D-AP5 confirmed that the concentration of D-AP5 in OFC was sufficient to antagonize NMDARs (Figures 1B and 1C). Infusions were done unilaterally to minimize the chance

of inducing behavioral effects, which could confound the interpretation of electrophysiological results if present. Rats performed a two-odor, go/no-go discrimination task, with novel odor-outcome associations for each session (Figures 2A and 2B; Schoenbaum et al., 1998; van Duuren et al., 2007a; van Wingerden et al., 2010a, 2010b). Task acquisition was manifested by the emergence of “No-go” and “Go” responses to the odors predicting a negative (S− condition; “correct rejections”) and positive outcome (S+ condition; “hits”), respectively. The acquisition phase of the task was terminated when rats reached a behavioral criterion (85% correct trials, i.e., hits + correct rejections, in a moving 20-trial block), after which a reversal phase followed, in which the previously presented stimulus-outcome pairings were switched. We first examined overall task performance, defined as the average number of trials to reach criterion, normalized per rat to the average number of trials to criterion for all drug and control sessions for that rat. Overall performance did not differ between control and drug sessions (mean ± SEM; control: 103% ± 8.6%, drug: 96.7% ± 9.6%, two-sided t test n.s.; Figure 2C). Reaction time (RT), i.e.