, 1996 and Dias et al.,

1997; Ragozzino et al., 1999; Chudasama et al., 2003; Floresco et al., 2008; Aron, 2011; Dalley et al., 2011). In rats, local injections of SCH23390 in the medial PFC, an area that resembles the monkey lateral PFC in connectivity and function, increased perseveration to the previously learned strategy this website (Ragozzino, 2002), similar to our finding of a moderate but significant increase in perseverative errors. The reduction in neural selectivity induced by SCH23390 was more pronounced for novel than familiar associations in single neurons. This suggests that the synapses that modify with new learning are modulated by D1Rs and are separate from those involved in encoding of familiar associations. This supports recent in vitro work suggesting that long-term potentiation (LTP), a cellular mechanism of synaptic plasticity thought to be critical for learning and memory consolidation, is D1R dependent (Xu and Yao, 2010). D1Rs may modulate reward-dependent plasticity of corticostriatal synapses. Increases of dopamine release may strengthen the efficacy of corticostriatal synapses after reward, while dopamine decreases may weaken synapses for nonreward (Hikosaka et al., 2006; Hong and Hikosaka, 2011). Our results suggest this may also occur in the PFC, because

during D1R blockade, neurons failed to achieve the see more learning-induced level of selectivity seen for familiar associations (as they do without blockade). Without the influence of D1Rs, there might be no potentiation of the synaptic strength necessary for learning, and behavior might then be captured by non-D1R plasticity mechanisms that strengthen the most recently activated pathways, resulting in increased perseveration. During familiar associations, synaptic strength might be already potentiated and thus less dependent on D1Rs. It is plausible that familiar associations are encoded in structures other than the PFC. However, the fact that neural selectivity (and PEV) during familiar associations is still partly reduced by the D1R antagonist supports the coexistence of D1R-sensitive and D1R-less-sensitive

sets of synapses on single prefrontal neurons. Neural selectivity and PEV the during washout periods did not return to the exact same state as the baseline before the drug was injected. Neural information returned but was more variable, and neurons continued to show elevated firing rates. It is likely that SCH23390 had lingering effects on neural activity that could have lasted hours. However, as our analyses demonstrate, in contrast to the drug period in which neural information about the associations was virtually gone from the PFC, there was a return of neural information during the washout period that could have supported behavioral performance. The decrease in neural selectivity seemed mostly due to an increase in activity to nonpreferred saccade directions.