, 2006). Thus, when dopamine level is low, such as when bursting activities are insufficient, it fails to produce and reinforce these networks’ connectivity underlying habit formation. Other than the striatum, reduced bursting of DA neurons may also affect activities of structures such as the PFC of which lesion of the medial infralimbic area was reported to impair expression

of a learned habit (Coutureau and Killcross, 2003). Studies have shown that tonic dopamine KPT330 concentration in the prefrontal area, likely due to the relatively slower dopamine reuptake (Seamans and Yang, 2004), may be affected by previous phasic dopamine release (Matsuda et al., 2006). The presence of background dopamine signal converts LTD to potentiation. This “priming” requires time to develop and requires D1 and D2 receptors, both of which have low affinity to dopamine. It is very likely that this phasic release-induced “priming” could also be affected by the amount of DA neurons bursting, thus, by blunting of DA response. It will be of great interest to dissect the various roles of those different brain regions in habit formation in future studies. It is also important for future research to further analyze the contributions of NMDARs within different dopamine subpopulations, BMS 907351 and temporally within

different phases of habit learning. The potential subregional circuitry within the DA neuron populations in the VTA and SNr regions can be highly crucial for integrating distinct cortical and subcortical inputs (Grace et al., 2007, Lammel et al., 2011 and Lisman and Grace, 2005). Thus, it is conceivable that additional subregional-specific manipulations and analyses could further elucidate

how the glutamatergic regulation of DA neurons, as revealed by our current study, modulates habit formation. In summary our study has provided several important insights about NMDAR in DA neurons and habit learning. First, NMDARs in DA neurons Oxygenase are required for learning habits, including appetitive lever pressing and spatial navigational habits. Second, the dependence of habit learning on NMDARs in DA neurons was observed in both positively and negatively reinforced trainings. Third, DA neurons lacking the NMDARs can still form the cue-reward association but with greatly reduced phasic activity as well as conditioned response robustness. Taken together, our results suggest that the NMDARs in DA neurons are an important modulator of DA neurons’ response robustness in cue-reward association and an essential element underpinning habit learning. Mice carrying alleles of NMDAR1 flanked by loxP sites (fNR1) were bred with Slc63a Cre transgenic mice. Offspring were genotyped by PCR for both the Cre transgene and for the floxed NMDAR1 (fNR1) locus.