Instead, our data showed that there are specific projections from S1 and motor cortices (M1 and M2) to SNc dopamine neurons. Whether the neocortex directly projects to the SNc, and where in the cortex these inputs originate, have received less attention partly due to inconsistent results in previous studies (Bunney and Aghajanian, 1976; Graybiel and Ragsdale, 1979; Naito and Kita, 1994; Zahm et al., 2011).

Although the role of somatosensory and motor inputs in dopamine regulation has not been fully explored previously, somatosensation constitutes an important component of rewarding and noxious stimuli. Furthermore, dopamine neurons increase their firing Epigenetics Compound Library mw when an animal initiates reward-oriented behavior (Jin and Costa, 2010). Given that these cortical inputs are most likely excitatory, they may play a role in short-latency activation of SNc dopamine neurons in response to stimuli predicting salient events or the salient stimulus itself. We also found that the STh provides specific

and relatively strong inputs to SNc dopamine neurons. Previous studies found only sparse projections from the STh to the SNc using anterograde tracers (Groenewegen and Berendse, 1990; Kita and Kitai, 1987; Smith et al., 1990). One possible reason for this discrepancy is that dopamine ATM/ATR phosphorylation neurons receive STh inputs at their dendrites that elongate into SNr. STh neurons respond to various motor events and rewards as well as a sudden change in the environment (Isoda and Hikosaka, 2008; Matsumura et al., 1992). Anatomically, STh constitutes the “hyperdirect pathway” as well as the “indirect” pathway of the corticobasal ganglia loops (Nambu et al., 2002) (Figure 8C). The former term emphasizes the high conduction velocity of this pathway. On the other hand, the LH is a major input for VTA dopamine neurons. LH neurons are known to process reward information (Ono et al., Liothyronine Sodium 1986), and these responses are modulated by internal states of the animal such as hunger (Burton et al., 1976), indicating that LH responses reflect subjective

values. Our results together with previous findings raise the possibility that STh and LH provide contrasting excitatory inputs encoding saliency- and value-related information, respectively. The striatum has received much attention as an important input to dopamine neurons. For example, various computational models of reinforcement learning posit an important role for direct projections of striatal neurons to dopamine neurons in calculating reward prediction error (Doya, 1999; Houk et al., 1996; Joel et al., 2002; Suri, 2002). Recent studies have indicated, however, that direct projections from striatal neurons to dopamine neurons are weak or nonexistent (Chuhma et al., 2011; Xia et al., 2011).