, 2009). Previous research found evidence from place learning studies suggesting that changes in stimulus-outcome associations can cause acetycholine release in

the anterior DMS ( Brown et al., 2010). It is not known, however, what processes mediate new learning after changes in the action-outcome contingency; the role that striatal cholinergic activity plays in new goal-directed learning; or, as goal-directed learning depends on the posterior DMS and not the anterior DMS ( Yin et al., 2005b), whether new learning also depends specifically on the pDMS. Given the role of acetylcholine in other brain regions in reducing interference of this kind, however, one possibility is that, rather than influencing initial action-outcome encoding, cholinergic activity in the pDMS functions MEK inhibitor cancer to integrate new with existing learning when instrumental contingencies change. In the face of cholinergic depletion, this account predicts, therefore, that initial learning should be intact but that any new learning induced by changes in the action-outcome contingency will interfere with that initial learning and

produce a loss of goal-directed control. Here we sought to assess this hypothesis by Tanespimycin clinical trial altering cholinergic activity in the pDMS both chronically, by disconnection of the thalamostriatal pathway, and acutely, using local pharmacological manipulations, and examining the effects of these treatments on (1) initial acquisition of specific action-outcome associations, (2) sensitivity to the selective degradation of those action-outcome contingencies, and (3) the rats’ ability to encode new action-outcome associations. Cholinergic interneurons (CINs) provide the main source of acetylcholine in the striatum (Bolam et al., 1984; Contant et al., 1996). Although they constitute only ∼3% of the neurons, they ramify extensively,

making cholinergic activity in the striatum among the highest in the brain (Sorimachi Digestive enzyme and Kataoka, 1975). Their activity can be influenced by a number of neuromodulators, most notably dopamine and acetylcholine itself (Calabresi et al., 1998; Threlfell and Cragg, 2011), although their activity is mostly determined by excitatory glutamatergic afferents arising in midline thalamic nuclei (Consolo et al., 1996a, 1996b; Lapper and Bolam, 1992). Prior tracing studies suggest that the region of midline thalamus containing the parafascicular thalamic nucleus (Pf) projects massively and extensively throughout all portions of the striatum (Deschênes et al., 1996; Groenewegen and Berendse, 1994). The specificity, however, of Pf afferents to the pDMS—the region we have previously shown to be critical for the acquisition of goal-directed learning in this species (Yin et al., 2005b)—has not been explicitly assessed.