In contrast, activation of MSNs associated with the direct pathway should decrease basal ganglia, output by directly suppressing activity at the level of GPi/SNr. Given the reentrant nature of basal ganglia-thalamocortical connections, cortically initiated activation of the direct pathway should therefore result, in positive feedback at cortical levels, due to thalamic disinhibition. Conversely, cortically initiated activation of the indirect pathway should have the opposite effect, due to the polarity-reversing effects of an intercalated stage of processing within GABAergic Inhibitors,research,lifescience,medical GPe. The direct, and indirect pathways differ sharply in their connections with the intralaminar thalamus. The basal ganglia output nuclei, GPi

and SNr, send GABAergic pallidothalamic and nigrothalamic projections to the centromedian (CM) and parafascicular (Pf) nuclei, respectively, as well as to the corresponding pallidal and nigral target zones in the ventrolateral or “motor” thalamus.264,274 Thalamostriatal projections from CM innervate the postcommissural (sensorimotor) putamen, while those from Pf are Inhibitors,research,lifescience,medical directed to the precommissural (associative) putamen, Inhibitors,research,lifescience,medical caudate sellectchem nucleus, and ventral striatum.261 The

projections from CM to putamen show considerable selectivity in their terminal ramifications. They both maintain strict topographical mappings that link corresponding thalamostriatal, striatopallidal, and pallidothalamic projection zones in CM, putamen, and GPi, respectively.261 Moreover, thalamostriatal axons of CM neurons terminate almost exclusively on the spines Inhibitors,research,lifescience,medical and dendrites of putaminal MSNs that project, to GPi, while avoiding those that project to GPe.253 The neuromodulatory effects of DA on the integrative activity of striatal MSNs differ considerably for the direct and indirect pathways, due to the dissimilar Inhibitors,research,lifescience,medical distributions of d1-like and d2-like receptors on the two types of MSNs.227,270 Multiple studies have shown that substance

Pcontaining, GPi/SNr-projecting striatal neurons of the direct, pathway express a preponderance of di-like receptors, while enkephalin-containing, GPe-projecting neurons of the indirect pathway express a higher proportion of d2like receptors227,275-277 despite variable degrees of colocalization of the two receptor types among a subset, of each of the two categories of striatal projection neurons.278 The direct- and indirect-projecting MSNs also differ with respect to their responses to ACh, due Batimastat to differences in the muscarinic receptors they express. Both types of MSNs express m1 receptors to comparable degrees.224 However, m4 receptors are expressed predominantly by the substance P-containing neurons of the direct pathway.279 Like the DA receptors, muscarinic receptors belong to the A family of seven-transmembrane receptors, and the G-protein to which the m4 receptor is coupled acts to decrease cAMP levels, making its ncuromodulatory effect, analogous to that of d2-like receptors.