Contributions of the mitogen-activated protein kinase and protein kinase C cascades in spatial learning and memory mediated by the nucleus accumbens.

Several studies have reported a role for the nucleus accumbens (NAcc) in learning and memory. Specifically, NAcc seems to function as a neural bridge for the translation of corticolimbic information to the motor system mediating locomotor learning, but the signaling mechanisms involved in this striatal learning await further investigation. The present experiments investigated the role of the mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) cascades within the NAcc of Long-Evans rats in a food-search spatial learning task (FSSLT). First, we used immunoblotting to examine changes in MAPK p42/p44 phosphorylation within the NAcc in the acquisition phase of the FSSLT. Second, we examined the effect on the acquisition and retention phases in the FSSLT of pretraining intra-accumbal microinjections of the MAPK [U0126; 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene, 1 microg/side] or PKC [GF109203X; bisindolylmaleimide or 1-(3-dimethylaminopropyl)-indol-3-yl]-3-(indol-3-yl) maleimide, 0.5 ng/side] inhibitors (four training sessions; one session/day). Third, the potential coupling of PKC and MAPK signaling pathways in the NAcc in spatial learning was studied using microinjections of GF109203X, radioactive activity assays, and immunoblotting. Results showed that 1) MAPK p42/p44 phosphorylation is augmented within the NAcc after spatial learning, 2) MAPK and PKC inhibition caused differential deficits in the acquisition and formation of spatial memories, and 3) inhibition of PKC activity by GF109203X caused a reduction in MAPKs phosphorylation in the NAcc in an early stage of the acquisition phase. Overall, these findings suggest that NAcc-PKC and -MAPK play important roles in spatial learning and that MAPKs phosphorylation seems to be mediated through the activation of the PKC signaling pathway.

Spatial learning in rats is impaired by microinfusions of protein kinase C-gamma antisense oligodeoxynucleotide within the nucleus accumbens.

The nucleus accumbens (NAcc) has been shown to play a role in motor and spatial learning. Protein kinase C (PKC) has been implicated in the mechanisms of initiation and maintenance of long-term potentiation that is thought to be involved in the storage of long-term memory. In the present study, the importance of de novo synthesis of PKC-gamma within the NAcc in the acquisition and retention of spatial discrimination learning was assessed using an antisense knockdown approach. Separate groups of Long-Evans rats were exposed to acute microinfusions (6microg/microl) of PKC-gamma antisense oligodeoxynucleotide (AS-ODN), control oligodeoxynucleotide (C-ODN) or vehicle into the NAcc at 24 and 3h before each training session. Behavioral findings showed that the blockade of NAcc-PKC-gamma translation caused impairments in the early phase of learning and retention of spatial information. Biochemical experiments showed that PKC-gamma expression was reduced and Ca(2+)/phospholipid-dependent protein kinase C (PKC) activity was blocked significantly in the AS-ODN-treated rats in comparison with control rats. The present findings suggest that NAcc-PKC-gamma plays a role during the early acquisition of spatial learning. Also, retention test results suggest that NAcc-PKC-gamma may be working as an intermediate factor involved in the onset of molecular mechanisms necessary for spatial memory consolidation within the NAcc.