Genetic dissection of neural pathways for appetitive associative learning

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 DESCRIPTION (provided by applicant): Dopamine signaling has been implicated in many aspects of reward. Despite the vast literature on this important subject, it is still highly debate if and how regional and cell-type-specific dopamine signaling plays distinct roles in specific aspects of reward. Both dopamine D1 and D2 receptors are mainly coupled to the cAMP pathway in striatal medium spiny neurons (MSNs). Our studies in recent years indicate that dopamine signaling through cAMP is essential for corticostriatal plasticity. Moreover, the adenylyl cyclase type 5 (AC5) deficient (AC5KO) mice are severely impaired in appetitive associative learning. AC5 is the main adenylyl cyclase in the striatum and nucleus accumbens for dopamine-cAMP signaling. Identification of such a key molecule in appetitive associative learning provides a unique opportunity to perform precise manipulations and to rigorously test the necessity and sufficiency of regional and cell type specific dopamine signaling in specific aspects of appetitive associative learning. One of the most important issues in the field is that the conditioned stimulus (CS) acquires both predictive value and incentive value. Dopamine is implicated in both processes. A second important issue that has not been resolved is that the lack of conditioned approach responses linked to dopamine signaling deficiency could be due to a true lack of CS-reward association or due to the animal's inability to engage motivational and motor systems and promote the approach behavior. Aim 1 of this application will address these issues. For Aim 2, we have generated a condition AC5 allele that will allow us to achieve AC5 gene deletion in specific regions and cell types using the Cre recombinase mediated gene deletion. These studies will allow us to test necessity of AC5 in these cells in supporting specifi behavioral processes. In addition, we will perform virus mediated regional and cell type specific AC5 re-expression on the AC5KO background. This will allow us to test sufficiency, i.e., to test if AC5 in this brain region and this cell type is sufficient in supporting specific behavioral processes.