Dopamine Effects on Striatal and Hippocampal Plasticity

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DESCRIPTION (provided by applicant): Patients with basal ganglia dysfunction show significant and striking cognitive impairments. The specific contribution of striatum to learning, however, remains unclear: rodent lesion studies suggests a selective role in stimulus-response or egocentric forms of learning (dissociating it from context-based learning performed by hippocampus), while primate electrophysiological evidence supports a dual role for striatum in both stimulus-response and context-dependent learning. Nevertheless, comparison with studies of hippocampal-dependent memory supports a common view that multiple memory systems exist in brain. Our past work, however, shows that regardless of task, there is significant parallel representation in different brain structures. Given this parallel neural representation, it becomes of interest to know how different memory systems are coordinated. With this grant, we propose a novel perspective on this issue, which is to study how neuromodulators (e.g. dopamine) might bias the relative contributions of different neural systems to learning depending on current environmental demands. Aim 1 will determine the nature of neural representation by neurons in structures known to supply striatum and hippocampus with dopamine, the ventral tegmentum (VTA) and substantia nigra (SNc). Aim 2 will determine whether context-sensitivity of striatum and hippocampal neurons is due to VTA and/or SNc input by reversibly inactivating these structures while testing the context-sensitivity of striatal and hippocampal neurons. To determine whether the inactivation effects are due to dopamine disruption, we will apply D1 or D2 receptor antagonists, and then monitor the context-sensitivity of striatal and hippocampal neurons. Aim 3 will determine whether the context-sensitivity of single striatal and hippocampal unit records is reflective of a larger population response by evaluating the context sensitivity of the expression of the immediate-early gene cFos in striatum and hippocampus, by testing the effects of VTA or SNc inactivation on cFos expression in striatum and hippocampus, by testing pharmacologically a role for dopamine in context-induced cFos expression, and by directly comparing cFos activation patterns with single unit data recorded from the same animals. These studies should provide a strong test for the hypothesis that dopamine functions to regulate the relative contribution of striatum and hippocampus to different forms of learning.