AMPA receptors mediate the majority of fast excitatory neurotransmission in the vertebrate nervous system and recent evidence has implicated AMPA receptor regulation in long-term potentiation (LTP) and long-term depression (LTD), cellular models of learning and memory. However, experimental evidence connecting synaptic plasticity and learning and memory remains scarce. Such evidence comes from demonstrations that behavioral performance on learning and memory tasks is impaired with manipulations of a molecular target in a relevant neural circuit. The present proposal aims to use an integrated and interdisciplinary approach, combining molecular, systems and behavioral neuroscience approaches, to investigate the role of AMPA receptor phosphorylation processes in incentive learning and memory. The specific aims of the proposal are: 1) to develop behavioral models to probe critical subprocesses involved in incentive learning and to test mice with point-mutations of AMPA-GluR1 Ser 831 and 845 phosphorylation sites on these tasks; 2) to use viral-vector mediated gene transfection to determine whether recovery (or rescue) of GluR1 phosphorylation in select brain regions will recover incentive learning processes; and 3) to study the role for GluR1 phosphorylation in the long-term effects of psychoactive drugs of abuse on incentive learning. By combining state-of-the-art molecular genetics approaches with advanced behavioral modeling to parse psychological processes that contribute to incentive learning, the experiments proposed are expected to yield new insights into the molecular basis of learning and memory, in particular incentive learning and memory. Such insights are important, as incentive learning processes play a vital role in many adaptive behaviors, as well as maladaptive conditions, such as eating disorders and drug addiction.
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