Molecular mechanisms of reward-related learning Natural selection requires a mechanism of variation and a mechanism of selection that operates on that variation. Reward-related or incentive learning is the acquisition by neutral stimuli of an increased ability to elicit approach and other responses. It is similarly a selectionist process, variations in behavioral responses in specific environments being selected by their consequences. The neural systems and molecular mechanisms underlying this selection are beginning to be understood. Behavioral responses and specific environmental stimuli activate assemblies of neurons that project into a brain region, the striatum, that interfaces with motor output regions controlling behavioral responses. When particular responses are made in the presence of particular stimuli, the cell assemblies they activate create a state of readiness in a subset of striatal synapsses by releasing glutamate that acts on receptors that alter calcium concentrations; these inputs lead to a wave of phosphorylation events in dendritic spines of postsynaptic neurons (targets include Kv4.2 channels, CaMKII, GluR1 subunits of AMPA receptors, ERK1/2, PP2A, DARPP-32). If no rewarding stimulus is encountered, these post-synaptic events are quickly undone by a wave of phosphatase events (e.g., activation of PP2B, PP1, pThr75DARPP-32, STEP). Neurons that use dopamine as their neurotransmitter project to this interface and play a critical role in reward-related learning. Dopaminergic neurons have bursts of action potentials when an animal encounters a biologically important rewarding stimulus such as food, water, a mate or safety from danger. The increase in dopamine concentration in its terminal regions acts via D1 receptors on the same dendritic spines as the glutamate inputs to initiate a series of events (cAMP, PKA, pThr34DARPP-32, CREB) in the target neurons that arrest the wave of phosphatase consequent to the glutamatergic input and thereby allow the wave of phosphorylation to endure (RSK2, Elk1, MSK1). The enduring wave of phosphorylation in cooperation with phosphorylation events produced by the dopaminergic input act to produce changes in local proteins and new protein synthesis that serves to strengthen recently active glutamatergic synapses. These modified synapses are the biological basis of reward-related learning. As a result of this learning, specific environmental stimuli and the particular responses directed towards those stimuli acquire an increased ability to elicit approach and other responses in the future. 11:30-12:30 BioSci Rm. 3110
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