Project Summary/Abstract Dopamine (DA) neurotransmission in the dorsal striatum and nucleus accumbens has been implicated in drug seeking and reward since the 1950s, when it was shown to mediate the effects of cocaine and opiates. However, our and other’s recent work has shown that DA also plays a role in another circuitry critical for drug dependence. Within the rostral striatum (tail of the striatum: TS) – the central locus where auditory DA, cortical and thalamic axons converge to control auditory learning – DA neurotransmission is necessary for learned association of a sound with a behavior, such as drug self-administration. To address this role for DA, we have developed novel technical approaches that allow us to measure activity and neuronal signaling during associative learning and recall tests, and then to correlate changes in animal behavior and in vivo synaptic activity with detailed ex vivo analysis after learning. These experiments have led to the identification of a new form of synaptic plasticity that occurs at auditory thalamic inputs to the TS projection neurons, consisting of a simultaneous decrease in overall activity with a concurrent increase in response to a specific sound cue. This form of enhanced signal-to-noise response by specific synapses may provide a basis of sensory cue learning. This project tests i) the precise physiological and molecular steps required for auditory sensory learning; ii) the role played by the TS dopamine and glutamate neurotransmission in this form of learning and synaptic plasticity, and iii) a role of DA in “refining” TS synaptic circuits in order to allow further learning. These experiments promise to unveil the molecular steps responsible for the action of addictive drugs such as amphetamine and opiates that drive self-administration, and will further be important for understanding language disorders, hallucinations and affective disorders including ADHD and PTSD.