Intrinsic amplification of synaptic inputs to nigral dopamine cells

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DESCRIPTION (provided by applicant): Our daily movements and habits rely on midbrain dopamine (DA) release. This is because DA cells are intricately connected to sensorimotor regions throughout the brain, including the basal ganglia, hippocampus, amygdala, and frontal cortex. Many excitatory and inhibitory inputs converge onto the DA cells, which must integrate this information. Therefore, the intrinsic excitability of single DA neurons is critical for information processing. This project will explore how the DA neuron amplifies or dampens synaptic inputs, and which membrane channels determine the responsiveness to input. Slice physiology and pharmacology will be combined to manipulate single DA cells. We hypothesize that a recently characterized TRP channel boosts phasic dopamine release and that several potassium channels regulate the timing of release. Furthermore, subsets of DA neurons may be dedicated to phasic release, while the remaining neurons maintain the baseline DA thought to be important for motivation. This study will demonstrate the mechanism of phasic release, which has been correlated with reinforcement learning. The amount of DA release at post-synaptic targets, such as the striatum and prefrontal cortex, ultimately affects action selection in goal-directed behaviors. Inappropriate amounts of DA in the brain cause various psychiatric disorders of motivation and rewardlearning, including Major Depression, Attention-deficit Hyperactivity Disorder (ADHD), Schizophrenia, and drug addiction. Thousands of prescription medications are given out daily for these disorders (e.g. Wellbutrin, Ritalin, Adderall, Zyban) without a detailed understanding of their long-term effects. These massmarketed drugs may cause permanent changes in wiring that complicate withdrawal from medication. Research on DA cell physiology may help tailor drug regimens for patients recovering from short-term treatment. Furthermore, the loss of DA cells is Parkinson's disease (PD) affects millions of people by impairing the ability to walk, talk, and complete simple tasks. Current L-DOPA therapy increases DA levels, but often to excess, causing unwanted and disordered movements. Thus, the ability to fine-tune the amount of DA release by targeting intrinsic membrane properties may help restore coordinated movement in these patients.