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. My project explores how the DA neuron amplifies or dampens synaptic inputs, and which membrane channels determine the responsiveness to input. Slice physiology and pharmacology are combined to manipulate single DA cells in the Substantia nigra, and molecular techniques (immunofluorescence, single-cell RT-PCR and knock-out mice) are used to confirm the expression of particular ion channels. I hypothesize that a recently characterized TRPM4 channel boosts phasic dopamine release and that several potassium channels regulate the timing of release. This study will demonstrate a calcium-dependent burst firing mechanism that may have implications for the selective vulnerability of DA neurons to cell death. In addition, the amount of DA released 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 reward-learning, including Major Depression, Attention-deficit Hyperactivity Disorder (ADHD), Schizophrenia, and drug addiction. 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.