Midbrain dopaminergic signaling is involved with associative learning, reward, and movement initiation (Schultz, 1998). Its dysfunction is implicated in addiction, schizophrenia, and ADHD, and the selective de- generation of dopamine cells of the substantia nigra pars compacta (SNc) is the hallmark of Parkinson's disease. Voltage-gated calcium current has been proposed to contribute both to the tonic activity of these cells and to their sensitivity to oxidative stress (Chan et al., 2007;Putzier et al., 2009). The proposed research is designed to identify the physiological characteristics of the voltage-gated calcium current and a large, but largely unexplored, calcium-activated potassium (K (Ca)) current in these cells. The long term goal is a comprehensive model of the activity of these cells in terms of their ionic conductances, and how modulating these conductances regulate activity. Calcium current in SNc dopamine cells has been suggested to play significant roles both in their tonic activity and in their degeneration in Parkinson's. In other cell types, calcium currents serv important functions regulating burst firing, which in SNc cells signals reward prediction error and behaviorally relevant stimuli. Earlier studies identified multiple types of calcium channels contributing to the total calcium current in these cells, but these studies used barium as a charge carrier instead of calcium and were performed at room rather than body temperature (Cardozo and Bean, 1995;Durante et al., 2004). Consequently, the physiological roles of these currents remain unclear. The proposed work uses a combination of pharmacology and electrophysiology on acutely dissociated SNc dopamine neurons to ask questions about the physiological properties of different calcium current components, when they are activated during pacemaking and burst firing, and how they are affected by neuromodulation. These experiments will be performed at physiological temperature with physiological charge carrier. There exists a lively interest in modeling the activity of SNc dopamine cells;the properties of the calcium current obtained in this work will be incorporated into a model and made available for use by the modeling community. In other cell types, K (Ca) channels shape activity patterns (Gu et al., 2007;Tabak et al., 2011). Preliminary experiments reveal a large-conductance calcium-activated potassium (BK) current in SNc dopamine cells, which has previously only been described at the single-channel level (Su et al., 2010). Using a combination of electrophysiology and pharmacology, the work proposed will determine the size of the macroscopic BK current in these cells, its activation during activity, and its regulation by neuromodulators. In light of the significance calcium is thought to play in SNc pacemaking and the large size of the BK current in preliminary experiments, BK activation may be a significant and hitherto unexplored regulator of SNc activity. Results of these experiments will also be incorporated into a freely-available model.

Public Health Relevance

The activity of midbrain dopamine neurons is involved in addiction, schizophrenia, ADHD, and Parkinson's disease. Calcium currents may play crucial roles in the activity of these cells and their degeneration in Parkinson's;calcium-activated potassium currents interact with calcium currents to shape cellular activity (Chan et al., 2007;Putzier et al., 2009;Wolfart and Roeper, 2002). The goal of this research is to identify the physiological roles of these currents and their regulation by neurotransmitters, and to model these results computationally.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Stewart, Randall R
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Harvard Medical School
Schools of Medicine
United States
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