Cellular Mechanisms Regulating VTA Dopamine Neurons

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The applicant's long-term career goal is to develop into an independent investigator studying the mechanisms underlying drug abuse and addiction. In order to achieve this objective, the applicant (Dr. Arthur Riegel) has prepared a Mentored Research Scientist Development Award (K01) designed to: 1) acquire important technical and theoretical training in state-of-the-art neuroimaging techniques, while investigating the dendritic physiology of dopamine neurons; and 2) prepare a competitive R01 grant proposal in order to establish an independent research program. The training proposed in this K01 application will be conducted in the context of a Career Development Plan. This Career Plan incorporates mentoring from an established neurophysiologist (Dr. John Williams), as well as important training opportunities for practical career development skills, didactic instruction and Responsible Conduct of Research. The applicant has the commitment of resources and expertise from the Vollum Institute, one of the finest cellular neuroscience environments in the country. The research element of the Career Plan investigates neuroadaptations in dendritic physiology following chronic exposure to morphine. Dr. Riegel's immediate goals are to develop an expertise in 2-photon microscopy, spinning confocal microscopy, photolysis, focal electrical stimulation, focal iontophoresis, and experimental models of chronic opioid administration. These techniques will be used to investigate preliminary data demonstrating that forskolin-activation of adenylyl cyclase (AC) enhances the mGluR-mediated activation of the sK-channel. The proposed specific aims will test the hypothesis that there exists a novel AC/PKA-dependent signaling cascade, which regulates the sK-channel current and is upregulated during chronic morphine treatment. The results from these experiments are expected to increase our understanding of the impact of sK-channel function on dopamine neuron excitability during addiction. With regard to public health, the relevance for the proposed research is that a better understanding of the cellular mechanisms underlying sK-channel function will lead to the development of neuropharmacological tools to exploit this channel as a therapeutic target. The training incorporated in this Career Plan will provide a solid basis upon which to develop a R01 proposal in Year-3.