CANDIDATE My immediate goals are to continue my research and training in electrophysiology, biological imaging and neuroscience. During the K99 phase (2 years), I will conduct experiments and be trained in electrochemical recording methods and multi-photon imaging. I will publish papers and search for a job as an independent faculty/investigator during the K99 phase, and will transition to the R00 independent phase (3 years) upon securing a faculty position. The total duration of the project is 5 years. ENVIRONMENT The K99 phase of this project will be conducted at the California Institute of Technology, which affords an excellent research and learning environment for postdoctoral scientists. Caltech has a strong neuroscience community, excellent faculty, and many highly productive and resourceful postdoctoral scholars and graduate students for one to collaborate with. Caltech also runs the Biological Imaging Center through the Beckman Institute, a resource that will be a very important part of my training plan. For the institution where I will conduct my R00 phase studies, I will choose an institute or university with excellent neuroscience resources and faculty that will put me in the best position for growth and success. RESEARCH This research program is designed to test the hypothesis that specific nicotinic ACh receptors are important for modulating release of neurotransmitters such as dopamine. In particular, I will test the idea that nicotinic receptors containing ?6 subunits, which are found on dopamine presynaptic terminals, are important mediators of dopamine release. I will also test the idea that the ability of these receptors to mediate dopamine release is governed by their subcellular regulation by the neurons where they reside. Finally, I will test the idea that ?6 receptor expression and function are significantly altered when animals are exposed to chronic nicotine. Thus, these experiments will determine whether these receptors are important in dopamine release and in disorders such as nicotine dependence. To carry out these experiments, I designed and built a set of novel transgenic mouse lines to particularly isolate aspects of ?6 nAChR biology. For example, some experiments will utilize mice with hypersensitive ?6 receptors that amplify and isolate ?6 physiology and behavior, while other experiments will make use of mice expressing fluorescently-labeled ?6 receptors that allow for direct visualization of these proteins in live neurons.
RELEVANCE TO PUBLIC HEALTH This project is designed to give the research and health care community a better understanding of particular neurotransmitter receptors that may be important in neural disorders such as nicotine dependence, Parkinson's disease, affective disorders, or schizophrenia. The knowledge that will be produced by this research may be useful in designing and testing better drug therapies for these or other related disorders.
|Engle, Staci E; McIntosh, J Michael; Drenan, Ryan M (2015) Nicotine and ethanol cooperate to enhance ventral tegmental area AMPA receptor function via Î±6-containing nicotinic receptors. Neuropharmacology 91:13-22|
|Berry, J N; Engle, S E; McIntosh, J M et al. (2015) Î±6-Containing nicotinic acetylcholine receptors in midbrain dopamine neurons are poised to govern dopamine-mediated behaviors and synaptic plasticity. Neuroscience 304:161-75|
|Shih, Pei-Yu; McIntosh, J Michael; Drenan, Ryan M (2015) Nicotine Dependence Reveals Distinct Responses from Neurons and Their Resident Nicotinic Receptors in Medial Habenula. Mol Pharmacol 88:1035-44|
|Wang, Yuexiang; Lee, Jang-Won; Oh, Gyeon et al. (2014) Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function *6* nAChRs. J Neurochem 129:315-27|
|Engle, Staci E; Shih, Pei-Yu; McIntosh, J Michael et al. (2013) Î±4Î±6Î²2* nicotinic acetylcholine receptor activation on ventral tegmental area dopamine neurons is sufficient to stimulate a depolarizing conductance and enhance surface AMPA receptor function. Mol Pharmacol 84:393-406|
|Powers, M S; Broderick, H J; Drenan, R M et al. (2013) Nicotinic acetylcholine receptors containing Î±6 subunits contribute to alcohol reward-related behaviours. Genes Brain Behav 12:543-53|
|Engle, Staci E; Broderick, Hilary J; Drenan, Ryan M (2012) Local application of drugs to study nicotinic acetylcholine receptor function in mouse brain slices. J Vis Exp :e50034|
|Cohen, B N; Mackey, E D W; Grady, S R et al. (2012) Nicotinic cholinergic mechanisms causing elevated dopamine release and abnormal locomotor behavior. Neuroscience 200:31-41|
|Mackey, Elisha D W; Engle, Staci E; Kim, Mi Ran et al. (2012) Ã½Ã½6* nicotinic acetylcholine receptor expression and function in a visual salience circuit. J Neurosci 32:10226-37|
|Xiao, Cheng; Srinivasan, Rahul; Drenan, Ryan M et al. (2011) Characterizing functional Î±6Î²2 nicotinic acetylcholine receptors in vitro: mutant Î²2 subunits improve membrane expression, and fluorescent proteins reveal responsive cells. Biochem Pharmacol 82:852-61|