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 16 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 16 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 16 nAChR biology. For example, some experiments will utilize mice with hypersensitive 16 receptors that amplify and isolate 16 physiology and behavior, while other experiments will make use of mice expressing fluorescently-labeled 16 receptors that allow for direct visualization of these proteins in live neurons.
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.
|Yan, Yijin; Peng, Can; Arvin, Matthew C et al. (2018) Nicotinic Cholinergic Receptors in VTA Glutamate Neurons Modulate Excitatory Transmission. Cell Rep 23:2236-2244|
|Bordia, T; McGregor, M; McIntosh, J M et al. (2015) Evidence for a role for ?6(?) nAChRs in l-dopa-induced dyskinesias using Parkinsonian ?6(?) nAChR gain-of-function mice. Neuroscience 295:187-97|
|Berry, J N; Engle, S E; McIntosh, J M et al. (2015) ?6-Containing nicotinic acetylcholine receptors in midbrain dopamine neurons are poised to govern dopamine-mediated behaviors and synaptic plasticity. Neuroscience 304:161-75|
|Henderson, Brandon J; Lester, Henry A (2015) Inside-out neuropharmacology of nicotinic drugs. Neuropharmacology 96:178-93|
|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|
|Shih, Pei-Yu; Engle, Staci E; Oh, Gyeon et al. (2014) Differential expression and function of nicotinic acetylcholine receptors in subdivisions of medial habenula. J Neurosci 34:9789-802|
|Henderson, Brandon J; Srinivasan, Rahul; Nichols, Weston A et al. (2014) Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptors. J Gen Physiol 143:51-66|
|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|
|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|
|Drenan, Ryan M; Lester, Henry A (2012) Insights into the neurobiology of the nicotinic cholinergic system and nicotine addiction from mice expressing nicotinic receptors harboring gain-of-function mutations. Pharmacol Rev 64:869-79|
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