Abstract: Despite the debilitating nature of addiction, and its associated societal and economic cost, there is currently no effective treatment. Here we propose to develop a bold new approach to the rampant neural plasticity induced by drugs of abuse. Although drug-induced plasticity is thought to be at the heart of the disease, it has not been possible to design circuit- level therapies to counteract these plastic changes because of technological limitations. My lab is now uniquely positioned to finally innovate such an approach, because of our expertise in both counteract the new field of optogenetics (the optical control of neural activity) and the emerging analysis of circuit-level mechanisms underlying addiction. To create this new approach to counteract addiction-related behavior, we will develop a novel panel of next-generation technologies togenetically and functionally target selected cell-types in rats. In order to counteract drug-induced plasticity, we will apply the new targeting technologies to activate the aversion and extinction in synchrony with the circuits that encode the drug experience, thereby circuits involved in weakening the drug-related associations and alleviating addiction-related behavior. Thus, we present here both a powerful new concept for the treatment of addiction, as well as the development of enabling technologies to achieve this vision. Public Health Relevance: Addiction is a devastating illness which destroys the lives of millions of people in the United States, is associated with enormous economic and societal cost, and is virtually without treatment. By developing a panel of new technologies designed to control neural activity in the appropriate cell-types in a rodent model of addiction, we open the door to the development of an exciting new approach to counteract drug-induced plasticity and addiction-related behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2DA035149-01
Application #
8352580
Study Section
Special Emphasis Panel (ZGM1-NDIA-C (01))
Program Officer
Pilotte, Nancy S
Project Start
2012-09-30
Project End
2017-08-31
Budget Start
2012-09-30
Budget End
2017-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$2,415,000
Indirect Cost
$915,000
Name
Princeton University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Parker, Nathan F; Cameron, Courtney M; Taliaferro, Joshua P et al. (2016) Reward and choice encoding in terminals of midbrain dopamine neurons depends on striatal target. Nat Neurosci 19:845-54
Lee, Junuk; Finkelstein, Joel; Choi, Jung Yoon et al. (2016) Linking Cholinergic Interneurons, Synaptic Plasticity, and Behavior during the Extinction of a Cocaine-Context Association. Neuron 90:1071-85
Akhlaghpour, Hessameddin; Wiskerke, Joost; Choi, Jung Yoon et al. (2016) Dissociated sequential activity and stimulus encoding in the dorsomedial striatum during spatial working memory. Elife 5:
Saddoris, Michael P; Sugam, Jonathan A; Stuber, Garret D et al. (2015) Mesolimbic dopamine dynamically tracks, and is causally linked to, discrete aspects of value-based decision making. Biol Psychiatry 77:903-11
Dautan, Daniel; Huerta-Ocampo, Icnelia; Witten, Ilana B et al. (2014) A major external source of cholinergic innervation of the striatum and nucleus accumbens originates in the brainstem. J Neurosci 34:4509-18
Steinberg, Elizabeth E; Boivin, Josiah R; Saunders, Benjamin T et al. (2014) Positive reinforcement mediated by midbrain dopamine neurons requires D1 and D2 receptor activation in the nucleus accumbens. PLoS One 9:e94771
McCutcheon, James E; Cone, Jackson J; Sinon, Christopher G et al. (2014) Optical suppression of drug-evoked phasic dopamine release. Front Neural Circuits 8:114
Tye, Kay M; Mirzabekov, Julie J; Warden, Melissa R et al. (2013) Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493:537-41
DePuy, Seth D; Stornetta, Ruth L; Bochorishvili, Genrieta et al. (2013) Glutamatergic neurotransmission between the C1 neurons and the parasympathetic preganglionic neurons of the dorsal motor nucleus of the vagus. J Neurosci 33:1486-97
Steinberg, Elizabeth E; Keiflin, Ronald; Boivin, Josiah R et al. (2013) A causal link between prediction errors, dopamine neurons and learning. Nat Neurosci 16:966-73

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