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Using Adultborn Neurons to Combat Nicotine Relapse

Institution: University of California, San Diego
Investigator(s): Darwin Berg, Ph.D.
Award Cycle: 2010 (Cycle 19) Grant #: 19XT-0072 Award: $250,000
Subject Area: Nicotine Dependence
Award Type: Exploratory/Developmental Award

Initial Award Abstract
Many tobacco smokers would very much like to quit but are unable to do so because of habitual relapses that seem beyond their control. Relapse behavior is triggered in part by memories linking specific places, events, or times with smoking. The hippocampus is a brain region that mediates memory formation of this type. Within it is located the dentate gyrus which relays incoming information and plays a critical role in the formation of new place- and time-linked memories. Importantly, the dentate gyrus has recently been shown to mediate some forms of nicotine-induced learning, and the dentate gyrus helps generate spatial memories as demonstrated in nicotine-induced behavioral assays. Remarkably, the dentate gyrus is one of only two brain regions that continues to add new cells (neurons) throughout adulthood. These adultborn neurons contribute importantly to the formation of memories encoding time and place information, as well as spatial pattern separation. We now have preliminary results showing that chronic nicotine levels comparable to those found in smokers dramatically kill off adultborn neurons during their initial stages of neurogenesis. And this die-off is mediated by the very same class of components (nicotinic receptors) that normally would promote the development and subsequent survival of adultborn neurons if not hijacked by nicotine. Together, these results suggest a new and intriguing model contributing to relapse behavior for smokers. Tobacco consumption, along with the circulating levels of nicotine it generates, prevents appearance of most new adultborn neurons. The few adultborn neurons that do survive become heavily committed to encoding nicotine-associated memories. When the individual attempts to stop smoking, few new adultborn neurons are available to facilitate production of new nicotine-free place memories. As a result, the smoker is continuously barraged with memories re-awakening the desire to smoke. Were it possible to readily generate new place and time memories free of tobacco consumption, these might increasingly override previous associations and help decrease chances of relapse. The experiments proposed here will first quantify the impact of chronic nicotine exposure on the fate of adultborn neurons, and will analyze the mechanisms involved. Methods will include chronic infusion of nicotine, birth-dating adultborn neurons and quantifying their survival, measuring their branches, and comparing their connections with pre-existing neurons to form circuits. Second, the proposal will take advantage of this information to design and test drug regimens in vivo predicted to protect new adultborn neurons from detrimental effects of chronically circulating nicotine. The drug treatment strategies will test combinations of compounds that block the relevant nicotinic receptor, or partially activate it, or alter its response to the natural activating compound in vivo. Effectiveness of these treatment strategies will be assessed by quantifying the number of adultborn neurons surviving through critical periods and the timing of their becoming functionally connected to other neurons. Third, treatments successful by these criteria will then be tested in behavioral assays designed to measure tendency to relapse. Successful treatments will be those that tend to extinguish the previous nicotine-based place choice and instead promote new choices. This proposal is highly appropriate for an Exploratory/Developmental Research Award. It makes use of new data to design and test a model directly relevant to the central goals of TRDRP. And if successful as envisioned, the results will provide a compelling basis for subsequent funding from other agencies to go forward as mandated for Exploratory Awards.

PMCA2 via PSD-95 controls signaling by á7-containing nicotinic acetylcholine receptors on aspiny neurons
Periodical: Journal of Neuroscience Index Medicus:
Authors: Gomez-Varela D, Schmidt M, Schoellerman J, Peters E, Berg DK ART
Yr: 2012 Vol: Nbr: 32 Abs: Pg: 6894-6905

Glutamatergic synapse formation is promoted by á7-containing nicotinic acetylcholine receptors.
Periodical: Journal of Neuroscience Index Medicus:
Authors: Lozada AF, Wang X, Gounko NV, Massey KA, Duan J, Liu Z, Berg DK ART
Yr: 2012 Vol: Nbr: 32 Abs: Pg: 7651-7661

Induction of dendritic spines by B2-containing nicotinic receptors
Periodical: Journal of Neuroscience Index Medicus:
Authors: Lozada AF, Wang X, Gounko NV, Massey KA, Duan J, Liu Z, Berg DK ART
Yr: 2012 Vol: Nbr: 32 Abs: Pg: 8391-8400

Nicotinic control of adult-born neuron fate
Periodical: Biochemical Pharmacology Index Medicus:
Authors: Campbell NR, Fernandes CC, John D, Lozada AF, Berg, DK ART
Yr: 2011 Vol: Nbr: 82 Abs: Pg: 820-827