Biomedical Engineering Reference
In-Depth Information
22
Viral-Mediated Gene Transfer to Study
the Behavioral Correlates of CREB Function
in the Nucleus Accumbens of Rats
William A. Carlezon, Jr. and Rachael L. Neve
1. Introduction
There is an enormous initiative to establish causal relationships between
brain biology (including patterns of gene expression) and behavior. Unfortu-
nately, genetic intervention is not accomplished easily in the brain. One strategy
is to engineer and deliver to the brain specialized viral vectors that carry a
gene (or genes) of interest, thereby exploiting the natural ability of viruses to
insert genetic material into cells. When delivered to the brain, these vectors
cause infected cells to increase expression of the genes of interest. Viral vectors
are particularly useful when the goal is to manipulate expression of a single
gene (1) in a specifi c brain region (2) at a specifi c time (3) in animals that
developed normally. As such, this technology has the potential to offer new
insights into the etiology of a wide variety of neuropsychiatric disorders;
ultimately it may usher in a new generation of “smart” pharmacotherapies that
are designed to negate or reverse alterations in the molecular structure of the
brain that lead to pathophysiological changes in behavior.
The use of any viral vector system for gene transfer studies in brain depends
on the dynamic interaction of a number of factors, ranging from the hypothesis
that is being tested, the brain region targeted for study, the viral backbone that
is used as the vector, the titer of the vector, and the volume of the vector that is
injected into the brain. Unfortunately, there is little information in the literature
about how one, once in possession of a vector of interest, would embark on
a gene transfer study. This chapter describes some of the protocols that we
developed for viral-mediated gene transfer studies in which we used herpes
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