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Dissertation Defense Announcement
To:  The George Mason University Community

Candidate: Robert Hallenberg
Program:    PhD Biosciences

Date:   Thursday August 9, 2012
Time:   9:30 a.m.
Place:  George Mason University
           Occoquan Bldg., #110-L
           Prince William Campus 
<http://www.gmu.edu/resources/welcome/Directions-to-GMU.html>
 
Dissertation Director/Committee Chair: Dr. Karl J. Fryxell
Committee members: Dr. Ancha Baranova, Dr. Daniel N. Cox, Dr. Robert F. 
Smith

Title: "ADOLESCENT-SPECIFIC REGULATORY GENE EXPRESSION RESPONSES TO 
SINGLE AND REPEATED NICOTINE INJECTIONS"

The dissertation is on reserve in the Johnson Center Library, Fairfax 
campus.
The doctoral project will not be read at the meeting, but should be read 
in advance.

All members of the George Mason University community are invited to attend.


*ABSTRACT:*

The subjective response of human adolescents to the first cigarette has 
been shown to be the strongest predictor of their later acquisition of 
nicotine dependence.  The difference in smoking behaviors between 
adolescents and adults is believed to be based on an age-specific 
neurophysiological response that represents an adolescent venerability 
to nicotine.  Here we investigated the effect of subcutaneous nicotine 
injections (0.5 mg/kg free base equivalent) on gene expression in 
several brain areas of C57BL/6J and A/J mice. Using quantitative reverse 
transcription PCR we analyzed the expression of the genes Slc6a3 (DAT), 
Bdnf (splice variants I, II, IV and VI), Cdk5, Arc, Fosb, ?-Fosb, Snca, 
Mecp2, Ntrk2, and Mir212 in adult and adolescent mice exposed to either 
a single nicotine (or saline) injection, or a series of four injections 
over seven days.  In the medial prefrontal cortex, at 24 h after a 
single nicotine injection, we found age-specific expression patterns, in 
which Slc6a3 was generally down-regulated across sexes and strain and 
Snca, Bdnf-II, and Bdnf-VI were generally up-regulated across sexes and 
strains.  No significant age-specific effects were observed in the 
ventral striatum.  The expression of Slc6a3, Bdnf-II, and Bdnf-VI were 
also found to be highly correlated (r = 0.95, -0.91, and -0.93, 
respectively) with the nicotine-induced down-regulation of Drd2 that we 
have previously shown was strongly correlated (r = 0.99) with the 
nicotine preference of these sexes and strains as adults.  We also 
report that expression of Fosb in the ventral tegmentum of adolescents 
was significantly altered by nicotine as early as 3 h after dosing.    
After repeated nicotine injections, expression of Cdk5, Snca and Arc in 
the mPFC and Cdk5, Snca and Mecp2 in the ventral striatum showed 
age-specific expression patterns.  The observed expression response was 
found to come from adolescent-specific changes in expression.  
Expression of these genes was generally up-regulated across sexes in 
C57BL/6J mice, but showed sex-specific expression patterns in A/J mice.  
Unsupervised clustering analysis of expression patterns showed that 
adolescent-specific transcripts tended to group together, suggesting a 
common regulatory pathway.  Results from the hippocampus are also 
reported.  Our results show a rapid and age-specific response, to a 
single nicotine injection, in the medial prefrontal cortex, which is 
still developing during the adolescent period.  This age-specific 
response transitions to the ventral tegmentum after repeated nicotine 
injections.  We believe that these brain area-specific responses in gene 
expression play a key role in the adolescent vulnerability to nicotine.

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