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
Dissertation Director/Committee Chair: Dr. Karl J. Fryxell
Committee members:
Dr. Ancha Baranova, Dr. Daniel N. Cox, Dr. Robert F. Smith


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.


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.