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FRISC: The Faculty Research Interests Science Comparator |
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Associate Professor of Psychiatry
Integrative
Biology
Office: 214-648-7380
FAX: 214-648-5599
Email: howard.gershenfeld@utsouthwestern.edu
Psychiatry Homepage: http://www3.utsouthwestern.edu/psychiatry/facbios/gershenf.htm
Our research interests
focus on genetic and molecular biological approaches to understanding
psychiatric disorders. We are interested in the general question “to what
extent and how do genetic factors influence such constructs as temperament,
anxiety, stress, depressive disorders, and obesity-related traits ”? We have
chosen to focus on mouse models of psychiatric illness (complex behaviors) as
our system. We hope these models will identify genetic factors with relevance to
humans. We have relied upon a “top down” (phenotype/trait ->gene)
quantitative trait loci (QTL) genetic mapping approach, supplemented with
a bottom up approach (from gene ->phenotype). gene-deficient mice
and ENU mutant mice. With these strategies, one can pursue influential loci and
genes without a priori knowledge of the genes’ function.
We have the following
projects ongoing in the lab:
1) Positional cloning of
Exploratory behavior QTL
In the past several years, we have successfully applied
this QTL mapping approach to loci influencing or modulating open field behavior
, fear-like behavior, obesity-related behaviors, and a depression-like model.
The basic method involves crossing two strains of mice (e.g., A/J and C57BL/6J)
that dramatically differ in these behaviors. By a whole genome search in an F2
intercross or a backcross population, we have mapped several loci. Of particular
interest, we have confirmed that a distal region of chromosome 10 harbors a
major locus ( Exq) or several closely linked loci that influence multiple traits,
namely exploratory behavior in an open field, fear-like behavior as measured by
a conflict paradigm, and seizure threshold. Overall, the QTL mapped explained
from 3.2% to 15% of the F2 population’s phenotypic variance.
More recently, we have focused on localizing the mapping of
these broadly defined QTLs (approximately 15 centimorgan regions) to smaller
regions of chromosomes (2-4 cM) by 1) generating a series interval specific
congenic strains for the chromosome 10 locus and 2) fine mapping loci in a
unique F12 advanced intercross line of mice (with Dr. Fuad Iraqi, ILRI, Nairobi,
Kenya), permitting a confidence interval of about 2-4 cM for all the loci. We
are currently positionally cloning this locus by skillfully employing candidate
region cDNA analysis (“database mining”), expression profiling on DNA
microarrays (Dr. G. Peltz- Roche Molecular biology), DNA sequencing of candidate
regions, genetic fine recombinational mapping of the congenic strain, and
ultimately gene swapping as proof of function via transgenics.
2) Neuropsychopharmacology
and Neurogenetics of the Tail Suspension Test (TST) / Stress vulnerability
We are pharmacologically
and genetically dissecting aspects of the tail suspension test (TST), a well
validated mouse model of behavioral despair and a primary screen for
antidepressant activity. Our aim is to expand the neurogenetic understanding of
stress vulnerability and antidepressant response. A broad, inclusive
approach dissects the TST, including 1) a positional cloning approach to map a
confirmed locus defined by QTL mapping, 2) the secondary screening of ENU mutant
mice, and 3) an analysis of selected gene-deficient, transgenic mice to
determine their role in Tail Suspension Induced Hyperthermia (TSIH). Given the
complexity of neuronal networks and the phenotype being at a distance from the
genotype, we favor assumption-free, genetic approaches. We anticipate
identifying genes and pathways affecting vulnerability to an inescapable
stressor, exploiting differences in behavioral responses. We view the genes and
loci to be identified as putative risk factors for psychiatric illness and
candidates genes for association studies.
3) Fine Mapping a Loci for
Obesity-related traits
Having defined several loci
contributing to early weight gain on a high fat diet, we are using genetic fine
mapping techniques to further localize the genes and positionally clone the loci
in mice. One region of particular interest corresponds to a replicate region of
linkage in humans on chr. 7.
4) The Genetics of Avoidance Learning
We have obtained the
Syracuse High and Low Avoidance (SHA and SLA) strains of rats. These lines have
been selectively bred for their learning ability in actively avoiding (namely
moving / shuttling to the other side of a two compartment shuttle box) a shock
after a warning signal. These mice have been lovingly developed and
characterized by Dr. F. Robert Brush over the last 35 years. These rats
dramatically differ in their Active avoidance behavior. More specifically, out
of 60 test trials of avoidance behavior, the Low's (SLA) avoid less than 10% of
the trials, while the high's (SHA) avoid greater than 70% of the time. We are
interested in using gene expression profiling in amygdala and hippocampus to
explore the mechanism of this phenomenon.
Selected Publications:
Gershenfeld,
H., Neumann, P, Mathis, C., Crawley, J. and Paul, S.(1997) Mapping Quantitative
Trait Loci for Open-Field Behavior in Mice, Behavior
Genetics 27(3): 201-210.
Gershenfeld,
H. and Paul, S.(1997) Mapping Quantitative Trait Loci for Fear-related Behaviors
in Mice, Genomics , 46:1-8.
Gershenfeld,
H. and Paul, S.(1998) Towards a Genetics of Anxious Temperament: Of mice and
men, Acta Psychiatrica Scandinavia , 98
(Suppl. 393):56-65.
Gershenfeld,
H.(1998) Factors Behavior Therapist ,
“Many Factors” 21: Winter, p.202.
Gershenfeld,
H., Neumann, P.E., Li,X., St. Jean, P.L. and Paul, S. (1999) Mapping
Quantitative Trait Loci for Seizure Response to a GABA A Receptor
Inverse Agonist, J. of Neuroscience ,
19(10):3731-3738
Sinton,
C.M., Fitch, T.E., and Gershenfeld, H.K. (1999) The Effects of Leptin on REM
Sleep and Slow Wave Delta in the Rat are Reversed by Food Deprivation ,
J Sleep Res. 8 (3): 197-203
Philibert,
RA, Cheung, D, Welsh, N, Damschroder-Williams,P, Thiel,B, Ginns,EI,
Gershenfeld,HK (2001) Absence of a Significant Association Between Na+,
K+-ATPase subunit (ATP1A3 & ATP1B3) genotypes and Bipolar Disorder in the
Old Order Amish, American J. of Medical Genetics(Neuropsychiatric Genetics)
105:291-294
Liu,
X. and Gershenfeld, H. (2001) Genetic Differences in the Tail Suspension Test
and its Relationship to Imipramine Response among 11 Inbred Strains of Mice, Biological
Psychiatry , 49: 575-581
Haley
R.W., Maddrey A.M. , Gershenfeld H.K. (2002) Severely reduced functional status
in veterans fitting a case definition of Gulf War syndrome. Am J Public
Health 92: 46-7
Extraction Method: Expand using Medical Synonyms-
Eliminated words list: MedlinePlus List
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Similarity Method: Weighted keyword count
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Database: Medline abstracts (1967 - Present)
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Publication Type: All
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Score Calculation Method: Cosine Similarity Method
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Sort by: Score
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Show: Top 100 hits
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Results computed on: 6/9/2006