Individual differences in general and specific cognitive function in humans are regulated in part by genetic factors but little is known about the genes mediating this variation. Genetic regulation of complex learning can be addressed in animal models due to the highly conserved nature of brain structures. Contextual and noncontextual fear conditioning, a form of complex emotional learning, can be measured in both human and rodents. In contextual fear conditioning, learning the association of a mild shock with a sound in a particular chamber is shown as a fear response. Until recently, the genes regulating this type of complex phenotype have been difficult to map because of the polygenic nature of this regulation. The recent application of quantitative trait loci (QTL) analysis, a form of linkage analysis, allowed the identification of five QTLs on chromosomes 1, 2, 3, 10 and 16 that explain 70% of the genetic variation between C57BL/6 (B6) and DBA/2 (D2) for contextual fear conditioning. Some of these QTLs overlap with QTLs identified in other laboratories regulating emotionality or contextual fear conditioning in other genetic crosses. Thus, both QTLs that generalize across strains of mice and QTLs specific to the differences between B6 and D2 strains have been identified. The goal of the proposed studies is to narrow these QTL regions for further study.
The specific aims of the proposal are: 1.) To create congenic mouse lines for QTLs on chromosomes 1 and 3 which regulate contextual fear conditioning and noncontextual fear conditioning identified previously in a cross of B6 and D2 mice. 2.) To examine whether the QTLs for fear conditioning also regulate genetic variation in other forms of complex learning or fear-related behaviors. 3.) To characterize differences in gene expression between interval-specific congenics and the B6 background strains in naive mice and after contextual fear conditioning. Our long-term goal is to identify the genes that regulate behavioral differences in mice with the hopes that applying this information to understand regulation of human learning. Studies of this form of learning are not only applicable to normal complex learning processes but also to certain psychopathologies like post-traumatic stress syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH053668-06
Application #
6392118
Study Section
Special Emphasis Panel (ZRG1-IFCN-7 (01))
Program Officer
Farmer, Mary E
Project Start
1995-09-01
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2003-05-31
Support Year
6
Fiscal Year
2001
Total Cost
$163,782
Indirect Cost
Name
University of Colorado at Boulder
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309
Smith, Amy M; Bowers, Barbara J; Radcliffe, Richard A et al. (2006) Microarray analysis of the effects of a gamma-protein kinase C null mutation on gene expression in striatum: a role for transthyretin in mutant phenotypes. Behav Genet 36:869-81
Bowers, Barbara J; Radcliffe, Richard A; Smith, Amy M et al. (2006) Microarray analysis identifies cerebellar genes sensitive to chronic ethanol treatment in PKCgamma mice. Alcohol 40:19-33
Talbot, Christopher J; Radcliffe, Richard A; Fullerton, Jan et al. (2003) Fine scale mapping of a genetic locus for conditioned fear. Mamm Genome 14:223-30
Gorski, J A; Balogh, S A; Wehner, J M et al. (2003) Learning deficits in forebrain-restricted brain-derived neurotrophic factor mutant mice. Neuroscience 121:341-54
Balogh, Seth A; Wehner, Jeanne M (2003) Inbred mouse strain differences in the establishment of long-term fear memory. Behav Brain Res 140:97-106
Smith, Amy M; Wehner, Jeanne M (2002) Aniracetam improves contextual fear conditioning and increases hippocampal gamma-PKC activation in DBA/2J mice. Hippocampus 12:76-85
Balogh, Seth A; Radcliffe, Richard A; Logue, Sheree F et al. (2002) Contextual and cued fear conditioning in C57BL/6J and DBA/2J mice: context discrimination and the effects of retention interval. Behav Neurosci 116:947-57
Wehner, J M; Radcliffe, R A; Bowers, B J (2001) Quantitative genetics and mouse behavior. Annu Rev Neurosci 24:845-67
Tecott, L H; Wehner, J M (2001) Mouse molecular genetic technologies: promise for psychiatric research. Arch Gen Psychiatry 58:995-1004
Saudino, K J; Cherny, S S; Plomin, R (2000) Parent ratings of temperament in twins: explaining the 'too low' DZ correlations. Twin Res 3:224-33

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