Academic journal article Genetics

Large-Scale Gene Expression Differences across Brain Regions and Inbred Strains Correlate with a Behavioral Phenotype

Academic journal article Genetics

Large-Scale Gene Expression Differences across Brain Regions and Inbred Strains Correlate with a Behavioral Phenotype

Article excerpt

ABSTRACT

Behaviors are often highly heritable, polygenic traits. To investigate molecular mediators of behavior, we analyzed gene expression patterns across seven brain regions (amygdala, basal ganglia, cerebellum, frontal cortex,hippocampus, cingulate cortex, and olfactory bulb) of 10 different inbred mouse strains (129S1/SvImJ, A/J, AKR/J, BALB/cByJ, BTBR T^sup +^ tf/J, C3H/HeJ, C57BL/6J, C57L/J, DBA/2J, and FVB/NJ). Extensive variation was observed across both strain and brain region. These data provide potential transcriptional intermediates linking polygenic variation to differences in behavior. For example, mice from different strains had variable performance on the rotarod task, which correlated with the expression of >2000 transcripts in the cerebellum. Correlation with this task was also found in the amygdala and hippocampus, but not in other regions examined, indicating the potential complexity of motor coordination. Thus we can begin to identify expression profiles contributing to behavioral phenotypes through variation in gene expression.

INVESTIGATIONS into the genetics of behavioral traits, from alcohol preference to depression to cognitive ability, have revealed that behavior is highly heritable and likely influenced by many genes (WINTERER and GOLDMAN 2003; OROSZI and GOLDMAN 2004; HAMET and TREMBLAY 2005). This genetic complexity has led to difficulty in identifying genes involved in psychiatric disorders as well as those contributing to general behavioral characteristics. To understand better how genotype influences behavioral phenotype, we performed a detailed analysis of expression profiles throughout the brain to determine which transcripts vary by genetic background and correlate with behavior. Recent catalogs of the mouse transcriptome indicate that there may be <30,000 protein-coding genes, but that alternate splicing, alternative start and stop sites, and microRNAs can add substantially to genetic complexity (CARNINCI et al. 2005). This makes the dissection of gene expression, an intermediate between polymorphic DNA sequence and variable phenotype, a logical choice to investigate relationships connecting genotype to complex phenotypes like behavior.

Previous studies have examined gene expression profiles in the brain by microarray analysis. ZAPALA et al. (2005) have shown that regional differences in gene expression in the adult brain are largely reflective of the developmental origin of a particular region. Investigations into strain-related differences have led to estimates that 1-2% of the genes may vary in expression between six brain regions of C57BL/6 and 129SvEv mice (SANDBERG et al. 2000; PAVLIDIS and NOBLE 2001).

To extend previous studies and gain a more accurate picture of transcriptional variation, we measured gene expression in seven different regions of the mouse brain: amygdala, basal ganglia, cerebellum, frontal cortex, hippocampus, cingulate cortex, and olfactory bulb. These regions all play roles in behavior, and they encompass a range of neurocognitive functions, including locomotion, emotion, sensation, learning, and memory. Furthermore, the gene expression profile from each region was examined in 10 different inbred mouse strains: 129S1/SvImJ, A/J, AKR/J, BALB/cByJ, BTBR T^sup +^ tf/J, C3H/HeJ, C57BL/6J, C57L/J, DBA/2J, and FVB/NJ. Taking advantage of the diversity of both brain region and strain, we found that 57% of all transcripts assayed show variation across region and/or genetic background, a marked increase over previous reports (SANDBERG et al. 2000; PAVLIDIS and NOBLE 2001; ZAPALA et al. 2005). This diversity is due to the inclusion of more distantly related strains and is a tool to focus on the molecular causes for the phenotypic diversity observed among these strains.

Performance on the accelerating rotarod is a common motor coordination task, utilized with genetically and pharmacologically modified mouse models. Comparison of this strain-specific phenotype to gene expression serves as a clear proof of principle for our approach relating expression to strain-specific phenotypes. …

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