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Genetic liability for internalizing versus externalizing behavior manifests in the developing and adult hippocampus: Insight from a meta-analysis of transcriptional profiling studies in a selectively-bred rat model

By Isabelle A. Birt, Megan Hastings Hagenauer, Sarah M. Clinton, Cigdem Aydin, Peter Blandino, John D. H. Stead, Kathryn L. Hilde, Fan Meng, Robert C. Thompson, Huzefa Khalil, Alex Stefanov, Pamela Maras, Zhifeng Zhou, Elaine K. Hebda-Bauer, David Goldman, Stanley J. Watson, Huda Akil

Posted 23 Sep 2019
bioRxiv DOI: 10.1101/774034 (published DOI: 10.1016/j.biopsych.2020.05.024)

Background For over 16 years, we have selectively bred rats to show either high or low levels of exploratory activity within a novel environment. These “bred High Responder” (bHR) and “bred Low Responder” (bLR) rats serve as a model for temperamental extremes, exhibiting large differences in many internalizing and externalizing behaviors relevant to mood and substance abuse disorders. Methods Our study elucidated persistent differences in gene expression related to bHR/bLR phenotype across development and adulthood in the hippocampus, a region critical for emotional regulation. We meta-analyzed eight transcriptional profiling datasets (microarray, RNA-Seq) spanning 43 generations of selective breeding (adult: n =46, P7: n =22, P14: n =49, P21: n =21; all male). We cross-referenced these results with exome sequencing performed on our colony to pinpoint candidates likely to mediate the effect of selective breeding on behavioral phenotype. Results Genetic and transcriptional profiling results converged to implicate two genes with previous associations with metabolism and mood: Thyrotropin releasing hormone receptor and Uncoupling protein 2. Our results also highlighted bHR/bLR functional differences in the hippocampus, including a network essential for neurodevelopmental programming, proliferation, and differentiation, containing hub genes Bone morphogenetic protein 4 and Marker of proliferation ki-67. Finally, we observed differential expression related to microglial activation, which is important for synaptic pruning, including two genes within implicated chromosomal regions: Complement C1q A chain and Milk fat globule-EGF factor 8. Conclusion These candidate genes and functional pathways have the capability to direct bHR/bLR rats along divergent developmental trajectories and promote a widely different reactivity to the environment.

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