Genetic Liability for Internalizing Versus Externalizing Behavior Manifests in the Developing and Adult Hippocampus: Insight From a Meta-analysis of Transcriptional Pro fi ling Studies in a Selectively Bred Rat Model

被引：11

作者：

Birt, Isabelle A. ^{[1
]}

Hagenauer, Megan H. ^{[1
]}

Clinton, Sarah M. ^{[2
]}

Aydin, Cigdem ^{[1
]}

Blandino, Peter ^{[1
]}

Stead, John D. H. ^{[3
]}

Hilde, Kathryn L. ^{[1
]}

Meng, Fan ^{[1
]}

Thompson, Robert C. ^{[1
]}

Khalil, Huzefa ^{[1
]}

Stefanov, Alex ^{[1
]}

Maras, Pamela ^{[1
]}

Zhou, Zhifeng ^{[4
]}

Hebda-Bauer, Elaine K. ^{[1
]}

Goldman, David ^{[4
]}

Watson, Stanley J. ^{[1
]}

Akil, Huda ^{[1
]}

机构：

[1] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA

[2] Virginia Tech, Sch Neurosci, Blacksburg, VA USA

[3] Carleton Univ, Dept Neurosci, Ottawa, ON, Canada

[4] NIAAA, NIH, Bethesda, MD USA

来源：

BIOLOGICAL PSYCHIATRY | 2021年 / 89卷 / 04期

关键词：

BONE MORPHOGENETIC PROTEINS; NOVELTY-SEEKING BEHAVIOR; INDIVIDUAL-DIFFERENCES; UNCOUPLING PROTEIN-2; ANIMAL-MODEL; DRUG-ABUSE; STEM-CELLS; STRESS; ANXIETY; EXPRESSION;

D O I：

10.1016/j.biopsych.2020.05.024

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

BACKGROUND: For more than 16 years, we have selectively bred rats for either high or low levels of exploratory activity within a novel environment. These bred high-responder (bHR) and bred low-responder (bLR) rats model temperamental extremes, exhibiting large differences in internalizing and externalizing behaviors relevant to mood and substance use disorders. METHODS: We characterized persistent differences in gene expression related to bHR/bLR phenotype across development and adulthood in the hippocampus, a region critical for emotional regulation, by meta-analyzing 8 transcriptional profiling datasets (microarray and RNA sequencing) spanning 43 generations of selective breeding (postnatal day 7: n = 22; postnatal day 14: n = 49; postnatal day 21: n = 21; adult: n = 46; all male). We crossreferenced expression differences with exome sequencing within our colony to pinpoint candidates likely to mediate the effect of selective breeding on behavioral phenotype. The results were compared with hippocampal profiling from other bred rat models. RESULTS: Genetic and transcriptional profiling results converged to implicate multiple candidate genes, including two previously associated with metabolism and mood: Trhr and Ucp2. Results also highlighted bHR/bLR functional differences in the hippocampus, including a network essential for neurodevelopmental programming, proliferation, and differentiation, centering on Bmp4 and Mki67. Finally, we observed differential expression related to microglial activation, which is important for synaptic pruning, including 2 genes within implicated chromosomal regions: C1qa and Mfge8. CONCLUSIONS: These candidate genes and functional pathways may direct bHR/bLR rats along divergent developmental trajectories and promote a widely different reactivity to the environment.

引用

页码：339 / 355

页数：17