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.
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.
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DOI：
10.1016/j.biopsych.2020.05.024
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发表时间：
2021-02-15
影响因子：
10.6
通讯作者：
Akil H
中科院分区：
文献类型：
--
作者：
Birt IA;Hagenauer MH;Clinton SM;Aydin C;Blandino P Jr;Stead JDH;Hilde KL;Meng F;Thompson RC;Khalil H;Stefanov A;Maras P;Zhou Z;Hebda-Bauer EK;Goldman D;Watson SJ Jr;Akil H
在超过16年的时间里，我们有选择地培育了在新环境中进行高水平或低水平探索活动的大鼠。这些培育的高反应者(BHR)和培育的低反应者(BLR)大鼠建立了气质极端的模型，表现出与情绪和物质使用障碍相关的内化和外化行为的巨大差异。我们通过荟萃分析8个转录图谱数据集(微阵列和RNA测序)，分析了43代选择性繁殖(出生后7天：22；出生后14天：49；出生后21天：n=21；成年：n=46；均为男性)海马体中与Bhr/Blr表型相关的基因表达在发育和成年期之间的持续差异。我们通过外显子组测序交叉参考我们群体内的表达差异，以确定可能介导选择性育种对行为表型影响的候选基因。将结果与其他饲养的大鼠模型的海马区图谱进行比较。遗传和转录分析结果汇聚在一起，发现了多个候选基因，其中包括之前与新陈代谢和情绪相关的两个基因：Trhr和Ucp2。结果还强调了Bhr/Blr在海马区的功能差异，包括以Bmp4和Mki67为中心的神经发育编程、增殖和分化所必需的网络。最后，我们观察到与小胶质细胞激活相关的差异表达，这对突触修剪很重要，包括相关染色体区域的两个基因：C1qA和Mfge8。这些候选基因和功能通路可能会引导BHR/BLR大鼠沿着不同的发育轨迹，并促进对环境的截然不同的反应。
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. 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 cross-referenced 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. 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. These candidate genes and functional pathways may direct bHR/bLR rats along divergent developmental trajectories and promote a widely different reactivity to the environment.
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影响因子：
5.3
作者：
Cerezo, Ana;Guadamillas, Marta C.;del Pozo, Miguel A.
通讯作者：
del Pozo, Miguel A.
影响因子：
11
作者：
Brooker SM;Gobeske KT;Chen J;Peng CY;Kessler JA
通讯作者：
Kessler JA
影响因子：
4.3
作者：
Cole AE;Murray SS;Xiao J
通讯作者：
Xiao J
影响因子：
9.8
作者：
Cichon, Sven;Muehleisen, Thomas W.;Noethen, Markus M.
通讯作者：
Noethen, Markus M.
影响因子：
3.3
作者：
Albert, Frank W.;Carlborg, Orjan;Paabo, Svante
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Paabo, Svante