Hippocampal Gene Expression in bred High Responder (bHR) vs. bred Low Responder (bLR) Rats: RNA-Seq Data from Generation F37

The strong pattern of comorbidity amongst psychiatric disorders is believed to be generated by a spectrum of latent liability, arising from a complex interplay of genetic risk and environmental factors, such as stress and childhood adversity. At one end of this spectrum are internalizing disorders, which are associated with neuroticism, anxiety, and depression. At the other end of the spectrum are externalizing disorders, which are associated with risk-taking and novelty-seeking, as seen in mania, substance abuse, and impulse-control disorders. We model the genetic contributions underlying both extremes of this spectrum by selectively breeding rats that react differently to a novel environment. “Bred high responder” (bHR) rats are highly exploratory with a disinhibited, novelty-seeking temperament, including hyperactivity, aggression, and drug-seeking. “Bred low responder” (bLR) rats are highly-inhibited, exhibiting reduced locomotor activity and anxious and depressive-like behavior. These behavioral propensities are robust and stable, beginning early in development similar to temperament in humans. This RNA-sequencing study examined gene expression in the hippocampus, a region critical for emotional regulation, in generation F37 adult male bHR rats and bLR rats (n=6/group), as well as in rats that showed an intermediate locomotor response to a novel field (“bred Intermediate Responder” or bIR rats, n=6), which were obtained by cross-breeding F37 bHR and bLR rats. Prior to sacrifice, the animals experienced behavioral testing. Locomotor response to a novel environment was assessed between age P50–75 as part of our selective breeding paradigm. We also measured anxiety-like behavior in adulthood (bHR/bLR: P160-P167; bIR: P65-75) using the percent time spent in the open arms of an Elevated Plus Maze (EPM; 5 min test). These behavioral testing results are provided here along with the gene expression data.学界普遍认为，精神障碍间显著的共病模式，源于一系列潜在易感性谱，该谱由遗传风险与压力、童年逆境等环境因素的复杂交互作用所产生。该易感性谱的一端为内化障碍，与神经质、焦虑及抑郁症状相关；另一端则为外化障碍，与冒险行为、求新特质相关，这类特质可见于躁狂、物质滥用及冲动控制障碍患者中。本研究通过对新奇环境反应不同的大鼠进行选择性繁育，以此建模该易感性谱两端的遗传贡献机制。其中，繁育高反应型（bred high responder, bHR）大鼠具有高度探索性，表现出脱抑制、求新的气质特征，包括活动亢进、攻击行为及药物渴求行为；繁育低反应型（bred low responder, bLR）大鼠则表现出高度抑制性，活动能力降低，并呈现焦虑及类抑郁行为。这些行为倾向稳定且持久，在发育早期即已显现，与人类的气质特征类似。本项RNA测序（RNA-sequencing）研究检测了第37代（F37）成年雄性bHR、bLR大鼠（每组n=6）以及经F37代bHR与bLR大鼠杂交获得的、对新奇环境具有中等运动反应的繁育中等反应型（bred intermediate responder, bIR）大鼠（n=6）海马体中的基因表达水平——海马体是情绪调控的关键脑区。所有大鼠在剖杀前均接受了行为学测试。作为本研究选择性繁育范式的一部分，新奇环境下的运动反应在大鼠出生后第50至75日龄时进行评估。本研究还采用高架十字迷宫（Elevated Plus Maze, EPM，测试时长5分钟），通过大鼠在开放臂停留时间占比评估其成年期的类焦虑行为：其中bHR/bLR大鼠的测试时段为出生后第160至167日龄，bIR大鼠则为第65至75日龄。本研究同步提供行为学测试结果与基因表达数据。