Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States.
Department of Genetics, University of Tennessee Health Science Center, Memphis, Tennessee, United States.
Physiol Genomics. 2024 Apr 1;56(4):327-342. doi: 10.1152/physiolgenomics.00114.2023. Epub 2024 Feb 5.
This study investigated the interaction between genetic differences in stress reactivity/coping and environmental challenges, such as acute stress during adolescence on adult contextual fear memory and anxiety-like behaviors. Fischer 344 (F344) and the inbred F344;WKY-/Eer congenic strain (congenic), in which chromosomal regions from the Wistar-Kyoto (WKY) strain were introgressed into the F344 background, were exposed to a modified forced swim test during adolescence, while controls were undisturbed. In adulthood, fear learning and memory, assessed by contextual fear conditioning, were significantly greater in congenic animals compared with F344 animals, and stress during adolescence increased them even further in males of both strains. Anxiety-like behavior, measured by the open field test, was also greater in congenic than F344 animals, and stress during adolescence increased it further in both strains of adult males. Whole genome sequencing of the F344;WKY-/Eer strain revealed an enrichment of WKY genotypes in chromosomes 9, 14, and 15. An example of functional WKY sequence variations in the congenic strain, cannabinoid receptor interacting protein 1 () had a transcript isoform that lacked two exons. Although the original hypothesis that the genetic predisposition to increased anxiety of the WKY donor strain would exaggerate fear memory relative to the background strain was confirmed, the consequences of adolescent stress were strain independent but sex dependent in adulthood. Molecular genomic approaches combined with genetic mapping of WKY sequence variations in chromosomes 9, 14, and 15 could aid in finding quantitative trait genes contributing to the variation in fear memory. This study found that ) whole genome sequencing of congenic strains should be a criterion for their recognition; ) sequence variations between Wistar-Kyoto and Fischer 344 strains at regions of chromosomes 9, 14, and 15 contribute to differences in contextual fear memory and anxiety-like behaviors; and ) stress during adolescence affects these behaviors in males, but not females, and is independent of strain.
这项研究调查了遗传差异与环境挑战之间的相互作用，例如青春期的急性应激对成年情境恐惧记忆和焦虑样行为的影响。Fischer 344（F344）和近交系 F344；WKY-/Eer 同源导入系（同源导入系）在青春期接受了改良的强迫游泳测试，而对照组则未受干扰。在成年期，通过情境恐惧条件反射评估，同源导入系动物的恐惧学习和记忆明显高于 F344 动物，青春期的应激进一步增加了两种品系雄性动物的恐惧记忆。通过旷场试验测量的焦虑样行为也高于 F344 动物，青春期的应激进一步增加了两种品系雄性动物的焦虑样行为。F344；WKY-/Eer 品系的全基因组测序显示，WKY 基因型在染色体 9、14 和 15 上富集。同源导入系中功能性 WKY 序列变异的一个例子，大麻素受体相互作用蛋白 1（），有一种缺乏两个外显子的转录本异构体。尽管最初的假设是 WKY 供体品系增加焦虑的遗传倾向会使恐惧记忆相对于背景品系夸大，但青春期应激的后果在成年期是独立于品系但依赖于性别的。结合 WKY 序列在染色体 9、14 和 15 上的遗传图谱的分子基因组方法可以帮助寻找导致恐惧记忆变异的数量性状基因。本研究发现：（1）同源导入系的全基因组测序应该是其识别的标准；（2）染色体 9、14 和 15 区域的 Wistar-Kyoto 和 Fischer 344 菌株之间的序列变异导致了情境恐惧记忆和焦虑样行为的差异；（3）青春期的应激影响这些行为在雄性中，但不在雌性中，且独立于品系。
