Stack Conor M, Lim Maria A, Cuasay Katrina, Stone Madeleine M, Seibert Kimberly M, Spivak-Pohis Irit, Crawley Jacqueline N, Waschek James A, Hill Joanna M
Laboratory of Behavioral Neuroscience, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Exp Neurol. 2008 May;211(1):67-84. doi: 10.1016/j.expneurol.2008.01.003. Epub 2008 Jan 19.
Blockage of vasoactive intestinal peptide (VIP) receptors during early embryogenesis in the mouse has been shown to result in developmental delays in neonates, and social behavior deficits selectively in adult male offspring. Offspring of VIP deficient mothers (VIP +/-) also exhibited developmental delays, and reductions in maternal affiliation and play behavior. In the current study, comparisons among the offspring of VIP deficient mothers (VIP +/-) mated to VIP +/- males with the offspring of wild type (WT) mothers mated to VIP +/- males allowed assessment of the contributions of both maternal and offspring VIP genotype to general health measures, social behavior, fear conditioning, and spatial learning and memory in the water maze. These comparisons revealed few differences in general health among offspring of WT and VIP deficient mothers, and all offspring exhibited normal responses in fear conditioning and in the acquisition phase of spatial discrimination in the water maze. WT mothers produced offspring that were normal in all tests; the reduced VIP in their VIP +/- offspring apparently did not contribute to any defects in the measures under study. However, regardless of their own VIP genotype, all male offspring of VIP deficient mothers exhibited severe deficits in social approach behavior and reversal learning. The deficits in these behaviors in the female offspring of VIP deficient mothers were less severe than in their male littermates, and the extent of their impairment was related to their own VIP genotype. This study has shown that intrauterine conditions had a greater influence on behavioral outcome than did genetic inheritance. In addition, the greater prevalence of deficits in social behavior and the resistance to change seen in reversal learning in the male offspring of VIP deficient mothers indicate a potential usefulness of the VIP knockout mouse in furthering the understanding of neurodevelopmental disorders such as autism.
在小鼠胚胎发育早期阻断血管活性肠肽（VIP）受体已被证明会导致新生儿发育延迟，并选择性地导致成年雄性后代出现社会行为缺陷。VIP基因缺陷母亲（VIP+/-）的后代也表现出发育延迟，以及母婴依恋和玩耍行为减少。在本研究中，将VIP基因缺陷母亲（VIP+/-）与VIP+/-雄性交配产生的后代，与野生型（WT）母亲与VIP+/-雄性交配产生的后代进行比较，从而评估母体和后代VIP基因型对一般健康指标、社会行为、恐惧条件反射以及水迷宫中的空间学习和记忆的影响。这些比较显示，WT和VIP基因缺陷母亲的后代在一般健康方面几乎没有差异，并且所有后代在恐惧条件反射和水迷宫空间辨别习得阶段均表现出正常反应。WT母亲所产后代在所有测试中均正常；其VIP+/-后代中VIP的减少显然并未导致所研究指标出现任何缺陷。然而，无论自身VIP基因型如何，VIP基因缺陷母亲的所有雄性后代在社会接近行为和逆向学习方面均表现出严重缺陷。VIP基因缺陷母亲的雌性后代在这些行为上的缺陷不如其雄性同窝仔严重，并且其受损程度与其自身的VIP基因型有关。本研究表明，宫内环境对行为结果的影响大于遗传因素。此外，VIP基因缺陷母亲的雄性后代中社会行为缺陷更为普遍，且在逆向学习中表现出对变化的抵抗力，这表明VIP基因敲除小鼠在进一步了解自闭症等神经发育障碍方面具有潜在用途。
