Stashi Erin, Wang Lei, Mani Shailaja K, York Brian, O'Malley Bert W
Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030.
Mol Endocrinol. 2013 Oct;27(10):1776-87. doi: 10.1210/me.2013-1192. Epub 2013 Aug 8.
Steroid receptor coactivators (SRCs) are important transcriptional modulators that regulate nuclear receptor and transcription factor activity to adjust transcriptional output to cellular demands. Highlighting their pleiotropic effects, dysfunction of the SRCs has been found in numerous pathologies including cancer, inflammation, and metabolic disorders. The SRC family is expressed strongly in the brain including the hippocampus, cortex, and hypothalamus. Studies focusing on the effect of SRC loss using congenic SRC knockout mice (SRC(-/-)) are limited in number, yet strongly indicate that the SRCs play important roles in regulating reproductive behavior, development, and motor coordination. To better understand the unique functions of the SRCs, we performed a neurobehavioral test battery focusing on anxiety and exploratory behaviors, motor coordination, sensorimotor gating, and nociception in both male and female null mice and compared them with their wild-type (WT) littermates. Results from the test battery reveal a role for SRC1 in motor coordination. Additionally, we found that SRC1 regulates anxiety responses in SRC1(-/-) male and female mice, and nociception sensitivity in SRC1(-/-) male but not female mice. By comparison, SRC2 regulates anxiety response with SRC2(-/-) females showing decreased anxiety in novel environments, as well as increased exploratory behavior in the open field compared with WT littermates. Additionally, SRC2(-/-) males were shown to have deficits in sensorimotor gating. Loss of SRC3 also shows sex differences in anxiety and exploratory behaviors. In particular, SRC3(-/-) female mice have increased anxiety and reduced exploratory activity and impairments in prepulse inhibition, whereas SRC3(-/-) male mice show no significant behavioral differences. In both genders, ablation of SRC3 decreases nocifensive behaviors. Collectively, these resource data suggest that loss of the SRCs results in behavioral phenotypes, underscoring the importance of understanding both the general and gender-based activity of SRCs in the brain.
类固醇受体辅激活因子（SRCs）是重要的转录调节因子，可调节核受体和转录因子活性，以根据细胞需求调整转录输出。SRCs功能失调在包括癌症、炎症和代谢紊乱在内的多种病理状况中均有发现，凸显了它们的多效性作用。SRC家族在大脑中高度表达，包括海马体、皮质和下丘脑。使用同源SRC基因敲除小鼠（SRC(-/-)）研究SRC缺失效应的研究数量有限，但有力地表明SRCs在调节生殖行为、发育和运动协调方面发挥重要作用。为了更好地理解SRCs的独特功能，我们对雄性和雌性基因敲除小鼠进行了一系列神经行为测试，重点关注焦虑和探索行为、运动协调、感觉运动门控和伤害感受，并将它们与其野生型（WT）同窝小鼠进行比较。测试结果显示SRC1在运动协调中发挥作用。此外，我们发现SRC1调节SRC1(-/-)雄性和雌性小鼠的焦虑反应，以及SRC1(-/-)雄性而非雌性小鼠的伤害感受敏感性。相比之下，SRC2调节焦虑反应，SRC2(-/-)雌性小鼠在新环境中表现出焦虑降低，与WT同窝小鼠相比，在旷场试验中的探索行为增加。此外，SRC2(-/-)雄性小鼠在感觉运动门控方面存在缺陷。SRC3缺失在焦虑和探索行为方面也表现出性别差异。特别是，SRC3(-/-)雌性小鼠焦虑增加、探索活动减少且前脉冲抑制受损，而SRC3(-/-)雄性小鼠未表现出明显的行为差异。在两性中，SRC3缺失均会降低伤害防御行为。总体而言，这些资源数据表明SRCs缺失会导致行为表型，强调了了解SRCs在大脑中的一般活性和基于性别的活性的重要性。
