Barrot Michel, Wallace Deanna L, Bolaños Carlos A, Graham Danielle L, Perrotti Linda I, Neve Rachael L, Chambliss Heather, Yin Jerry C, Nestler Eric J
Department of Psychiatry and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8357-62. doi: 10.1073/pnas.0500587102. Epub 2005 May 27.
Sexual deficits and other behavioral disturbances such as anxiety-like behaviors can be observed in animals that have undergone social isolation, especially in species having important social interactions. Using a model of protracted social isolation in adult rats, we observed increased anxiety-like behavior and deficits in both the latency to initiate sexual behavior and the latency to ejaculate. We show, using transgenic cAMP response element (CRE)-LacZ reporter mice, that protracted social isolation also reduces CRE-dependent transcription within the nucleus accumbens. This decrease in CRE-dependent transcription can be mimicked in nonisolated animals by local viral gene transfer of a dominant negative mutant of CRE-binding protein (CREB). We previously showed that this manipulation increases anxiety-like behavior. We show here that it also impairs initiation of sexual behavior in nonisolated animals, a deficit that can be corrected by anxiolytic drug treatment. This local reduction in CREB activity, however, has no influence on ejaculation parameters. Reciprocally, we used the viral transgenic approach to overexpress CREB in the nucleus accumbens of isolated animals. We show that this local increase in CREB activity completely rescued the anxiety phenotype of the isolated animals, as well as their deficit in initiating sexual behavior, but failed to rescue the deficit in ejaculation. Our data suggest a role for the nucleus accumbens in anxiety responses and in specific aspects of sexual behavior. The results also provide insight into the molecular mechanisms by which social interactions affect brain plasticity and behavior.
在经历过社会隔离的动物中，尤其是在具有重要社会互动的物种中，可以观察到性缺陷和其他行为障碍，如焦虑样行为。利用成年大鼠长期社会隔离模型，我们观察到焦虑样行为增加，性行为启动潜伏期和射精潜伏期均出现缺陷。我们利用转基因环磷酸腺苷反应元件（CRE）-LacZ报告基因小鼠表明，长期社会隔离还会降低伏隔核内依赖CRE的转录。在未隔离的动物中，通过局部病毒基因转移CRE结合蛋白（CREB）的显性负突变体，可以模拟这种依赖CRE的转录减少。我们之前表明，这种操作会增加焦虑样行为。我们在此表明，它还会损害未隔离动物的性行为启动，这种缺陷可以通过抗焦虑药物治疗得到纠正。然而，CREB活性的这种局部降低对射精参数没有影响。相反，我们使用病毒转基因方法在隔离动物的伏隔核中过表达CREB。我们表明，CREB活性的这种局部增加完全挽救了隔离动物的焦虑表型及其性行为启动缺陷，但未能挽救射精缺陷。我们的数据表明伏隔核在焦虑反应和性行为的特定方面发挥作用。这些结果还为社会互动影响大脑可塑性和行为的分子机制提供了见解。
