Department of Biochemistry and Molecular Genetics, and Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
J Neurosci. 2010 Jul 28;30(30):9967-72. doi: 10.1523/JNEUROSCI.1988-10.2010.
Sexual behavior is variable between individuals, ranging from celibacy to sexual addictions. Within normal populations of individual men, ranging from young to middle aged, testosterone levels do not correlate with libido. To study the genetic mechanisms that contribute to individual differences in male sexual behavior, we used hybrid B6D2F1 male mice, which are a cross between two common inbred strains (C57BL/6J and DBA/2J). Unlike most laboratory rodent species in which male sexual behavior is highly dependent upon gonadal steroids, sexual behavior in a large proportion of these hybrid male mice after castration is independent of gonadal steroid hormones and their receptors; thus, we have the ability to discover novel genes involved in this behavior. Gene expression arrays, validation of gene candidates, and transgenic mice that overexpress one of the genes of interest were used to reveal genes involved in maintenance of male sexual behavior. Several genes related to neuroprotection and neurodegeneration were differentially expressed in the hypothalamus of males that continued to mate after castration. Male mice overexpressing the human form of one of these candidate genes, amyloid beta precursor protein (APP), displayed enhanced sexual behavior before castration and maintained sexual activity for a longer duration after castration compared with controls. Our results reveal a novel and unexpected relationship between APP and male sexual behavior. We speculate that declining APP during normal aging in males may contribute to the loss of sexual function.
性行为在个体之间存在差异，范围从独身到性成瘾。在个体男性的正常人群中，从年轻到中年，睾丸激素水平与性欲无关。为了研究导致男性性行为个体差异的遗传机制，我们使用了杂交 B6D2F1 雄性小鼠，这是两种常见近交系（C57BL/6J 和 DBA/2J）的杂交种。与大多数依赖性腺类固醇的雄性性行为高度依赖于性腺类固醇的实验室啮齿动物物种不同，这些杂交雄性小鼠中的很大一部分在去势后，其性行为独立于性腺类固醇激素及其受体；因此，我们有能力发现参与这种行为的新基因。使用基因表达阵列、基因候选物的验证和过表达感兴趣基因之一的转基因小鼠，揭示了维持男性性行为的相关基因。在去势后仍继续交配的雄性下丘脑，一些与神经保护和神经退行性变相关的基因表达存在差异。与对照组相比，过表达这些候选基因之一的人类形式——淀粉样前体蛋白（APP）的雄性小鼠，在去势前表现出增强的性行为，并且在去势后维持性行为的时间更长。我们的研究结果揭示了 APP 与男性性行为之间的一种新的、出人意料的关系。我们推测，男性正常衰老过程中 APP 的下降可能导致性功能丧失。
