Neurobiology of Female Sexual Desire

女性性欲的神经生物学

基本信息

批准号：
10260871
负责人：
Robert L Meisel
金额：
$ 5.61万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2024-02-29
项目状态：
已结题

项目摘要

DESCRIPTION Sexual dysfunction in women is primarily characterized by low levels of sexual arousal and desire. Because no effective treatments exist for disorders of sexual desire in women, the FDA was pressured to fast-track approval for the drug Addyi despite the absence of clinical evidence that the drug provided any therapeutic benefit. Underlying the inability to construct a rational approach to developing therapeutics for disorders of sexual desire in women is the lack of research on the mechanistic basis for female sexual desire in pre-clinical models. We have developed a Syrian hamster model of sexual desire that captures several essential elements needed to translate the findings to women. We developed a procedure to evaluate the rewarding properties of female sexual behavior, an element reported to be lacking in women with low sexual desire. Women with low sexual desire also do not initiate sexual contacts with their spouse or partner. In this regard we discovered an experimental approach to test the female hamster's willingness to initiate sexual contacts with a male. Based on these hamster studies we demonstrated that the rewarding consequences of sexual interactions with a male feed forward to increase the female's sexual contacts. We further identified the mesolimbic dopamine system, and prefrontal glutamatergic afferents, centered on the nucleus accumbens, as a critical neural node mediating the rewarding effects of sexual behavior in females. The research in this proposal takes three specific approaches to establish a programmatic understanding of the neurobiology of female sexual desire. In the first aim we will use inhibitory DREADDs to determine the relative contribution of dopamine and glutamate afferents to the nucleus accumbens to the development of sexual reward and initiation of sexual interactions with the male in our hamster model. We will also examine the contributions of these afferents to changes in dendritic spine morphology consequent to female sexual experience. The second aim takes a discovery approach to examining three possible intracellular signaling pathways mediating the effects of sexual experience on behavioral and morphological plasticity. The last aim will pharmacologically manipulate the individual signaling pathways to identify which of these pathways are potential molecular targets for therapeutic development to treat problems of sexual desire in women. Collectively this research will take a systematic approach to developing a neurobiology of female sexual desire with an eye to the rational development of effective therapies.

描述女性的性功能障碍主要以低水平的性唤醒和特征欲望。因为没有有效的女性性欲疾病治疗，所以FDA 尽管没有临床证据该药物提供了任何治疗益处。根本无法构建理性的为女性发展治疗症的方法是缺乏基于临床前模型中女性性欲的机械基础的研究。我们有开发了叙利亚性仓鼠的性欲模型，该模型捕获了几个基本要素需要将发现转化为女性。我们制定了一个评估的程序女性性行为的奖励特性，据报道女性缺乏元素性欲低下。性欲低下的妇女也不会与他们的配偶或伴侣。在这方面，我们发现了一种测试的实验方法女仓鼠愿意与男性发生性接触。基于这些仓鼠我们的研究表明，与男性性互动的有益后果向前喂食以增加女性的性接触。我们进一步识别了中脑的多巴胺系统和前额谷氨酸能传入，以伏隔核为中心作为介导女性性行为的有益影响的关键神经节点。这该提案中的研究采用三种特定方法来建立程序化了解女性性欲的神经生物学。在第一个目标中，我们将使用抑制作用恐怖分以确定多巴胺和谷氨酸传入对相对的贡献核心振容性奖励的发展和性互动的启动与我们的仓鼠模型中的男性。我们还将研究这些传入对女性性经历导致的树突状脊柱形态的变化。第二个 AIM采用发现检查三个可能的细胞内信号通路的方法介导性经验对行为和形态可塑性的影响。最后 AIM将在药理上操纵单个信号通路，以识别哪个这些途径是治疗治疗问题的潜在分子靶标女性的性欲。总的来说，这项研究将采用系统的方法来开发女性性欲的神经生物学，着眼于有效的理性发展疗法。