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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.

描述女性性功能障碍的主要特征是性唤起水平低，欲望由于没有有效的治疗方法存在的障碍，性欲的妇女，食品药品监督管理局尽管缺乏临床证据，这种药物有任何治疗效果无法建立一个合理的开发治疗女性性欲障碍的方法是缺乏在临床前模型中研究女性性欲的机制基础。我们有我开发了一个叙利亚仓鼠的性欲模型，它包含了几个基本要素需要将这些发现转化为女性。我们开发了一个程序来评估女性性行为的奖励属性，据报道，女性缺乏这种元素性欲低下。性欲低下的女性也不会主动与男性发生性接触。配偶或伴侣。在这方面，我们发现了一种实验方法来测试雌仓鼠主动与雄仓鼠进行性接触的意愿。根据这些仓鼠我们的研究表明，与男性发生性关系的回报以增加雌性的性接触。我们进一步确定了中脑边缘多巴胺系统和前额叶皮层神经元传入，集中在延髓核，作为一个关键的神经节点调解性行为的奖励效果的女性。的本提案中的研究采取三种具体方法，对女性性欲的神经生物学的理解。在第一个目标中，我们将使用抑制性 DREADDs，以确定多巴胺和谷氨酸传入的相对贡献，性奖赏的发展和性互动的启动和雄性仓鼠的关系我们还将研究这些传入的贡献，树突棘形态学的变化导致女性性经验。第二 aim采用了一种发现的方法来检查三种可能的细胞内信号通路介导性经验对行为和形态可塑性的影响。最后一 aim将自动操纵单个信号通路，以确定这些途径是治疗药物开发的潜在分子靶点，女人的性欲总的来说，这项研究将采取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治疗