Neurobiology of Female Sexual Desire

女性性欲的神经生物学

基本信息

批准号：
10590616
负责人：
Robert L Meisel
金额：
$ 32.07万
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

来源：
https://reporter.nih.gov/project-details/10590616
关键词：
Age Animal Model Arousal Behavior Behavioral Chemosensitization Clinical Conflict (Psychology)Dendritic Spines Development Disease Distress Dopamine Dopamine D1 Receptor Drug Approval Elements Eye Failure Female GTP-Binding Proteins Glutamates Goals Hamsters Individual Link Literature MAP kinase activator MAPK3 gene Measures Mediating Mesocricetus auratus Mitogen-Activated Protein Kinases Modeling Molecular Molecular Target Morphology Motivation Neurobiology Neurons Neurotransmitters Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Phosphorylation Pre-Clinical Model Prefrontal Cortex Prevalence Procedures Process Property Reporting Research Rewards Rodent Severities Sex Behavior Sexual Arousal Sexual Dysfunction Signal Pathway Signal Transduction Signaling Protein Source Spouses Testing Therapeutic Translating Viral Woman base behavioral plasticity conditioned place preference density design designer receptors exclusively activated by designer drugs drug development effective therapy experience interest male mesolimbic system molecular targeted therapies neural novel pharmacologic pre-clinical pressure prevent public health relevance reproductive self esteem sexual debut therapeutic development therapeutic target willingness

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下欲望。由于尚无针对女性性欲障碍的有效治疗方法，FDA 尽管缺乏临床证据，但仍被迫快速批准药物 Addyi 该药物提供了任何治疗益处。无法构建理性的根本原因开发治疗女性性欲障碍的方法是缺乏临床前模型中女性性欲机制基础的研究。我们有开发了叙利亚仓鼠的性欲模型，该模型捕捉了几个基本要素需要将研究结果转化为女性。我们开发了一个程序来评估女性性行为的奖励特性，据报道女性缺乏这一要素性欲低下。性欲低下的女性也不会主动与性接触他们的配偶或伴侣。在这方面，我们发现了一种实验方法来测试雌性仓鼠是否愿意与雄性进行性接触。基于这些仓鼠我们的研究表明，与男性发生性行为的有益后果前馈以增加雌性的性接触。我们进一步确定了中边缘多巴胺系统和前额叶谷氨酸传入神经，以伏隔核为中心，作为介导女性性行为的奖励效应的关键神经节点。这该提案的研究采用了三种具体方法来建立一个计划性的方案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 DREADDs 确定多巴胺和谷氨酸传入对大脑的相对贡献伏隔核负责性奖赏的发展和性互动的启动与我们仓鼠模型中的雄性。我们还将研究这些传入神经的贡献女性性经历导致树突棘形态的变化。第二个 Target 采用发现方法来检查三种可能的细胞内信号通路调节性经历对行为和形态可塑性的影响。最后一个目的是通过药理学手段操纵各个信号通路来识别哪些信号通路这些途径是治疗开发治疗问题的潜在分子靶点女性的性欲。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，着眼于有效性欲的合理发展疗法。