Olfactory Circuits for Reproduction and Reward

用于繁殖和奖励的嗅觉回路

• 批准号: 8197182
• 负责人: JAMES A. CHERRY
• 金额: $ 29.78万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-05 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197182
• 关键词: Accessory Olfactory Bulbs; Adult; Affect; Afferent Neurons; Alleles; Amygdaloid structure; Animals; Area; Auditory; Axon; Behavior; Biological Preservation; Brain; Brain Part; Brain region; Cations; Cell Nucleus; Cells; Cholera Toxin; Cognitive; Cues; Data; Discrimination; Dopaminergic Cell; Dorsal; Environment; Estrus; Exposure to; Failure; Female; Fiber; Future; Goals; Gonadal Steroid Hormones; Heterogeneity; Histocompatibility; Hormones; Human; Human Pheromones; Human body; Hypothalamic structure; Image; Incentives; Injection of therapeutic agent; Label; Laboratories; Lesion; Link; Location; Mammals; Maps; Medial; Mediating; Motivation; Mus; Neural Pathways; Neurons; Neurosecretory Systems; Nose; Odors; Olfactory Cortex; Olfactory Epithelium; Olfactory Pathways; Partner in relationship; Pathway interactions; Pattern; Peripheral; Preparation; Process; Prosencephalon; Psychological reinforcement; Reporting; Reproduction; Research; Rewards; Route; Sensory; Sex Characteristics; Sexual Arousal; Sexual Partners; Signal Transduction; Site; Social Perception; Stereotyping; Stimulus; Structure of terminal stria nuclei of preoptic region; System; TRPM5 gene; Testing; Testosterone; Time; Tracer; Ventral Tegmental Area; Visual; Woman; base; exposed human population; insight; male; men; mesolimbic system; neuronal cell body; olfactory bulb; preference; relating to nervous system; reproductive; response; sensor; sex; social communication; transcription factor; urinary; ventromedial hypothalamic nucleus

In humans exposure to body odorants can produce sex-specific neuroendocrine responses, permit the discrimination of scents based on differences in major histocompatibility alleles, and sex-dependently activate regions of the hypothalamus involved in reproduction. However, failure to identify the neural pathways through which such signals access reproductive circuits has impeded our understanding of how human "pheromones" may affect behavior. Moreover, despite evidence in animals that such biologically relevant odors may act as natural rewards, the routes through which odors are conveyed to the mesolimbic dopamine system that mediates reinforcement have yet to be identified. Using mice, we have identified a direct projection of the main olfactory bulb (MOB) to the medial amygdala (Me), which projects to areas in the hypothalamus that control reproduction. Preservation of this pathway in humans could explain how odors influence sex partner preference and mating behavior. As chemosignals can be detected by both the main and accessory olfactory systems in the mouse, we will compare the involvement of each system in regulating responses to olfactory cues that control sexual motivation and reward. First, we will determine whether the direct pathway from the ventral MOB to the Me is differentially activated by male and female urinary volatiles in the two sexes and whether adult exposure to testosterone modulates the intensity of such responses. Next we will determine whether a subset of olfactory sensory neurons that express the M5 subtype of a TRP cation channel project to MOB glomeruli that are innervated by Me projecting mitral cells and selectively respond to opposite-sex urinary volatiles. Because we have observed that many of the ventral MOB projections to the Me also send branches to the olfactory cortex, we will map the targets of these projections to determine if specific sites in the olfactory cortex are preferentially innervated and differ in males and females. Choi et al (2005) suggested that odors of reproductive significance in mice activate a circuit of neurons that express the transcription factor, Lhx6, in the Me and bed nucleus of the stria terminalis (BNST) and then terminate in the ventromedial hypothalamic nucleus (VMH). We will determine the extent to which main vs accessory olfactory inputs selectively induce Fos (a marker of neuronal activity) in Lhx6- expressing neurons in the Me, BNST and VMH of male mice, and determine whether these neurons send axons to the ventral tegmental area, the location of dopaminergic cell bodies of the mesolimbic system. Finally, we will use a conditioned place preference paradigm to compare the incentive qualities of body odorants detected by the main vs accessory systems in male mice. Our results should provide insight into the olfactory and limbic circuits that process reproductively salient odor cues, and may also help elucidate the mechanism whereby non-olfactory (visual, auditory, or purely cognitive) inputs control sex partner preference and sexual arousal in humans.

在人类中，暴露于身体气味可以产生性别特异性神经内分泌反应， 基于主要组织相容性等位基因差异的气味辨别， 下丘脑中与生殖有关的区域。然而，无法识别神经通路， 这些信号进入生殖回路的方式阻碍了我们对人类“信息素”如何 影响行为此外，尽管在动物中有证据表明，这种生物相关的气味可能会作为自然的， 奖赏，气味被传递到中脑边缘多巴胺系统的途径， 增援尚待确定。利用小鼠，我们已经确定了主要嗅球的直接投射， (MOB)到内侧杏仁核（Me），它投射到下丘脑中控制生殖的区域。 在人类中保存这一通路可以解释气味如何影响性伴侣偏好和交配 行为由于化学信号可以被小鼠的主嗅觉系统和副嗅觉系统检测到， 将比较每个系统在调节对控制性行为的嗅觉线索的反应中的参与情况， 动机和奖励。首先，我们将确定从腹侧MOB到Me的直接通路是否是 男性和女性尿挥发物在两种性别中的差异激活，以及成人暴露于 睾酮调节这种反应的强度。接下来，我们将确定是否有一个子集的嗅觉 表达TRP阳离子通道M5亚型的感觉神经元投射到MOB肾小球， 由Me支配的突出的二尖瓣细胞和选择性地响应于异性尿挥发物。因为我们 我们已经观察到，许多到Me的腹侧MOB投射也向嗅觉皮层发送分支， 将绘制这些投射的目标，以确定嗅觉皮层中的特定部位是否优先 受神经支配，并且在雄性和雌性中不同。Choi等人（2005年）认为，在哺乳动物中， 小鼠激活了纹状体的Me和床核中表达转录因子Lhx6的神经元回路 终末核（BNST），然后终止于下丘脑腹内侧核（VMH）。康贝特人将以 在Lhx6中，主要嗅觉输入与辅助嗅觉输入选择性诱导Fos（神经元活动的标志物）的程度。 在雄性小鼠的Me，BNST和VMH中表达神经元，并确定这些神经元是否发送轴突 腹侧被盖区，中脑边缘系统多巴胺能细胞体的位置。最后我们将 使用条件性位置偏好范式来比较由身体气味检测到的刺激质量， 雄性小鼠的主副系统。我们的研究结果应该能让我们更深入地了解嗅觉和大脑边缘回路 处理生殖性显著的气味线索，也可能有助于阐明非嗅觉的机制， （视觉，听觉或纯粹的认知）输入控制人类的性伴侣偏好和性唤起。