Olfactory Circuits for Reproduction and Reward

描述（由申请人提供）：在人体中，暴露于身体气味可以产生性别特异性神经内分泌反应，允许基于主要组织相容性等位基因的差异来区分气味，以及涉及生殖的下丘脑的性别依赖性激活区域。然而，由于无法确定这些信号进入生殖回路的神经通路，阻碍了我们对人类“信息素”如何影响行为的理解。此外，尽管在动物身上有证据表明，这种生物相关的气味可能是一种自然的奖励，但气味传递给中脑边缘多巴胺系统的途径尚未被确定。在小鼠实验中，我们发现主嗅球（MOB）直接投射到内侧杏仁核（Me），内侧杏仁核投射到下丘脑控制繁殖的区域。在人类中保留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辅助嗅觉系统检测到，我们将比较每个系统在调节对嗅觉线索的反应时的参与，这些嗅觉线索控制着性动机和奖励。首先，我们将确定两性尿液挥发物是否不同地激活了从腹侧MOB到Me的直接通路，以及成人暴露于睾酮是否会调节这种反应的强度。接下来，我们将确定表达TRP阳离子通道M5亚型的嗅觉感觉神经元亚群是否会投射到由Me投射二尖瓣细胞支配的MOB肾小球，并选择性地对异性尿液挥出物做出反应。因为我们已经观察到，许多腹侧的MOB投射到Me也向嗅觉皮层发送分支，我们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，并且在男性和女性中存在差异。Choi等人（2005）认为，在小鼠中具有生殖意义的气味激活了终纹（BNST）中表达转录因子Lhx6的神经元回路，然后在下丘脑腹内侧核（VMH）终止。我们将确定主要和辅助嗅觉输入在多大程度上选择性地诱导雄性小鼠Me、BNST和VMH中表达Lhx6的神经元的Fos（神经元活动的标志物），并确定这些神经元是否将轴突发送到腹侧被皮层，即中脑边缘系统多巴胺能细胞体的位置。最后，我们将使用条件位置偏好范式来比较雄性小鼠主系统和辅助系统检测到的体臭的激励质量。我们的研究结果将有助于深入了解嗅觉和边缘回路对生殖显著气味线索的处理，也可能有助于阐明非嗅觉（视觉、听觉或纯认知）输入控制人类性伴侣偏好和性唤起的机制。我们已经发现了一种新的直接联系，从老鼠鼻子里的气味传感器到大脑中对交配很重要的部分。在人类中保留这一途径可能有助于解释其他结果，这些结果表明，体味成分可以激活人类类似的大脑区域。我们建议在老鼠身上研究这一途径，以确定气味如何参与调节配偶选择、性动机和奖励。

DESCRIPTION (provided by applicant): 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. We have identified a new direct connection from odor sensors in the nose of mice to parts of the brain important for mating. Preservation of this pathway in humans may help explain other results showing that body odor components can activate similar brain areas in people. We propose to study this pathway in the mouse to determine how odors may be involved in regulating mate choice, sexual motivation and reward.