Olfactory Circuits for Reproduction and Reward

描述(申请人提供)：在人类中，接触体臭可以产生性别特异性的神经内分泌反应，允许基于主要组织相容性等位基因的差异来辨别气味，并与性别相关地激活参与生殖的下丘脑区域。然而，未能确定这些信号进入生殖回路的神经路径，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起到自然奖励的作用，但气味传递到中脑边缘多巴胺系统的途径尚未确定。在老鼠身上，我们已经确定了主嗅球(MOB)到杏仁内侧核(Me)的直接投射，该投射到下丘脑中控制生殖的区域。在人类身上保存这一途径可以解释气味是如何影响性伴侣偏好和交配行为的。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参与调节对控制性动机和奖励的嗅觉线索的反应。首先，我们将确定从腹侧MOB到Me的直接通路是否被两性的男性和女性的尿液挥发物差异激活，以及成年后暴露于睾酮是否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亚型的一组嗅觉感觉神经元是否投射到被Me投射的二尖瓣细胞支配的肾小球，并选择性地对异性尿挥发物做出反应。因为我们已经观察到，许多到Me的腹侧暴民投射也向嗅皮层发送分支，所以我们将绘制这些投射的目标图，以确定嗅皮层中的特定部位是否优先受到神经支配，并在男性和女性之间存在差异。Choi等人(2005)提出，在小鼠身上，具有生殖意义的气味激活了终纹Me和床核(BNST)中表达转录因子Lhx6的神经元电路，然后终止于下丘脑腹内侧核(VMH)。我们将确定主和副嗅觉输入在多大程度上选择性地在雄性小鼠的Me、BNST和VMH的Lhx6表达神经元中诱导Fos(神经元活动的标志)，并确定这些神经元是否向腹侧被盖区发送轴突，以及中脑边缘系统的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由雄性小鼠的主系统和辅助系统检测到的体臭的刺激性质。我们的结果应该有助于深入了解嗅觉和边缘神经回路，这些神经回路负责处理可复制的显著气味线索，还可能有助于阐明非嗅觉(视觉、听觉或纯认知)输入控制性伴侣偏好和性唤醒的机制。我们已经确定了一种新的直接连接，从小鼠鼻子里的气味传感器到大脑中对交配至关重要的部分。在人类身上保存这一途径可能有助于解释其他结果，即体味成分可以激活人类类似的大脑区域。我们建议在小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.