Olfactory Circuits for Reproduction and Reward

描述（由申请人提供）：在人类中，暴露于体臭剂可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，并以性别依赖方式激活下丘脑中涉及生殖的区域。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，尽管在动物中有证据表明，这种生物相关的气味可能会作为自然奖励，气味传递到介导强化的中脑边缘多巴胺系统的途径尚未确定。使用小鼠，我们已经确定了一个直接投射的主要嗅球（MOB）的内侧杏仁核（Me），该项目在下丘脑的区域，控制生殖。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。由于小鼠的主要和辅助嗅觉系统都可以检测到化学信号，因此我们将比较每个系统对控制性动机和奖励的嗅觉线索的调节反应。首先，我们将确定是否从腹侧MOB到我的直接途径是由男性和女性的尿挥发物在两种性别差异激活，以及成年人是否暴露于睾酮调节这种反应的强度。接下来，我们将确定是否一个子集的嗅觉感觉神经元，表达M5亚型的TRP阳离子通道项目的MOB肾小球的神经支配的我投射二尖瓣细胞和选择性地响应于异性尿挥发物。因为我们已经观察到，许多腹侧MOB的预测，我也发送分支到嗅觉皮层，我们将映射这些预测的目标，以确定在嗅觉皮层的特定网站优先受神经支配，并在男性和女性的不同。Choi等人（2005年）提出，小鼠生殖意义的气味激活了一个神经元回路，该回路在终纹的Me和床核（BNST）中表达转录因子Lhx6，然后终止于下丘脑腹内侧核（VMH）。我们将确定在何种程度上主要与辅助嗅觉输入选择性诱导Fos（神经元活动的标志物）在Lhx6表达的神经元在我，BNST和VMH的雄性小鼠，并确定这些神经元是否发送轴突腹侧被盖区，多巴胺能细胞体的中脑边缘系统的位置。最后，我们将使用一个条件性位置偏爱范例，比较雄性小鼠的主要与辅助系统所侦测到的身体气味的刺激品质。我们的研究结果应该提供洞察嗅觉和边缘系统的电路，处理生殖显着的气味线索，也可能有助于阐明机制，即非嗅觉（视觉，听觉，或纯粹的认知）输入控制性伴侣的偏好和性唤起在人类。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。在人类中保存这一通路可能有助于解释其他结果，这些结果表明身体气味成分可以激活人类类似的大脑区域。我们建议在小鼠中研究这一通路，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.