Olfactory Circuits for Reproduction and Reward

人体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和性别激活对气味的识别 下丘脑中与生殖有关的区域。然而，未能确定神经通路通过 这些信号进入生殖回路，阻碍了我们对人类“信息素”如何 影响行为。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会起到自然的作用 奖赏，气味被传递到中脑边缘多巴胺系统的途径，它调节 增援力量尚未确定。在老鼠身上，我们发现了主嗅球的直接投射。 (MOB)到杏仁内侧核(Me)，它投射到下丘脑中控制生殖的区域。 在人类中保存这一途径可以解释气味如何影响性伴侣的偏好和交配 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，我们 将比较每个系统在调节对控制性别的嗅觉线索的反应中的参与程度 激励和奖励。首先，我们将确定从腹侧暴徒到我的直接路径是否是 男性和女性尿挥发性物质激活的差异以及成人是否暴露于 睾丸素调节这种反应的强度。接下来我们将确定嗅觉的一个子集 表达Trp阳离子通道M5亚型的感觉神经元投射到 被我支配，投射二尖瓣细胞，对异性尿挥发物有选择性的反应。因为我们 观察到许多向Me的腹侧暴民投射也向嗅皮层发出分支，我们 将绘制这些投射的目标图，以确定嗅皮层中的特定位置是否优先 受神经支配，并在雄性和雌性上有所不同。Choi等人(2005)认为，气味的生殖意义在 小鼠激活纹状体Me和床核中表达转录因子Lhx6的神经元电路 终末(BNST)，然后终止于下丘脑腹内侧核(VMH)。我们将确定 在Lhx6中，主嗅觉输入与副嗅觉输入选择性地诱导Fos(神经元活动的标志)的程度。 在雄性小鼠的Me、BNST和VMH内表达神经元，并确定这些神经元是否发出轴突 腹侧被盖区，中脑边缘系统的多巴胺能胞体的位置。最后，我们会 使用有条件的地点偏好范例来比较体味物质的刺激性质 雄性小鼠的主要和辅助系统。我们的研究结果应该有助于深入了解嗅觉和边缘神经回路。 这一过程可以复制出突出的气味提示，也可能有助于阐明非嗅觉的机制 (视觉、听觉或纯认知)输入控制性伴侣的偏好和人类的性唤起。

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.