Olfactory Circuits for Reproduction and Reward

用于繁殖和奖励的嗅觉回路

• 批准号: 7986358
• 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/7986358
• 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

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.

描述（由申请人提供）：在人类中，暴露于体气味的人可以产生性别特异性的神经内分泌反应，允许根据主要组织相容性等位基因的差异来歧视香气，并依赖性依赖性地激活与生殖有关的下丘脑的区域。但是，未能确定此类信号访问生殖电路的神经途径阻碍了我们对人类“信息素”如何影响行为的理解。此外，尽管动物有证据表明这种生物学相关的气味可能是自然的奖励，但介导的增强剂的气味传达给中菜的多巴胺系统的途径尚未确定。使用小鼠，我们已经确定了主嗅球（MOB）对内侧杏仁核（ME）的直接投影，该杏仁核（ME）投射到控制繁殖的下丘脑的区域。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。由于小鼠中的主要和附属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在调节控制性动机和奖励的嗅觉线索中的响应。首先，我们将确定从腹虫到ME的直接途径是否被两个性别中的男性和女性尿挥发物差异激活，以及成人接触睾丸激素是否会调节此类反应的强度。接下来，我们将确定表达TRP阳离子通道项目的M5亚型的子集是否向我支配二尖瓣细胞支配并有选择地响应异性尿路挥发物的MOB肾小球。因为我们已经观察到，许多腹部暴子投影也将分支发送到嗅皮层，所以我们将绘制这些投影的靶标，以确定嗅觉皮质中的特定位点是否优先支配并在男性和女性中有所不同。 Choi等人（2005年）提出，小鼠的生殖意义气味激活了在质子末端（BNST）中表达转录因子LHX6的神经元的回路（BNST），然后在腹膜内侧下丘脑下丘脑核（VMH）中终止。我们将在LHX6中选择性地诱导雄性小鼠的ME，BNST和VMH的神经元的主要诱导FOS（神经元活性的标志），确定主要与附属嗅觉输入的程度，并确定这些神经元是否将轴突发送到腹侧段落区域，是否将轴突发送到腹膜细胞的位置，多巴胺类细胞的位置。最后，我们将使用条件的地方偏好范例来比较雄性小鼠中主要与附件系统检测到的体气味的激励质量。我们的结果应提供对嗅觉和边缘电路的洞察力，这些嗅觉和边缘电路会处理生殖出色的气味提示，还可以帮助阐明该机制，从而在人类中控制性别伴侣的偏好和性伴侣，从而使非野性（视觉，听觉或纯粹的认知）输入。我们已经确定了从小鼠鼻子的气味传感器到大脑部分的新直接连接，对交配很重要。在人类中保存这一途径可能有助于解释其他结果，表明体味成分可以激活人们的类似大脑区域。我们建议在小鼠中研究这种途径，以确定可能如何参与调节伴侣选择，性动机和奖励的气味。