MECHANISMS UNDERLYING OLFACTORY EFFECTS ON APPETITE

嗅觉影响食欲的机制

• 批准号: 10359795
• 负责人: Linda B Buck
• 金额: $ 69.71万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359795
• 关键词: Affect; Afferent Neurons; Appetitive Behavior; Area; Axon; Behavior; Body Weight; Brain; Desire for food; Eating; Food; Health; Human; Hypothalamic structure; Individual; Label; Ligands; Link; Location; Mammals; Maps; Messenger RNA; Methods; Molecular; Mus; Neurons; Nose; Odorant Receptors; Odors; Olfactory Cortex; Olfactory Epithelium; Olfactory Pathways; Peptides; Personal Satisfaction; Pro-Opiomelanocortin; Rodent; Role; Sensory; Signal Transduction; Stereotyping; Structure of nucleus infundibularis hypothalami; Synapses; Testing; Travel; activity marker; high throughput screening; increased appetite; insight; mad itch virus; neural circuit; olfactory bulb; olfactory bulb glomeruli; olfactory sensory neurons; presynaptic neurons; receptor; sensory input; transcriptome sequencing

Appetite is a basic drive that is essential to survival. The olfactory system can have potent effects on appetite in mammals, with certain odors stimulating appetite in humans, and either increasing or decreasing food intake and body weight in rodents. In the mouse, as in other mammals, olfactory sensory signals travel from olfactory sensory neurons in the nasal olfactory epithelium through the olfactory bulb to the olfactory cortex and then to other brain areas. Odorants are detected in the nose by ~1000 different odorant receptors (ORs), each expressed by a different subset of sensory neurons. Neurons with the same OR are scattered in one nasal spatial zone, but their axons converge in a few specific glomeruli in the olfactory bulb, creating a semi- stereotyped sensory map in which each glomerulus and its associated mitral and tufted relay neurons, which project to the cortex, appears dedicated to one OR. Signals from each glomerulus travel to multiple distinct areas of the olfactory cortex. How the vast array of sensory information generated by this organization might impact appetite is unexplored. To begin to investigate this question, we conducted preliminary studies on olfactory inputs to two subsets of neurons linked to appetite, both of which are located in the arcuate nucleus of the hypothalamus: AGRP (agouti related peptide) neurons, which can enhance appetite, and POMC (pro- opiomelanocortin) neurons, which can suppress appetite. We found that only some odors affect the activity of AGRP or POMC neurons and that different odors activate AGRP versus POMC neurons. Using a Pseudorabies virus (PRV) that travels retrogradely across multiple synapses, we found evidence for neurons upstream of AGRP and POMC neurons in the olfactory cortex, but only in certain olfactory cortical areas. These observations are consistent with the idea that some olfactory sensory inputs can have innate effects on appetite and that those effects involve genetically programmed neural circuits that convey signals from specific ORs in the nose through the olfactory system to hypothalamic neurons that regulate appetite. In the studies proposed in this application, we will test the hypotheses that 1) AGRP and POMC neurons can receive input from selected ORs that are similar among individuals and recognize odorants that affect the activity of the appetite neurons and appetite behaviors, 2) neurons within specific areas of the olfactory cortex can influence AGRP or POMC neuron activity and appetite-associated behaviors, and 3) odor-responsive neurons in other brain areas can relay signals from the olfactory cortex to AGRP or POMC neurons to modulate their activity and regulate behaviors associated with appetite. Together, these studies should provide significant new insights into the molecular mechanisms and neural circuits that govern the impact of olfactory sensory signals on appetite.

食欲是一种基本的驱动力，对生存至关重要。嗅觉系统对食欲有很强的影响 在哺乳动物中，某些气味刺激人类的食欲，增加或减少食物摄入量 和体重之间的关系老鼠和其他哺乳动物一样，嗅觉感觉信号从嗅觉器官传递到嗅觉器官。 鼻嗅上皮的感觉神经元通过嗅球到达嗅皮质， 其他脑区。气味在鼻子中被大约1000种不同的气味受体（OR）检测到， 由不同的感觉神经元子集表达。具有相同OR值的神经元散在分布于一侧鼻腔 空间区，但它们的轴突会聚在嗅球中的一些特定的肾小球中，形成半- 刻板的感觉地图，其中每个肾小球及其相关的二尖瓣和簇状中继神经元， 投射到大脑皮层，似乎是专用于一个手术室来自每个肾小球的信号传播到多个不同的 嗅觉皮层的区域这个组织产生的大量感官信息 影响食欲是未经探索的。为了开始研究这个问题，我们进行了初步研究， 嗅觉输入到与食欲相关的两个神经元亚群，这两个亚群都位于丘脑弓状核， 下丘脑：AGRP（agglutination related peptide）神经元，可增强食欲，POMC（pro- 阿黑皮素）神经元，其可以抑制食欲。我们发现只有某些气味会影响 AGRP或POMC神经元，不同的气味激活AGRP与POMC神经元。使用 伪狂犬病病毒（PRV）逆行穿越多个突触，我们发现了神经元的证据 上游的AGRP和POMC神经元的嗅觉皮层，但只在某些嗅觉皮层区域。 这些观察结果与一些嗅觉感官输入可以对大脑产生先天性影响的观点一致。 食欲，这些影响涉及遗传编程的神经回路，这些神经回路传递特定的信号， 鼻内的ORs通过嗅觉系统传递给调节食欲的下丘脑神经元。研究中 在本申请中提出的，我们将测试的假设，1）AGRP和POMC神经元可以接受输入 从选择的OR中，这些OR在个体之间是相似的，并且识别影响细胞活性的气味。 食欲神经元和食欲行为，2）嗅觉皮层特定区域内的神经元可以影响 AGRP或POMC神经元活动和食欲相关行为，和3）其他气味反应神经元 大脑区域可以将信号从嗅觉皮层传递到AGRP或POMC神经元，以调节它们的活动 并调节与食欲相关的行为。总之，这些研究应该提供重要的新的 深入了解控制嗅觉感觉信号影响的分子机制和神经回路 食欲。