Centrifugal regulation of olfactory function by melanin-concentrating hormone
黑色素浓缩激素对嗅觉功能的离心调节
基本信息
- 批准号:10610404
- 负责人:
- 金额:$ 31.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAcuteAddressAffectAnimalsAnteriorAreaAxonBehaviorBehavioralBiochemicalBiological AssayBrainBrain regionCellsCentral Nervous SystemChemicalsCiliaDetectionDiscriminationEatingEnvironmentExcisionFeeding behaviorsFoodFood deprivation (experimental)Functional disorderFutureGene ExpressionGenesGeneticGoalsGrantHealthHumanHungerHypothalamic structureImageImmediate-Early GenesInterneuronsLateralMCHR1 geneMapsMediatingModelingMolecularMonitorMusMutant Strains MiceNasal cavityNeuronsNeuropeptidesNeurophysiology - biologic functionObesityOdorsOlfactory EpitheliumOlfactory PathwaysOlfactory tubercleOrganellesOrganismPathway interactionsPatientsPeptidesPhenotypePhysiologicalPlayPopulationProcessQuality of lifeREM SleepRegulationResearchRoleSatiationSensorySignal PathwaySignal TransductionSiteSleepSleep DeprivationSmell PerceptionTechniquesTestingViralVolatilizationWakefulnessWestern BlottingWhole Body Plethysmographybehavior testbehavioral outcomebehavioral responsecellular targetingciliopathycircadiandesignexperimental studyfeedingfood restrictiongenetic manipulationglutamatergic signalinghabituationhormonal signalsinsightmelanin-concentrating hormonemelanin-concentrating hormone receptormitral cellmouse modelmutantneuroregulationolfactory bulbolfactory nucleiolfactory sensory neuronsopen field behaviorpharmacologicpiriform cortexreceptorresponsesensory mechanismsensory systemsleep patterntransmission process
项目摘要
Project Summary
The sense of smell is essential for maintaining full human health and quality of life. It plays an
important role in the detection of environmental dangers as well guiding decisions such as what
foods to eat. However, olfactory processing is influenced by the physiological state of an organism.
Both sleep deprivation and changes in satiety are connected with changes in the function of the
olfactory system. Physiological changes such as these are integrated in the hypothalamus, where
different neuropeptides are expressed by specific populations of neurons. These peptides can
regulate transitions between wakefulness and sleep, or promote feeding behaviors. One peptide
that functions in both promoting feeding and sleep is melanin-concentrating hormone (MCH).
Neurons expressing MCH project to several areas of the brain including the olfactory bulb (OB),
where the MCH receptor, MCHR1, is expressed. This connection represents a previously
understudied pathway providing a potential mechanism for sleep or satiety induced changes in
olfactory function. The proposed research will investigate the role of MCH signaling and
hypothalamic MCH neurons in contributing to odor processing. The aims of this proposal will test
the central hypothesis centrifugal MCH neurons integrate physiological states and regulate
olfactory function. Aim 1 will use molecular and biochemical techniques to investigate changes in
MCH levels in the OB in response to food restriction. It will also use complementary mouse
models to determine the cellular targets of hypothalamic MCH neurons in olfactory regions. Aim
2 will investigate the effects of MCH on the activity of mitral cells in the olfactory bulb, and how
changes in MCH effect odor threshold detection and cross-habituation in animals that lack
components of the MCH signaling pathway. It will also test how activation of hypothalamic MCH
neurons modulates these behaviors. Using AAV mediated approaches, we will target MCHR1
removal specifically in the OB to isolate its contribution to regulating behavioral changes. Finally,
in Aim 3 we will investigate how disruption of primary cilia, the cellular site of MCHR1
localization, on neurons in the OB impacts an animal's ability to detect and discriminate odors.
Completion of the proposed studies will provide new mechanistic insight into the role of the lateral
hypothalamus in regulating olfactory function. The results from the proposed research will be
important for understanding how changes in satiety or in wakefulness can impact the sense of
smell. It will also provide insight into mechanisms of sensory dysfunction that occur in some
ciliopathy patients. Completion of this project will establish future experiments to address the
molecular mechanisms of MCH modulation in the OB.
项目摘要
嗅觉对于保持人类的全面健康和生活质量至关重要。它播放了一个
在检测环境危险以及指导决策方面发挥重要作用,如
吃的食物。然而,嗅觉处理受到生物体的生理状态的影响。
睡眠不足和饱腹感的改变都与大脑功能的改变有关。
嗅觉系统。像这样的生理变化整合在下丘脑中,在那里
不同的神经肽由特定的神经元群体表达。这些多肽可以
调节清醒和睡眠之间的转换,或促进进食行为。一种多肽
在促进进食和睡眠方面起作用的是黑色素浓缩激素(MCH)。
表达MCH的神经元投射到大脑的几个区域,包括嗅球(OB),
其中表达了MCH受体MCHR1。此连接表示以前的
未被研究的通路提供了睡眠或饱腹感引起的改变的潜在机制
嗅觉功能。拟议的研究将调查妇幼保健素信号和
下丘脑MCH神经元参与气味加工。这项提案的目的将考验
中枢假说离心式MCH神经元整合生理状态和调节
嗅觉功能。目标1将使用分子和生化技术来研究
OB中的MCH水平对食物限制的反应。它还将使用互补的鼠标
确定嗅觉区下丘脑MCH神经元细胞靶点的模型。目标
2将研究MCH对嗅球二尖瓣细胞活动的影响,以及如何
缺乏MCH效应的动物嗅觉阈值检测和交叉习服的变化
MCH信号通路的组成部分。它还将测试下丘脑MCH的激活
神经元调节这些行为。使用AAV介导的方法,我们将针对MCHR1
特别是在OB中去除,以隔离其对调节行为变化的贡献。最后,
在目标3中,我们将研究初级纤毛是如何破坏MCHR1的细胞位置的
OB区神经元的定位会影响动物检测和辨别气味的能力。
拟议研究的完成将为侧翼的作用提供新的机械洞察力
下丘脑参与调节嗅觉功能。拟议研究的结果将是
对于了解饱腹感或清醒状态的变化如何影响
闻。它还将提供对感觉障碍的机制的洞察,这些机制发生在一些
纤毛病患者。该项目的完成将建立未来的实验,以解决
失眠状态下MCH调节的分子机制。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Neuronal primary cilia integrate peripheral signals with metabolic drives.
- DOI:10.3389/fphys.2023.1150232
- 发表时间:2023
- 期刊:
- 影响因子:4
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