An olfactory subsystem that mediates innate behaviors

调节先天行为的嗅觉子系统

基本信息

批准号：
9137838
负责人：
Gilad Barnea
金额：
$ 2.52万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9137838
关键词：
Acute Address Agreement Alleles Amines Amygdaloid structure Automobile Driving Aversive Stimulus Behavior Control Behavioral Brain Cell Separation Chronic Code Collaborations Cues Data Development Dorsal Enhancers Ensure Epigenetic Process Family Fluorescence-Activated Cell Sorting Fluorescent Dyes Foundations Genes Health Human Implant Instinct Knock-in Knock-out Label Laboratories Learning Ligands Light Link Maps Measures Mediating Mental disorders Molecular Mus Nature Neurons Neurosciences Odorant Receptors Odors Olfactory Epithelium Olfactory Pathways Organism Partner in relationship Pattern Pheromone Physiological Population Reporter Rodent Running Sensory Smell Perception Sorting - Cell Movement Stereotyping Stimulus Structure Study models System Testing Work base behavioral outcome behavioral response behavioral study driving behavior insight learned behavior member nervous system disorder neuromechanism neurophysiology offspring olfactory bulb olfactory sensory neurons olfactory stimulus optogenetics preference receptor recombinase relating to nervous system research study response selective expression stem transcriptome sequencing two-photon

项目摘要

DESCRIPTION (provided by applicant): The mammalian olfactory system responds both to neutral odors, whose significance for the organism is assigned by learning, and to odors that elicit innate behaviors. A subset of olfactory sensory neurons expresses trace amine associated receptors (TAARs) that respond to volatile amines that are mostly aversive to rodents. We recently described the projection patterns of TAAR-expressing neurons (TRNs) to the olfactory bulb and examined the molecular mechanisms that control the expression of a single TAAR per TRN. Based on these findings, our overall hypothesis is that the TRNs constitute a distinct olfactory subsystem and that they integrate into hard-wired circuits that enable them to extract specific environmental cues and drive robust innate behavioral responses. Several predictions stem from this hypothesis: 1. TRNs are molecularly distinct from ORNs and they use specific mechanisms to ensure expression of a single receptor per neuron; 2. Activation of the TRNs is sufficient to elicit innate behavioral responses and, 3. The projections from the TAAR glomeruli are stereotyped and target central neural structures appropriate to aversive behavior responses. To test these predictions, we will conduct an interdisciplinary, multi-tiered approach that spans the molecular, neuroanatomical, neurophysiological and behavioral levels. At the molecular level, we will use unbiased approaches to unequivocally determine whether TRNs express only TAARs or co-express a subset of ORs. Further, we will definitively determine whether TRNs are molecularly committed to exclusively express TAARs, or can switch to express ORs upon choosing a deleted Taar gene. We will also analyze sorted populations of TRNs to identify repressive epigenetic marks and activating enhancer sequences that control expression of a single TAAR per TRN. Together, these studies will provide the molecular evidence for defining the TRNs as a distinct olfactory subsystem. At the anatomical level, we will map the projections from the TAAR glomeruli in the bulb to higher olfactory centers in the brain. We predict that these projections will be stereotyped and these glomeruli may project predominantly to the amygdala. At the systems/behavioral level, we will determine the behavioral consequences of selective optogenetic activation of TRNs, following systematic characterization of the optimal stimuli for driving bulb responses. These experiments will test whether TAAR circuits are hard wired to induce innate behavioral responses such as sniffing, and hard wired to assign aversive valence. Our studies are the first to examine innate responses to aversive olfactory stimuli in the context of known receptors and ligands. They will shed light on the molecular and anatomical substrate of innate responses to aversive stimuli, and provide foundation for direct links between molecular and anatomical organization and behavioral outcomes. Understanding the neural mechanisms mediating the conversion of sensory information to eliciting innate behaviors may provide new insight into the underpinnings of several psychiatric conditions.

描述（由申请人提供）：哺乳动物的嗅觉系统既对中性气味做出反应，中性气味对生物体的重要性是通过学习来确定的，也对引起先天行为的气味做出反应。嗅觉感觉神经元的一个子集表达痕量胺相关受体（TAAR），这些受体对啮齿动物最厌恶的挥发性胺做出反应。我们最近描述了表达 TAAR 的神经元 (TRN) 向嗅球的投射模式，并检查了控制每个 TRN 单个 TAAR 表达的分子机制。基于这些发现，我们的总体假设是，TRN 构成了一个独特的嗅觉子系统，并且它们集成到硬连线电路中，使它们能够提取特定的环境线索并驱动强大的先天行为反应。一些预测源于这一假设： 1. TRN 在分子上与 ORN 不同，它们使用特定的机制来确保每个神经元表达单个受体； 2. TRN 的激活足以引发先天行为反应，并且， 3. TAAR 肾小球的投射是定型的，并且针对适合厌恶行为反应的中枢神经结构。为了检验这些预测，我们将采取跨学科、多层次的方法，涵盖分子、神经解剖学、神经生理学和行为层面。在分子水平上，我们将使用公正的方法来明确确定 TRN 是仅表达 TAAR 还是共表达 OR 的子集。此外，我们将明确确定 TRN 是否在分子上致力于专门表达 TAAR，或者可以在选择删除的 Taar 基因后转而表达 OR。我们还将分析排序的 TRN 群体，以确定抑制性表观遗传标记和激活增强子序列，这些序列控制每个 TRN 的单个 TAAR 的表达。总之，这些研究将为将 TRN 定义为独特的嗅觉子系统提供分子证据。在解剖层面，我们将绘制从球部 TAAR 肾小球到大脑中更高嗅觉中心的投影。我们预测这些投射将被定型，并且这些肾小球可能主要投射到杏仁核。在系统/行为层面，我们将在对驱动灯泡反应的最佳刺激进行系统表征后，确定 TRN 选择性光遗传学激活的行为后果。这些实验将测试 TAAR 电路是否硬连线以诱导先天行为反应，例如嗅探，并硬连线以分配厌恶价。我们的研究首次考察了人类对厌恶性嗅觉刺激的先天反应。已知受体和配体的背景。它们将揭示对厌恶刺激的先天反应的分子和解剖学基础，并为分子和解剖组织与行为结果之间的直接联系提供基础。了解介导感觉信息转换以引发先天行为的神经机制可能会为几种精神疾病的基础提供新的见解。