An olfactory subsystem that mediates innate behaviors

描述(申请人提供)：哺乳动物的嗅觉系统对中性气味和引发先天行为的气味都有反应，中性气味对有机体的意义是通过学习来分配的。嗅觉感觉神经元的一个子集表达示踪胺相关受体(TAAR)，该受体对大多数啮齿动物厌恶的挥发胺做出反应。我们最近描述了TAAR表达神经元(TRN)向嗅球的投射模式，并研究了控制每个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，它们整合到硬连线电路中，使它们能够提取特定的环境线索，并驱动强大的天生行为反应。几种预测源于这个假设：1.TRN在分子上与ON不同，它们使用特定的机制来确保每个神经元只有一个受体的表达；2.TRN的激活足以引起固有的行为反应；3.来自TAAR小球的投射是定型的，并以适合厌恶行为反应的中枢神经结构为靶标。为了测试这些预测，我们将进行跨学科、多层次的方法，跨越分子、神经解剖学、神经生理学和行为水平。在分子水平上，我们将使用无偏见的方法来明确地确定TRN是只表达TAAR还是共表达ORs的子集。此外，我们将最终确定TRN是否在分子上致力于独占表达TAAR，或者是否可以在选择缺失的TaR基因时切换到表达ORS。我们还将分析TRN的分类群体，以确定抑制表观遗传标记和激活增强子序列，这些序列控制每个TRN中单个TAAR的表达。总之，这些研究将为将TRNS定义为一个独特的嗅觉子系统提供分子证据。在解剖学层面上，我们将把球内TAAR小球的投射映射到大脑中的高级嗅觉中心。我们预测这些投射将是定型的，这些肾小球可能主要投射到杏仁核。在系统/行为水平上，我们将在系统地描述驱动灯泡反应的最佳刺激之后，确定TRN选择性光遗传激活的行为后果。这些实验将测试TAAR电路是否硬连接以诱导嗅探等先天行为反应，以及是否硬连接以分配厌恶价态。我们的研究首次考察了老年人对厌恶嗅觉刺激的先天反应。 已知受体和配体的背景。它们将阐明对厌恶刺激的先天反应的分子和解剖学基础，并为分子和解剖学组织与行为结果之间的直接联系提供基础。了解将感觉信息转换为诱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。

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.