An olfactory subsystem that mediates innate behaviors

描述（由申请人提供）：哺乳动物的嗅觉系统对中性气味（其对生物体的重要性是通过学习分配的）和引起先天行为的气味都有反应。嗅觉感觉神经元的一个子集表达痕量胺相关受体（TAARs），该受体对大多数啮齿动物厌恶的挥发性胺作出反应。我们最近描述了表达TAAR的神经元（TRN）向嗅球的投射模式，并研究了控制每个TRN中单个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，它们整合到硬连接电路中，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。以下几点预测都源于这一假设：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. 2 . trn的激活足以引起先天行为反应；来自TAAR肾小球的投射是定型的，目标是适合厌恶行为反应的中枢神经结构。为了验证这些预测，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，我们将使用无偏方法明确确定trn是否仅表达TAARs或共同表达一部分ORs。此外，我们将明确确定trn是否在分子上专门表达Taar，或者在选择缺失的Taar基因后切换到表达ORs。我们还将分析分类的TRN群体，以确定抑制表观遗传标记和激活增强子序列，这些增强子序列控制每个TRN中单个TAAR的表达。总之，这些研究将为定义trn作为一个独特的嗅觉子系统提供分子证据。在解剖学层面上，我们将绘制从球内的TAAR肾小球到大脑高级嗅觉中心的投影图。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/行为层面，我们将确定trn选择性光遗传激活的行为后果，随后系统地描述驱动灯泡反应的最佳刺激。这些实验将测试TAAR回路是否会诱发诸如嗅探之类的先天行为反应，以及是否会分配厌恶效价。我们的研究是第一个检查先天反应厌恶的嗅觉刺激

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.