Mechanisms Underlying Innate Odor Fear

 描述(申请人提供)：对危险的防御性反应对生存是必不可少的，在整个动物界都可以看到，包括人类。在啮齿动物中，捕食者的气味会刺激本能的恐惧反应，包括特有的行为和血液中应激激素水平的增加。应激激素对捕食者气味和其他应激源的反应是HPA轴激活的结果，HPA轴涉及下丘脑中促肾上腺皮质激素释放激素(CRH)神经元的一个子集。在人类中，就像在啮齿类动物中一样，应激刺激会增加血液中应激激素的水平，这表明对恐惧和压力做出生理反应的潜在机制在进化上是保守的。HPA轴的失调在某些人类精神疾病中被发现，这进一步表明，对控制啮齿动物应激激素的神经机制的了解最终可能提供与人类疾病相关的见解。老鼠对捕食者气味的恐惧反应的刻板印象表明，存在由基因决定的神经电路，其中包括鼻子中的嗅觉受体(OR)，它选择性地检测这些气味和脑神经元的特定亚群，这些神经元从这些受体接收信号，并对生理和行为产生深刻的下游影响。为了深入了解应激激素对捕食者气味的反应背后的分子机制和神经回路，我们建议使用一系列工具，包括通过一个或多个突触传播的嗜神经病毒的神经回路追踪，下一代RNA测序(RNA-Seq)，高通量筛选，神经活动标记分析，以及激活或沉默特定神经元亚群的药物遗传操作。使用这些工具，我们将识别鼻子中向CRH神经元传递信号的受体，识别由这些受体检测到的气味分子，并确定单个气味分子是刺激模拟恐惧的应激激素增加，还是像现在似乎一些气味那样阻止应激激素增加。为了确定受体信号如何被大脑转化为特定的反应，我们将测试这一假设，即这是通过嗅皮层中特定的神经元亚群的行动和选定的非嗅觉大脑来完成的。 将恐惧信号从嗅皮层传递到CRH神经元的区域。为了做到这一点，我们将调查嗅觉皮质和其他大脑区域中神经元的位置，这些区域被捕食者气味激活，并有能力向CRH神经元传递信号。通过激活和抑制特定区域的神经元，将有可能评估单个区域是否可以诱导或抑制恐惧，以及这些区域是否需要将兴奋或抑制信号传递到影响应激激素的CRH神经元。总之，这些研究应该为控制恐惧和应激诱导气味刺激对生理的深刻影响的分子机制和神经回路提供重要的见解。

 DESCRIPTION (provided by applicant): Defensive responses to danger are essential to survival and are seen throughout the animal kingdom, including in humans. In rodents, predator odors stimulate instinctive fear responses that include characteristic behaviors and increases in blood levels of stress hormones. The stress hormone response to predator odors and other stressors results from activation of the HPA (hypothalamic-pituitary-adrenal) axis, which involves a subset of corticotropin releasing hormone (CRH) neurons in the hypothalamus. In humans, as in rodents, stressful stimuli increase blood levels of stress hormones, suggesting the evolutionary conservation of mechanisms underlying physiological responses to fear and stress. Dysregulation of the HPA axis is seen in certain human psychiatric conditions, further suggesting that an understanding of the neural mechanisms that control stress hormones in rodents might ultimately provide insights relevant to human disease. The stereotyped nature of fear responses to predator odors in mice suggests the existence of genetically determined neural circuits that include olfactory receptors (ORs) in the nose that selectively detect those odors and specific subsets of brain neurons that receive signals from those receptors and generate their profound downstream effects on physiology and behavior. To gain insight into the molecular mechanisms and neural circuits that underlie stress hormone responses to predator odors, we propose to employ a combination of tools, including neural circuit tracing with neurotropic viruses that travel across one or multiple synapses, next generation RNA sequencing (RNA-Seq), high throughput screening, analyses of neural activity markers, and pharmacogenetic manipulation to activate or silence specific subsets of neurons. Using these tools, we will identify receptors in the nose that transmit signals to CRH neurons, identify odor molecules detected by those receptors, and determine whether the individual odor molecules stimulate stress hormone increases that mimic fear or instead block stress hormone increases, as it now appears some odors can do. To determine how the receptor signals are translated into specific responses by the brain, we will test the hypothesis that this is accomplished via the actions of specific subsets of neurons in the olfactory cortex and by selected non- olfactory brain areas that relay fear signals from the olfactory cortex to CRH neurons. To do this, we will investigate the locations of neurons in the olfactory cortex and other brain areas that are activated by predator odors and have the ability to transmit signals to CRH neurons. By activating and inhibiting neurons in specific areas, it will be possible to assess whether individual areas can either induce or suppress fear and whether those areas are required for the transmission of excitatory or inhibitory signals to CRH neurons that affect stress hormones. Together, these studies should provide significant insights into the molecular mechanisms and neural circuits that govern the profound impact of fear and stress-inducing odor stimuli on physiology.