Molecular and Cellular Mechanisms of a Neuronal Network that Regulates Olfactory

描述（由申请人提供）：我们感兴趣的是了解个体如何通过嗅觉与环境交流，特别是嗅觉反应如何被经验和环境线索塑造和修改。为此，我们利用一种遗传模式生物秀丽隐杆线虫和这种动物模型中一种新形式的嗅觉可塑性来提出以下问题：嗅觉学习背后的神经元回路的功能组织是什么？经验是如何产生调节线索来改变嗅觉的？嗅觉回路的内在属性是如何随着经验的变化而改变，从而产生嗅觉学习的？我们之前的研究表明，秀丽隐杆线虫在摄入病原体后学会避免致病菌的气味。来自一对血清素能神经元ADF和嗅觉回路的血清素信号对于指导这一学习过程至关重要。感染生理应激通过CaMKII和Gq通路增强ADF血清素信号；强化的信号通过几个中间神经元中的血清素通道促进学习。这种学习需要两对感觉神经元下游的嗅觉神经回路。我们假设，增强的血清素信号调节嗅觉回路的特性，导致嗅觉的变化。为了验证这一假设并表征这一学习过程的分子和细胞机制，我们将首先使用基因消融和激光手术来绘制嗅觉学习背后的神经回路，并定义该网络的神经元成分。然后，我们将使用钙成像来检查嗅觉回路的神经元特性，在无知和有学问的动物中。最后，我们将使用分子遗传学和生化工具来描述训练经验如何通过CaMKII和Gq信号通路产生神经调节血清素信号。公共卫生相关性：嗅觉学习是神经可塑性的基本形式之一，它使我们能够与环境互动并从经验中学习。然而，许多人在学习和记忆方面患有不同形式的残疾，这些残疾与各种毁灭性的神经系统疾病有关，严重损害了他们发展或维持心智能力的能力，这往往导致生活质量下降。对这些神经缺陷的分子和细胞病理学知之甚少。我们对嗅觉学习机制的基础研究将帮助我们理解正常学习过程的生理需求，为精神残疾的基础提供见解，并指导这些破坏性神经系统疾病的潜在治疗。

DESCRIPTION (provided by applicant): We are interested to understand how individuals communicate with environment by olfaction and, particularly, how olfactory responses are shaped and modified by experience and environmental cues. To this end, we use a genetic model organism Caenorhabditis elegans and a new form of olfactory plasticity in this animal model to ask the following questions: What is the functional organization of the neuronal circuit underlying olfactory learning? How does experience generate modulatory cues to modify olfaction? How does the intrinsic property of the olfactory circuitry change in response to experience to generate olfactory learning? We previously showed that C. elegans learns to avoid the smell of pathogenic bacteria after ingestion of the pathogens. Serotonin signaling from a pair of serotonergic neurons ADF and an olfactory circuit are essential to direct this learning process. The physiological stress of infection enhances ADF serotonin signals through CaMKII and a Gq pathway; and the strengthened signaling promotes learning through a serotonin-gated channel in several interneurons. An olfactory neural circuit downstream of two pairs of sensory neurons is required for this learning to occur. We hypothesize that the enhanced serotonin signaling modulates the properties of the olfactory circuit, resulting in a change in olfaction. To test this hypothesis and characterize the molecular and cellular mechanisms of this learning process, we will first use genetic ablation and laser surgery to map the neural circuit underlying the olfactory learning and define the neuronal components of this network. Then we will use calcium imaging to examine the neuronal properties of the olfactory circuit in both na¿ve and learned animals. And finally we will use molecular genetics and biochemical tools to characterize how the training experience generates a neuromodulatory serotonin signaling through CaMKII and a Gq signaling pathway. PUBLIC HEALTH RELEVANCE: Olfactory learning is one of the fundamental forms of neural plasticity that enables us to interact with environment and to learn from experience. However, many people suffer from different forms of disabilities in learning and memory that are associated with varies devastating neurological diseases and are seriously compromised in their ability to develop or maintain their mental capacities, which often result in a marginal life quality. Little is known about the molecular and cellular pathology of these neurological defects. Our basic research on the mechanisms of olfactory learning will help us understand the physiological requirements of normal learning processes, provide insights into the basis of mental disability and guide potential treatments for these devastating neurological disorders.