Synaptic and circuit mechanisms of olfactory processing

描述（由申请人提供）：气味分子由嗅觉受体神经元感知，然后将气味刺激信息发送到嗅球（脊椎动物）或触角叶（昆虫）。所有表达相同嗅觉受体基因的受体神经元将信息发送到大脑中相同的离散区域（肾小球）。接下来会发生什么——嗅觉信息被大脑中的神经回路处理——我们仍然知之甚少。其中一个困难是嗅觉回路的复杂性：每个肾小球包含周期性的兴奋性和抑制性神经回路，并接受来自其他肾小球的横向连接。考虑到果蝇的遗传工具范围，果蝇是研究这个问题的一个很好的模型系统。此外，苍蝇的嗅觉系统与脊椎动物的大体相似，但要简单得多。这项研究探讨嗅觉信息是如何被触角叶的电路处理的。特别地，这些实验将剖析触角叶中二级嗅觉神经元（称为投射神经元，或PNs）的气味诱发电生理反应，使用特定的基因操作来破坏或挽救针对单个肾小球的感觉输入功能。体内全细胞膜片钳记录将用于评估嗅觉刺激苍蝇触角的PN反应。特异性目的#1询问肾小球之间的抑制性突触和兴奋性突触是否都有助于PNs中气味诱发的活动。目的2验证了肾小球之间的抑制性和/或兴奋性突触既有刻板性又有特异性的假设。目的3研究每个肾小球内的突触相互作用对PNs中气味诱发活动的特定特征的贡献。这个项目将大大有助于我们理解大脑嗅觉处理的最初步骤。了解早期嗅觉编码应该有助于治疗人类患者的嗅觉障碍，并有助于理解为什么这些疾病通常是神经退行性疾病的早期预警信号。此外，了解大脑如何对气味进行编码，对设计所谓的“人造鼻子”（用于检测和区分特定挥发性化学物质的传感器）提供了有价值的见解。这些传感器在医学诊断和生物防御方面有着重要的应用，并且在通过测量受试者呼吸中的化学物质来诊断1期肺癌方面显示出特别的前景

DESCRIPTION (provided by applicant): Odor molecules are sensed by olfactory receptor neurons, which in turn send information about odor stimuli to the olfactory bulb (in vertebrates), or the antennal lobe (in insects). All the receptor neurons that express the same olfactory receptor gene send information to the same discrete region (glomerulus) in the brain. What happens next-when olfactory information is processed by neural circuits in the brain-is still poorly understood. One difficulty is the complexity of the olfactory circuit: each glomerulus contains recurrent excitatory and inhibitory neural circuits, and receives lateral connections from other glomeruli. Drosophila is a good model system for investigating this problem, given the range of genetic tools available in the fruit fly. Also, the fly olfactory system is broadly similar to that of vertebrates, but much simpler. This study examines how olfactory information is processed by the circuitry of the antennal lobe. In particular, these experiments will dissect the odor-evoked electrophysiological response of second-order olfactory neurons in the antennal lobe (termed projection neurons, or PNs), using specific genetic manipulations that destroy or rescue function in the sensory inputs targeting single glomeruli. In vivo whole-cell patch-clamp recordings will be used to assess PN responses to olfactory stimulation of the fly's antennae. Specific aim #1 asks whether both inhibitory and excitatory synapses between glomeruli contribute to odor-evoked activity in PNs. Aim #2 tests the hypothesis that inhibitory and/or excitatory synapses between glomeruli are both stereotyped and specific. Aim #3 investigates the contribution of synaptic interactions within each glomerulus to the specific features of odor-evoked activity in PNs. This project should contribute substantially to our understanding of the very first steps of olfactory processing in the brain. Understanding early olfactory coding should help in treating olfactory disorders in human patients, and could aid in understanding why these disorders are often early warning signs of neurodegenerative diseases. Furthermore, understanding how the brain encodes odors has contributed valuable insights to the design of so-called "artificial noses", sensors designed to detect and discriminate between specific volatile chemicals. These sensors have important applications in medical diagnosis and biodefense, and have shown particular promise in diagnosing stage 1 lung cancer by measuring the chemicals present in a subject's breath