Modulation of Glomerular Function

描述(申请人提供)：嗅觉系统的感觉输入最初由嗅球(OB)肾小球的神经回路处理。这个回路是来自神经调节中心的离心式输入的目标。通过二尖瓣/簇状(MT)细胞输出的OB对清醒动物的感觉反应有显著的调节作用。了解气味信息处理的这些最早阶段是如何调制的，对于全面了解嗅觉系统的功能至关重要。这个项目将首次研究乙酰胆碱(ACh)和5-羟色胺(5HT)如何调节肾小球回路中的感觉处理。这项研究建立在我们对这些电路及其在塑造OB输出中的重要性方面的最新进展的基础上。该项目将整合来自OB切片以及麻醉和清醒的头部固定小鼠的信息。这种多维方法旨在将肾小球回路的调节与特定神经调节系统的激活联系起来-来自斜角带的胆碱能输入和来自中缝核团的5-羟色胺能输入。我们的工作假设是，ACh和5HT对肾小球的加工进行不同的调节，以形成突触前和突触后的抑制以及MT细胞的兴奋性。我们进一步假设ACh的调制减少了感觉输入的影响，同时增加了MT细胞的兴奋性。这可能会限制气味检测，但会提高辨别能力。这项拟议的研究是两位知名研究人员高度整合的努力，目的是在麻醉和未麻醉的动物中，从细胞和回路到单个神经元的水平上了解早期嗅觉加工的调节。 公共卫生相关性：神经调节系统对大脑功能有广泛的影响，包括对感觉系统的影响，神经调节通路的功能障碍与深刻影响人类健康的疾病有关，包括抑郁症、精神分裂症和阿尔茨海默病。本项目研究胆碱能和5-羟色胺能调节在嗅觉通路最早水平的感觉信息的初始检测和处理中所起的作用。这应该会使人们更好地理解神经调节系统如何增强信息处理和感官感知，并有可能改进与这些系统相关的疾病的治疗。

DESCRIPTION (provided by applicant): Sensory inputs to the olfactory system are initially processed by neural circuits in olfactory bulb (OB) glomeruli. This circuitry is targeted by centrifugal inputs from neuromodulatory centers. OB output via mitral/tufted (MT) cells shows remarkable modulation of sensory responses in the awake animal. Knowing how these earliest stages of odor information processing are modulated is critical to fully understanding olfactory system function. This project will investigate - for the first time - how acetylcholine (ACh) and serotonin (5HT) modulate sensory processing in glomerular circuits. The research builds on recent advances in our understanding of these circuits and their importance in shaping OB output. The project will integrate information from OB slices and anesthetized and awake head-fixed mice. This multidimensional approach aims to link the modulation of glomerular circuits to the activation of specific neuromodulatory systems - cholinergic inputs from the diagonal band and serotonergic inputs from the raphe nuclei. Our working hypothesis is that ACh and 5HT differentially modulate glomerular processing to shape both pre- and postsynaptic inhibition as well as MT cell excitability. We further hypothesize that ACh modulation reduces the impact of sensory input while at the same time increasing the excitability of MT cells. This could limit odor detection but increase discrimination ability. The proposed research is a highly integrated effort from two established investigators to understand the modulation of early olfactory processing at levels ranging from cells and circuits to single neurons in anesthetized and unanesthetized animals. PUBLIC HEALTH RELEVANCE: Neuromodulatory systems have widespread effects on brain function, including on sensory systems, and dysfunction in neuromodulatory pathways is linked to diseases that profoundly effect human health, including depression, schizophrenia and Alzheimer's disease. This project investigates the roles that cholinergic and serotonergic modulation play in the initial detection and processing of sensory information in the earliest levels of the olfactory pathway. This should lead to a greater understanding of how neuromodulatory systems enhance information processing and sensory perception, and potentially lead to improved treatments for diseases linked to these systems.