CRCNS: Computational and experimental analysis of noradrenergic function in early

CRCNS：早期去甲肾上腺素能功能的计算和实验分析

• 批准号: 7425949
• 负责人: CHRISTIANE LINSTER
• 金额: $ 30.68万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7425949
• 关键词: Address; Afferent Neurons; Affinity; Behavior; Binding; Biological Assay; Brain; Chemicals; Chromosome Pairing; Computer Simulation; Data; Degenerative Disorder; Dependence; Development; Electrophysiology (science); Knowledge; Mediating; Modeling; Neuromodulator; Neurons; Norepinephrine; Odors; Perception; Physiology; Property; Public Health; Rattus; Regulation; Sensory; Sensory Process; Signal Transduction; Slice; Smell Perception; Synapses; System; Testing; Translating; Translations; behavior test; behavioral pharmacology; experimental analysis; granule cell; interdisciplinary approach; noradrenergic; olfactory bulb; receptor; relating to nervous system; research study; sensory system; tool

DESCRIPTION (provided by applicant): This proposal presents a multidisciplinary approach to understanding a fundamental property of noradrenergic modulation in the mammalian brain: the non-linear action of the neuromodulator noradrenaline on cellular properties and the translation of these cellular effects into the modulation of sensory perception. The proposal addresses this question in the olfactory bulb of rats, using a combination of brain slice electrophysiology, behavioral pharmacology and computational modeling tools. The olfactory system represents an ideal system for such studies for several reasons, each of which is taken advantage of by the proposed studies. First, the mammalian olfactory system is anatomically relatively simple, and this simplicity has resulted in an extensive knowledge of synaptic connections and physiology and their regulation by neuromodulatory systems. Second, because olfactory bulb principal neurons are only a single synapse removed from primary olfactory sensory neurons, a relatively good understanding of the relationship between neural representations and perception of chemical signals has been developed. Third, this knowledge in turn has enabled the development of computational models which include the olfactory bulb and its neuromodulatory inputs. Finally, aided by the importance of olfaction to rats' survival, a variety of assays relying on these natural behaviors have been developed that can assess the effect of noradrenergic modulation on odor-guided behavior. It is specifically proposed to 1) determine the effects of increasing concentrations of the neuromodulator noradenaline on olfactory bulb mitral and granule cell properties, 2) test how the net concentration-dependence of noradrenergic effects is mediated by the different noradrenergic receptor subtypes and their binding affinities, 3) use a biophysical modeling approach to determine whether the cellular experimental data are sufficient to explain the overall network effects of noradrenaline, and 4) test functional predictions from these results using pharmacological manipulations during behavioral tests in rats. Taken together, the proposed experiments will elucidate how the nonlinear effects of noradrenergic modulation in sensory systems arise from the interaction with various receptor subtypes as well as how these nonlinear effects at the cellular level translate into perceptual modulation, and hence will have a broad impact on our understanding of sensory processing and neuromodulation. Neuromodulation is involved in many major degenerative diseases of brain function; a better understanding of the functions of these systems will have a high impact on public health.

描述（由申请人提供）：该提案提出了一种多学科方法来理解哺乳动物大脑中去甲肾上腺素能调节的基本特性：神经调节剂去甲肾上腺素对细胞特性的非线性作用以及将这些细胞效应转化为感觉调节洞察力。该提案结合脑切片电生理学、行为药理学和计算建模工具，解决了大鼠嗅球的这个问题。由于多种原因，嗅觉系统代表了此类研究的理想系统，所提出的研究都利用了每一个原因。首先，哺乳动物的嗅觉系统在解剖学上相对简单，这种简单性导致了对突触连接和生理学及其神经调节系统调节的广泛了解。其次，由于嗅球主要神经元只是从初级嗅觉感觉神经元中移除的单个突触，因此已经对神经表征和化学信号感知之间的关系有了相对较好的理解。第三，这些知识反过来又促进了包括嗅球及其神经调节输入在内的计算模型的发展。最后，由于嗅觉对大鼠生存的重要性，人们开发了多种依赖这些自然行为的测定方法，可以评估去甲肾上腺素能调节对气味引导行为的影响。特别建议 ​​1) 确定神经调节剂去甲肾上腺素浓度增加对嗅球二尖瓣和颗粒细胞特性的影响，2) 测试不同去甲肾上腺素受体亚型及其结合亲和力如何介导去甲肾上腺素效应的净浓度依赖性，3）使用生物物理建模方法来确定细胞实验数据是否足以解释去甲肾上腺素的整体网络效应，以及4）测试在大鼠行为测试期间使用药理学操作根据这些结果进行功能预测。总而言之，所提出的实验将阐明感觉系统中去甲肾上腺素能调节的非线性效应如何产生于与各种受体亚型的相互作用，以及细胞水平上的这些非线性效应如何转化为知觉调节，从而对感觉系统产生广泛的影响。我们对感觉处理和神经调节的理解。神经调节与许多主要的脑功能退行性疾病有关；更好地了解这些系统的功能将对公共卫生产生重大影响。