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

基本信息

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
项目类别：
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

项目摘要

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的方法，可以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感知的调节作用。该提案结合了脑切片电学，行为药理学和计算建模工具，在大鼠的嗅球大鼠中解决了这个问题。嗅觉系统代表了此类研究的理想系统，原因有几个原因，每个系统都被提议的研究利用。首先，哺乳动物的嗅觉系统在解剖学上相对简单，这种简单性使人们对突触连接和生理学及其对神经调节系统的调节有了广泛的了解。其次，由于嗅球主神经元仅是从原发性嗅觉感觉神经元中删除的单个突触，因此已经开发了对神经代表和化学信号感知之间关系的相对良好的理解。第三，这些知识反过来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，在嗅觉对大鼠生存的重要性的帮助下，已经开发出了各种依赖这些自然行为的测定，可以评估去甲肾上腺素能调节对气味引导行为的影响。 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去甲肾上腺素的网络效应，以及4）在大鼠行为测试期间使用药理操作从这些结果中测试功能预测。综上所述，所提出的实验将阐明甲肾上腺素能调节在感觉系统中的非线性效应如何来自与各种受体亚型的相互作用以及这些在细胞水平的这些非线性效应如何转化为感知调节，因此，这些非线性效应如何对我们对感觉处理和神经化的理解产生广泛的影响。神经调节参与了许多主要的脑功能退化性疾病。更好地了解这些系统的功能将对公共卫生产生很大的影响。