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Functional Segregation Within the Whisker-Barrel Neuraxis

晶须桶神经轴内的功能分离

基本信息

批准号：
10424659
负责人：
Mitra J Hartmann
金额：
$ 10.67万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10424659
关键词：
Functional Segregation Within Whisker Barrel

项目摘要

DESCRIPTION (provided by applicant): The long-term objectives of this multi-PI R01 proposal are two-fold. First, the functions of specific parallel neural pathways (lemniscal, paralemniscal) linking brainstem and forebrain trigeminal (V) representations will be revealed. This will be done in the rodent whisker-to-barrel cortex neuraxis, which has become the model of choice for discovery of information processing mechanisms, due to the prominence of barrels in the cerebral cortex of transgenic mice. Yet, there are major gaps in our knowledge of subcortical components that hamper our grasp of the whisker-barrel circuit. These gaps will be filled by applying a set of multidisciplinary tools to studies of the neural control of whisker-related sensation and movement. Our overarching hypothesis is that neural activity in the spinal V subnucleus interpolaris (SpVi, paralemniscal) is necessary for whisker-mediated object detection and orientation responses, while whisker-mediated object identification and discrimination require neural activity in a topographically patterned (barrelettes) V nucleus principalis (PrV, lemniscal). Three Specific Aims employ: a) transgenic mice that lack barrelettes in PrV, but not in SpVi, b) reversible allatostatin- induced silencing of adenovirus transduced multi-whisker responsive SpVi cells or single-whisker PrV cells, and c) anatomical and electrophysiological assessments of the integrity and neurotransmission properties of V brainstem neurons in animals studied in the above 2 Aims. Thus, "gene deletion" and "neural silencing" approaches are coupled with parallel validation of the extent to which these 2 approaches produce "functional lesions" in V brainstem neurons. This permits discovery of components of the barrel neuraxis that are unequivocally responsible for whisker-mediated detection, orientation, identification and discrimination behaviors. Second, this research will als provide technical 'proof of principle' for the potential use of above- listed allatostatin-induced silencing of adenovirus infected neurons to treat human neurological disorders, such as epilepsy, chronic pain, obesity and addiction, where hyperexcitability characterizes defined neuronal populations, reduction or elimination of which could constitute a new treatment strategy. Self-administration of allatostatin could be a transformative treatment option, the efficacy of which will be evaluated here in a simple model system, with an eye towards possible side effects. A collaborative venture is offered with 3 PIs that are indispensable to the accomplishment of all 3 Specific Aims. Dr. Zeigler developed the "head-fixed" technology required to deliver stimuli to single whiskers, to monitor their movements and to bring such movements under voluntary control. These tools will be used in Aims 1 and 2. Dr. Hartmann developed the "head-free" technology required to measure and control movements of single whiskers, as well as means to analyze video materials of such. These tools will be used in Aims 1 and 2. Dr. Jacquin's career has been largely devoted to the trigeminal system and brings expertise on transgenic mice, allatostatin/adenoviruses and single unit recording to bear upon the behavioral issues and technology offered here by Drs. Hartmann and Zeigler.

描述（由申请人提供）：该多 PI R01 提案的长期目标有两个。首先，将揭示连接脑干和前脑三叉神经（V）表征的特定并行神经通路（丘系、副系膜）的功能。这将在啮齿类动物的胡须到桶状皮层神经轴中完成，由于转基因小鼠大脑皮层中桶状结构的突出，该神经轴已成为发现信息处理机制的首选模型。然而，我们对皮层下成分的了解存在重大差距，这阻碍了我们对胡须桶回路的理解。这些空白将通过应用一套多学科工具来研究胡须相关感觉和运动的神经控制来填补。我们的总体假设是，脊髓 V 极间亚核（SpVi，副系膜）中的神经活动对于晶须介导的物体检测和定向反应是必要的，而晶须介导的物体识别和辨别则需要地形图案（桶形）V 主核（PrV，丘系）中的神经活动。采用三个具体目标：a) PrV 中缺乏桶状结构但 SpVi 中没有的转基因小鼠，b) 腺病毒转导的多晶须反应性 SpVi 细胞或单晶须 PrV 细胞的可逆尿抑素诱导沉默，以及 c) 对上述研究的动物中 V 脑干神经元的完整性和神经传递特性进行解剖学和电生理学评估 2 目标。因此，“基因删除”和“神经沉默”方法与这两种方法在 V 脑干神经元中产生“功能性损伤”的程度的并行验证相结合。这使得我们能够发现桶状神经轴的组成部分，这些组成部分明确负责胡须介导的检测、定向、识别和辨别行为。其次，这项研究还将提供技术“原理证明”，说明上述尿抑素诱导的腺病毒感染神经元沉默治疗人类神经系统疾病的潜在用途，例如癫痫、慢性疼痛、肥胖和成瘾，其中特定神经元群体具有过度兴奋的特征，减少或消除过度兴奋可能构成一种新的治疗策略。自行施用尿抑素可能是一种变革性的治疗选择，其疗效将在一个简单的模型系统中进行评估，同时关注可能的副作用。合作企业提供 3 个 PI，这对于实现所有 3 个具体目标是不可或缺的。齐格勒博士开发了一种“头部固定”技术，可以向单根胡须提供刺激，监测它们的运动并将这些运动置于自愿控制之下。这些工具将用于目标 1 和 2。Hartmann 博士开发了测量和控制单个胡须运动所需的“无头”技术，以及分析此类视频材料的方法。这些工具将用于目标 1 和目标 2。 Jacquin 博士的职业生涯主要致力于三叉神经系统，并带来了转基因小鼠、尿抑素/腺病毒和单单位记录方面的专业知识，以解决行为问题和 Drs. Jacquin 提供的技术。哈特曼和齐格勒。