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（由适用提供）：该多PI R01提案的长期目标是两个方面。首先，将揭示特定平行神经元途径（Lemniscal，paralessisal）的功能，将脑干和前脑三叉神经（V）表示。这将在啮齿动物到桶的皮层神经毒性中进行，该神经毒素已成为发现信息处理机制的首选模型，这是由于转基因小鼠脑皮质中桶的突出性。然而，我们对皮层下部成分的知识存在主要差距，这些差距阻碍了我们对晶须桶电路的掌握。通过将一组多学科工具应用于与晶须相关的感觉和运动的神经控制的研究，这些差距将填补。我们的总体假设是，对于晶须介导的对象检测和取向反应，晶须介导的对象识别和歧视需要神经活动，需要在超核核pritter otalettes v核原理（PRV，prv，lemniscal，lemniscal，lemnsiscal）中，晶须介导的对象识别和歧视需要神经活动。 Three Specific Aims employee: 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 studiod in以上2个目标。这是“基因删除”和“神经沉默”方法与脑干神经元中这两种方法产生“功能性病变”的程度并行验证。这允许发现桶神经氧的成分，这些成分明确负责晶须介导的检测，定向，识别和歧视行为。其次，这项研究将提供技术“原理证明”，以潜在使用上述腺病毒感染的神经元的沉默，以治疗人类神经系统疾病，例如癫痫，慢性疼痛，肥胖，肥胖和成瘾，在此策略中构成了新的策略，在此策略中定义了可抑制神经元群体的特征。 Allostatin的自我管理可能是一种变革性的治疗选择，其有效性将在此处简单的模型系统中进行评估，并着眼于可能的副作用。提供了3个PI提供的合作企业，这对于所有3个特定目标的实现都是必不可少的。 Zeigler博士开发了向单晶须传递刺激，监测其运动并将此类运动带到自愿控制所需的“固定”技术。这些工具将用于目标1和2。Hartmann博士开发了测量和控制单晶须运动所需的“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2。Jacquin博士的职业生涯在很大程度上专门用于三叉系统，并为DRS提供的行为和技术带来了转基因小鼠，Allatostatin/adenoviruses和单个单元记录的专业知识。哈特曼和齐格勒。