Functional Segregation Within the Whisker-Barrel Neuraxis

晶须桶神经轴内的功能分离

• 批准号: 9312907
• 负责人: Mitra J Hartmann
• 金额: $ 61.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312907
• 关键词: Address; Adenoviruses; Adverse effects; Affect; Air; Allatostatin; Anatomy; Animals; Attention; Behavior; Behavior Control; Behavioral; Biological Assay; Biological Models; Brain; Brain Stem; Cell Count; Cell Nucleus; Cells; Cerebral cortex; Coupled; Data; Detection; Development; Discrimination; Electric Stimulation; Electrophysiology (science); Epilepsy; Esthesia; Eye; Ganglia; Gene Deletion; Gifts; Glutamates; Goals; Head; Human; Infusion procedures; Ipsilateral; Knockout Mice; Knowledge; Lesion; Link; Measures; Mechanical Stimulation; Mediating; Modeling; Molecular Genetics; Monitor; Movement; Mus; Neocortex; Neural Pathways; Neuraxis; Neurons; Obesity; Ocular dominance columns; Pathway interactions; Pattern; Peer Review; Performance; Population; Property; Prosencephalon; Reporting; Research; Retina; Rodent; Self Administration; Specific qualifier value; Speed; Spinal; Spinal Cord; Stimulus; Structure; System; Tactile; Technology; Testing; Thalamic structure; Transfection; Transgenic Mice; Transgenic Organisms; Trigeminal System; Ursidae Family; Validation; Ventricular; Vibrissae; Visual system structure; Work; addiction; barrel cortex; behavioral study; career; cell type; chronic pain; genetic analysis; grasp; information processing; kinematics; multidisciplinary; mutant; nervous system disorder; neurobehavioral; neurophysiology; neuroregulation; neurotransmission; ovid; public health relevance; receptive field; relating to nervous system; response; segregation; tool; treatment strategy

 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。这将在啮齿动物的胡须到桶状皮层神经轴中完成，由于桶状结构在大脑中的突出地位，该神经轴已成为发现信息处理机制的首选模型。然而，我们对皮质下成分的了解存在重大空白，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，副脑膜）的神经活动对于胡须介导的物体检测和定向反应是必要的，而胡须介导的物体识别和辨别则需要神经活动。拓扑图案（桶状）V 主核（PrV，丘系）采用三个特定目标：a）PrV 中缺乏桶状核但 SpVi 中没有的转基因小鼠，b）腺病毒转导的多晶须响应性 SpVi 的可逆性尿抑素诱导沉默。细胞或单晶须 PrV 细胞，以及 c) V 脑干完整性和神经传递特性的解剖学和电生理学评估因此，“基因删除”和“神经沉默”方法与这两种方法在 V 脑干神经元中的“功能性损伤”程度的平行验证相结合，从而可以发现 V 脑干神经元的成分。其次，这项研究还将为上述尿抑素诱导的沉默的潜在用途提供技术“原理证明”。腺病毒感染的神经元用于治疗人类疾病，例如癫痫、慢性疼痛、肥胖和神经成瘾，其中特定的神经元群体具有过度兴奋性，减少或消除这些疾病可能构成一种新的治疗策略，自我施用尿抑素可能是一种变革性的治疗方法。选项，其功效将在一个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 的合作项目，这对于完成所有 3 个特定项目是不可或缺的。目标。齐格勒博士开发了向单个胡须提供刺激、监测其运动并将此类运动置于自愿控制之下的“头部固定”技术。哈特曼博士开发了该技术。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此。 Hartmann 和 Zeigler 博士提供了转基因小鼠、尿抑素/腺病毒和单单位记录方面的专业知识，以解决行为问题和技术。