Synaptic mechanisms of somatosensory circuit assembly

体感电路组装的突触机制

基本信息

批准号：
10567510
负责人：
Bryan Copits
金额：
$ 51.67万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10567510
关键词：
Affect American Axon Behavior Binding Biological Assay Biology Brain Cell Adhesion Molecules Central Nervous System Coculture Techniques Complex Dangerousness Development Diabetes Mellitus Disease Electrophysiology (science)Ensure Esthesia Event Family Fibroblasts Future Gene Family Heart Diseases In Vitro Inflammation Investigation Knockout Mice Label Ligands Link Maintenance Malignant Neoplasms Modality Molecular Mus Nerve Nervous System Neurodevelopmental Disorder Neurons Neurosciences Nociception Nociceptors Patients Perception Peripheral Peripheral Nervous System Persons Phenotype Physiology Positioning Attribute Postdoctoral Fellow Presynaptic Terminals Process Property Protein Isoforms Public Health Quality of life Role Sensory Sensory Process Slice Specific qualifier value Spinal Spinal Cord Stimulus Synapses System Testing Training Trauma Vertebral column Viral Viral Vector Work abuse liability autism spectrum disorder behavioral phenotyping central pain chronic pain comorbidity conditional knockout effective therapy experimental study in vivo insight knockout gene nerve supply optogenetics pain behavior pain processing postsynaptic prescription opioid presynaptic sensory integration somatosensory success synaptic function synaptogenesis

项目摘要

Abstract Chronic pain is debilitating disease that affects more Americans than cancer, heart disease, and diabetes combined. Despite this significant public health problem, effective treatments are scarce and commonly prescribed opioids possess significant abuse liabilities. One possible reason for this poor translational success is that we still lack a detailed understanding of how these circuits are connected to process sensory information and their plasticity mechanisms. In our preliminary experiments we have identified important roles for trans-synaptic adhesion molecules in regulating somatosensory synapse function in the spinal cord. Here we will determine the trans- synaptic molecules that influence somatosensory synapse formation, understand how presynaptic adhesion molecules in somatosensory neurons instruct the formation and function of native synapses in the spinal cord, and establish their role in coordinating nociceptive circuit assembly to regulate pain behaviors. This proposal will use a combination of in vitro synapse induction assays, conditional gene knockout and rescue approaches, peripheral viral circuit tracing, optogenetic slice recordings, and somatosensory phenotyping to understand how trans- synaptic adhesion molecules regulate somatosensory circuit assembly and function.

抽象的慢性疼痛是一种使人衰弱的疾病，对美国人的影响比癌症、心脏病和糖尿病还要多合并。尽管存在这一重大的公共卫生问题，但有效的治疗方法却很少且通常是处方药阿片类药物具有严重的滥用倾向。转化成功率低下的一个可能原因是我们仍然对这些电路如何连接以处理感官信息及其可塑性缺乏详细的了解机制。在我们的初步实验中，我们已经确定了跨突触粘附的重要作用调节脊髓体感突触功能的分子。在这里我们将确定反式影响体感突触形成的突触分子，了解突触前粘附如何体感神经元中的分子指导脊髓中天然突触的形成和功能，以及确定它们在协调伤害性回路组装以调节疼痛行为中的作用。该提案将使用结合体外突触诱导测定、条件基因敲除和拯救方法、外周血病毒回路追踪、光遗传学切片记录和体感表型分析，以了解病毒如何跨突触粘附分子调节体感电路的组装和功能。