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Neuroinflammation grading and adjusting of spinal sensorimotor circuitries in response to remote injuries in peripheral nerves

神经炎症分级和脊髓感觉运动回路的调整以应对周围神经的远程损伤

基本信息

批准号：
9885850
负责人：
FRANCISCO J ALVAREZ
金额：
$ 36.31万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9885850
关键词：
Affect Alleles Animal Model Axon Blood Brachial plexus structure Brain CCL2 gene Cells Complement Data Disease Excision Face Feedback Functional disorder Future Goals Horns Immune Immune system Impairment Infiltration Inflammatory Injury Joints Knowledge Label Length Lesion Life Ligands Light Locomotion Mediating Methods Microglia Motor Motor output Movement Mus Muscle Natural regeneration Nerve Nerve Crush Nerve Regeneration Neuraxis Neuronal Plasticity Operative Surgical Procedures Outcome Parents Patients Pattern Peripheral Peripheral Nerves Phagocytes Phagocytosis Physiological Process Reaction Recovery Recovery of Function Role Sensorimotor functions Sensory Severities Signal Transduction Site Specific qualifier value Specificity Speed Spinal Spinal Cord Stretching Structure Synapses Synaptic plasticity Techniques Testing Time Up-Regulation Ventral Horn of the Spinal Cord Work awake axon injury axon regeneration cell type chemokine chemokine receptor design diphtheria toxin receptor dorsal column dorsal horn genetic approach improved injured macrophage monocyte motor control motor deficit motor disorder motor function improvement nerve injury nerve supply nerve transection neural circuit neuroinflammation novel strategies outcome forecast peripheral nerve regeneration preservation prevent recruit reinnervation response sciatic nerve stretch reflex time use treadmill two photon microscopy

项目摘要

Project Summary / Abstract Nerve injury patients face life-long sensorimotor deficits despite continued improvements in microsurgical techniques and nerve regeneration. These are usually believed to result from poor or unspecific regeneration of the peripheral nerve. However, deficits are still present when experimental nerve injuries are designed in animal models for rapid, specific and efficient nerve regeneration and muscle re-innervation. We have proposed that structural remodeling of spinal cord circuitry after nerve lesions is in part responsible. Thus, future advances in nerve regeneration will predictably be limited by deficits caused by this much less studied central synaptic plasticity. Remarkably, the central synaptic branches of Ia afferent proprioceptive axons injured in the periphery are removed from the spinal cord ventral horn after nerve injury resulting in dysfunction of critical motor control circuits. We recently found that this synaptic plasticity is graded to the type of nerve injury and correlated with the more or less target specificity obtained during muscle reinnervation. Our preliminary data suggest that neuroinflammation occurring inside the otherwise intact spinal cord ventral horn, is critical for grading circuit remodeling to the severity of the nerve injury. Ventral horn microglia are activated after nerve injuries and although their capacity for synapse phagocytosis has been frequently proposed, their function inside the spinal cord after a remote nerve injury continues to be debated. Moreover, we found that microglia activation is followed by infiltration of cells from the adaptive and innate peripheral immune system, but this is variable depending on injury type. When occurs, it correlates with maximal Ia synapse and axon removal from the ventral horn. These cells, particularly monocyte/macrophages were missed in previous studies because they share many markers with activated microglia, preventing their identification. Thus, their function inside the spinal cord ventral horn after nerve injury is unexplored. We will use genetic approaches to distinguish microglia from blood-derived immune cells and investigate their significance for Ia afferent removal. In Aim 1 we will genetically label and manipulate each cell type to test their roles in Ia axon and synapse deletions and probe cellular signaling mechanisms. In Aim 2 we will visualize with time-lapse two-photon microscopy genetically labeled sensory afferents and microglia or monocyte-derived cells to directly observe and analyze their interactions. Finally, in Aim 3 we will test the relevance of this mechanism for motor function, whether is maladaptive, causing long-lasting motor deficits or adaptive, to preserve the best function possible when peripheral connectivity becomes highly scrambled after regeneration. The new knowledge generated will allow us to consider new methods for optimization of central circuitry function through modulation of central neuroinflammation. This will be critical for developing strategies to improve sensorimotor function recovery in conjunction with methods to improve the speed, efficiency and specify of axon regeneration in the periphery.

项目摘要/摘要