Jeon S M, Pradeep A, Chang D, McDonough L, Chen Y, Latremoliere A, Crawford L K, Caterina M J
bioRxiv. 2023 Sep 13:2023.09.12.557420. doi: 10.1101/2023.09.12.557420.
Following peripheral nerve injury, denervated tissues can be reinnervated via regeneration of injured neurons or via collateral sprouting of neighboring uninjured afferents into the denervated territory. While there has been substantial focus on mechanisms underlying regeneration, collateral sprouting has received relatively less attention. In this study, we used immunohistochemistry and genetic neuronal labeling to define the subtype specificity of sprouting-mediated reinnervation of plantar hind paw skin in the mouse spared nerve injury (SNI) model, in which productive regeneration cannot occur. Following an initial loss of cutaneous afferents in the tibial nerve territory, we observed progressive centripetal reinnervation by multiple subtypes of neighboring uninjured fibers into denervated glabrous and hairy plantar skin. In addition to dermal reinnervation, CGRP-expressing peptidergic fibers slowly but continuously repopulated the denervated epidermis, Interestingly, GFRα2-expressing nonpeptidergic fibers exhibited a transient burst of epidermal reinnervation, followed by trend towards regression. Presumptive sympathetic nerve fibers also sprouted into the denervated territory, as did a population of myelinated TrkC lineage fibers, though the latter did so less efficiently. Conversely, rapidly adapting Aβ fiber and C fiber low threshold mechanoreceptor (LTMR) subtypes failed to exhibit convincing collateral sprouting up to 8 weeks after nerve injury. Optogenetics and behavioral assays further demonstrated the functionality of collaterally sprouted fibers in hairy plantar skin with restoration of punctate mechanosensation without hypersensitivity. Our findings advance understanding of differential collateral sprouting among sensory neuron subpopulations and may guide strategies to promote the progression of sensory recovery or limit maladaptive sensory phenomena after peripheral nerve injury.
Following nerve injury, whereas one mechanism for tissue reinnervation is regeneration of injured neurons, another, less well studied mechanism is collateral sprouting of nearby uninjured neurons. In this study, we examined collateral sprouting in denervated mouse skin and showed that it involves some, but not all neuronal subtypes. Despite such heterogeneity, a significant degree of restoration of punctate mechanical sensitivity is achieved. These findings highlight the diversity of collateral sprouting among peripheral neuron subtypes and reveal important differences between pre- and post-denervation skin that might be appealing targets for therapeutic correction to enhance functional recovery from denervation and prevent unwanted sensory phenomena such as pain or numbness.
周围神经损伤后，失神经支配的组织可通过损伤神经元的再生或邻近未损伤传入神经纤维向失神经支配区域的侧支芽生实现重新神经支配。虽然人们大量关注再生的潜在机制，但侧支芽生受到的关注相对较少。在本研究中，我们利用免疫组织化学和基因神经元标记来确定在小鼠保留神经损伤（SNI）模型中，侧支芽生介导的后足底皮肤重新神经支配的亚型特异性，在该模型中不会发生有效的再生。在胫神经支配区域的皮肤传入神经最初丧失后，我们观察到邻近未损伤纤维的多个亚型向失神经支配的无毛和有毛足底皮肤进行渐进性的向心性重新神经支配。除了真皮的重新神经支配外，表达降钙素基因相关肽（CGRP）的肽能纤维缓慢但持续地重新填充失神经支配的表皮。有趣的是，表达胶质细胞源性神经营养因子受体α2（GFRα2）的非肽能纤维表现出短暂的表皮重新神经支配爆发，随后有消退趋势。推测的交感神经纤维也向失神经支配区域芽生，一群有髓鞘的TrkC谱系纤维也是如此，尽管后者的效率较低。相反，快速适应的Aβ纤维和C纤维低阈值机械感受器（LTMR）亚型在神经损伤后8周内未能表现出令人信服的侧支芽生。光遗传学和行为学分析进一步证明了有毛足底皮肤侧支芽生纤维的功能，点状机械感觉得以恢复且无超敏反应。我们的发现推进了对感觉神经元亚群间差异侧支芽生的理解，并可能指导促进感觉恢复进程或限制周围神经损伤后适应不良感觉现象的策略。
神经损伤后，组织重新神经支配的一种机制是损伤神经元的再生，另一种研究较少的机制是附近未损伤神经元的侧支芽生。在本研究中，我们研究了失神经支配小鼠皮肤中的侧支芽生，结果表明它涉及一些但并非所有神经元亚型。尽管存在这种异质性，但点状机械敏感性仍有显著程度的恢复。这些发现突出了周围神经元亚型间侧支芽生的多样性，并揭示了失神经支配前后皮肤之间的重要差异，这些差异可能是治疗矫正的有吸引力靶点，以增强从失神经支配中恢复的功能并预防诸如疼痛或麻木等不必要的感觉现象。
