How does presynaptic inhibition influence axonal regeneration?

转化神经科学的一个主要目标是增强神经系统在损伤后自我修复的能力。该项目将从能够成功自我修复的神经系统部分-嗅觉神经（Grubb实验室）-学习有效再生的经验教训，并将其应用于不能再生的神经系统部分-脊髓（Bradbury实验室）。我们将集中在突触前抑制，神经元回路用来调节神经递质释放的反馈机制从传入轴突输入。Grubb实验室正在进行的工作表明，突触前抑制在嗅觉神经轴突中很强，这些轴突处于与目标回路重新连接的早期阶段，并且改变这种突触前抑制的强度可以影响该系统中自然发生的轴突再生。但是，突触前抑制的改变对嗅觉系统的成功修复至关重要吗？类似的机制能否被用来促进脊髓损伤后的功能恢复？这个项目将提出这些问题。主要的研究问题是建立突触前抑制对成年哺乳动物中枢神经系统自然发生和实验诱导再生的影响。该项目将使用切片电生理学，体内活动操作，体外组织学和行为分析的组合，所有这些都伴随着定量数值分析。第一年将涉及在嗅球和脊髓准备切片电生理学的培训。随后将对嗅球和脊髓中的突触前抑制进行功能评估--包括其直接影响和产生突触前抑制的局部回路。最重要的是，将在突触前抑制的基线机制和水平以及损伤后发生的可塑性变化之间进行比较。第二年将看到体内突触前抑制的慢性药理学和/或化学发生学操作，在两个系统中进行神经元再生的解剖和功能评估。这里的目的将是看看是否改变突触前抑制再生电路可以用来增强轴突再生和/或功能重新连接。第3年将涉及行为分析，研究与第2年研究的突触前抑制相同的体内操作后的功能恢复，包括再生嗅神经和脊髓投射。在第四年的6个月里，将分析数据并撰写论文。总的来说，这项工作计划旨在从嗅觉系统的自然再生中吸取教训，然后将这些教训应用于脊髓损伤的恢复模型，以期促进功能恢复。

A major goal in translational neuroscience is to enhance the ability of the nervous system to repair itself after injury. This project will learn lessons in effective regeneration from part of the nervous system which can repair itself successfully - the olfactory nerve (Grubb lab) - and apply them to part of the nervous system which cannot regenerate - the spinal cord (Bradbury lab). We will focus on presynaptic inhibition, a feedback mechanism used by neuronal circuits to regulate neurotransmitter release fromincoming axonal inputs. Ongoing work in the Grubb lab has shown that presynaptic inhibition is strong in olfactory nerve axonsthat are in the early stages of re-connecting with their target circuits, and that altering the strength of this presynaptic inhibition can affect naturally-occurring axonal regeneration in this system. But are alterations in presynaptic inhibition crucial for successful brain repair in the olfactory system, and can similar mechanisms be co-opted to promote functional recovery from spinal cord injury? This project will ask precisely these questions. The primary research question is to establish the influence of presynaptic inhibition on naturally occurring and experimentally induced regeneration in the adult mammalian central nervous system. The project will use a combination of slice electrophysiology, in vivo activity manipulations, ex vivo histology, and behavioural analysis, all accompanied by quantitative numerical analysis. Year 1 will involve training in slice electrophysiology in both olfactory bulb and spinal cord preparations. This will be followed by functional assessments of presynaptic inhibition - both its direct effects, and the local circuits involved in generating it - in the olfactory bulb and spinal cord. Crucially, comparisons will be made between baseline mechanisms and levels of presynaptic inhibition, and the plastic changes that occur after injury. Year 2will see chronic pharmacological and/or chemogenetic manipulations of presynaptic inhibition in vivo, assayed with anatomical and functional assessments of neuronal regeneration in both systems. The aim here will be to see whether altering presynaptic inhibition in regenerating circuits can be used to enhance axon regrowth and/or functional re-connectivity. Year 3 will involve behavioural analyses, studying functional recovery after the same in vivo manipulations of presynaptic inhibition studied in Year 2, in both regenerating olfactory nerve and spinal cord projections. In the 6 months of Year 4, data will be analysed and the thesis will be written. Overall, the plan of work is designed to learn lessons from naturally occurring regeneration in the olfactory system, and then to apply those lessons to models of recovery from spinal cord injury in the hope of boosting functional recovery.