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损伤后的自我修复能力。该项目将从神经系统中能够自我修复的部分——嗅觉神经（Grubb实验室）——学习有效再生的经验，并将其应用于神经系统中不能再生的部分——脊髓（Bradbury实验室）。我们将重点关注突触前抑制，这是一种神经元回路用来调节来自轴突输入的神经递质释放的反馈机制。Grubb实验室正在进行的研究表明，在与目标回路重新连接的早期阶段，嗅觉神经轴突的突触前抑制很强，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是否对嗅觉系统成功的脑修复至关重要？是否可以采用类似的机制来促进脊髓损伤后的功能恢复？这个项目将会提出这些问题。主要的研究问题是确定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。该项目将结合切片电生理学，体内活动操作，离体组织学和行为分析，所有这些都伴随着定量数值分析。第一年将包括嗅球和脊髓准备的切片电生理学培训。接下来将是对突触前抑制的功能评估——包括它的直接影响，以及在嗅球和脊髓中产生它的局部回路。至关重要的是，将比较基线机制和突触前抑制水平，以及损伤后发生的可塑性变化。第2年将看到体内突触前抑制的慢性药理学和/或化学发生操作，并在两个系统中进行神经元再生的解剖和功能评估。这里的目的是观察是否改变再生回路中的突触前抑制可以用来增强轴突再生和/或功能重新连接。三年级将涉及行为分析，研究在二年级研究的突触前抑制的体内操作后的功能恢复，包括再生嗅觉神经和脊髓投射。在4年级的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经验教训，然后将这些经验教训应用于脊髓损伤恢复的模型，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.