How does presynaptic inhibition influence axonal regeneration?

突触前抑制如何影响轴突再生？

• 批准号: 2748388
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2748388
• 关键词: How; does; presynaptic; inhibition; influence

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.

翻译神经科学的主要目标是增强神经系统受伤后修复自身的能力。该项目将从一部分可以成功修复自身修复的神经系统的有效再生中学习课程 - 嗅觉神经（Grubb Lab），并将其应用于无法再生的神经系统的一部分 - 脊髓（Bradbury Lab）。我们将重点关注突触前抑制，这是一种反馈机制，用于调节辅助轴突输入的神经递质释放。 Grubb实验室中正在进行的工作表明，嗅觉神经轴突的突触前抑制作用很强，正处于与目标电路重新连接的早期阶段，并且这种突触前抑制的强度会影响该系统中这种自然抑制的强度。但是，突触前抑制作用的改变对于嗅觉系统中成功的脑修复至关重要，并且是否可以选择类似的机制来促进脊髓损伤的功能恢复？该项目将准确提出这些问题。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天然发生和实验诱导的再生的影响。该项目将结合切片电生理学，体内活性操纵，离体组织学和行为分析，均伴随定量数值分析。 1年级将涉及嗅球和脊髓制剂中的切片电生理学培训。在嗅球和脊髓中，这将进行突触前抑制的功能评估 - 其直接作用以及与之产生的局部电路有关。至关重要的是，将在基线机理和突触前抑制水平以及受伤后发生的塑性变化之间进行比较。 2年将参见体内突触前抑制的慢性药理和/或化学发生操作，并在这两个系统中对神经元再生进行了解剖和功能评估。这里的目的是查看是否可以使用再生电路中的突触前抑制作用来增强轴突再生和/或功能重新连接。第三年级将涉及行为分析，研究在第2年研究的相同体内抑制体体内恢复后，在再生嗅觉神经和脊髓投影中。在第4年的6个月中，将分析数据，并将撰写论文。总体而言，工作计划旨在从嗅觉系统中自然发生的再生中学习课程，然后将这些课程应用于脊髓损伤的恢复模型，以期增强功能恢复。