How does presynaptic inhibition influence axonal regeneration?

点击翻译按钮获取中文摘要

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.