New expert-led consensus to shape the future of MND drug discovery and development research
6th December 2023
The extensively branching axonal arbour of neurons can frequently dwarf the size of the other two principal structural components of a neuron, namely the soma and the dendrite. For example hippocampal CA3 pyramidal cells have around 1 metre of axon compared to 2-3 centimetres of dendrite. In rodent neurons whose axons are restricted to the brain, more distal aspects of an axon can still be located at sites quite distant (10s of mm) from the cell body. As well as this physical distance, distal axonal segments can be 10s of axonal bifurcations downstream from the cell body. These distances are even more pronounced for cells that project throughout the CNS (e.g. between brain and spinal cord) and outwith the CNS (e.g. motorneurons). In larger species, including man, the physical distances of axonal transmission can enter the metre scale.
Action potentials (APs) typically initiate at the axonal hillcock/initial segment, an axonal structure close to the cell body. They then propagate away into the deeper recesses of the branching axonal arbour. En route, APs activate the numerous en passant synapses they encounter in each axonal segment. It is generally assumed that when APs encounter axonal bifurcations “daughter APs” appear in both downstream branches. Indeed, this has been shown experimentally, at least for branches proximal to the cell body of cortical neurons. However, there is also evidence that “branch point failures” can occur at axonal bifurcations in some cells or under some defined conditions. Notably, branch point failure rates as low as 1% could have substantial functional consequences for the fidelity of AP invasion to distal aspects of highly branching axons.
To date it has not been technically possible to address how well APs survive bifurcations of axonal branches distant from the cell body. This project initially involves developing methods that will allow this question to be addressed by optically monitoring electrical activity in distal axonal branches of rodent neurons. Specifically, this will involve establishing methods to transduce or transfect single cortical or hippocampal neurones in vivo with optical reporters, including the most recently described indicators of membrane voltage and intracellular Ca2+. With these approaches established the major investigational aspects of the project will involve using state of the art imaging methods to measure AP arrival and propagation in distal axonal segments, having previously initiated the spikes journey peri-somatically with electrical or optogenetic stimuli. Initial work of this nature will involve imaging an intact whole hippocampal in vitro preparation looking at spikes spreading caudally and ventrally from a cell transduced in the ipsilateral dorsal and rostral aspect. Further work will use in vivo 2 photon imaging methods to look at AP in axons of cortical layer 1. Interlaced with these fundamental neurobiological studies, the student will make comparisons of axonal AP invasion between normal and disease model mice. Key models for such studies will be those exhibiting the key dementia-associated pathology amyloidopathy, as this is has been reported to produce an axonal pathology in cortical structures, which we hypothesize will be detrimental to complete AP invasion of the axonal arbour.
This 4 year project will require bench fees for consumables and equipment, which will total approximately £27,000 over the duration of the project.
For more information about the project and informal enquiries, please contact the primary supervisor. Professor Andrew Randall https://medicine.exeter.ac.uk/people/profile/index.php?web_id=Andrew_Randall
Entry requirements:
You should have or expect to achieve at least a 2:1 Honours degree from a UK university, or equivalent international degree. Appropriate disciplines include: Neuroscience, Biomedical Science, Physiology, Pharmacology or Biochemistry. We would also be interested in seeing applications from biologically-minded mathematicians and physicists. Masters degrees are unquestionably advantageous as is any significant experience in experimental or theoretical Neurobiology. You must be prepared to work with laboratory animals, and experience in this regard, especially that including a UK Home Office licence, will be advantageous.
If English is not your first language you will need to meet the English language requirements and provide proof of proficiency.
This project is self funded.
Information about current fees can be found here
Information about possible funding sources can be found here
For more information and to apply, click here
uems-graduateresearch@exeter.ac.uk