Using DREADDs to deconstruct motor neuron disease
Motor neuron disease is caused by selective loss of both brain and spinal cord motor neurons, leading to progressive muscle weakness, paralysis and death typically by respiratory failure. The loss of brain and spinal cord motor neurons is postulated to result from their chronic electrical over-activity (hyperexcitability) – increasingly recognised as an important pathological factor in MND. However, knowledge of which neuronal population initiates the degenerative process in MND remains unclear.
Aim
- Examine the effect on neuronal degeneration, muscular atrophy and subsequent motor behaviour deficits following chronic stimulation/activity of:
- brain motor neurons that physically project to spinal cord motor neurons and,
- spinal cord motor neurons that directly connect to muscle fibres.
To achieve the aim of this project, we plan to use an innovative and powerful tool called DREADD technology. This method allows for the selective and chronic ‘activation’ of targeted neuronal pathways in the rodent central nervous system, therefore allowing us to experimentally model chronic neuronal hyperexcitability that occurs in MND patients.
This project will employ stereotaxic viral surgeries to deliver DREADDs to discrete brain and spinal cord regions, mouse behavioural studies, advanced microscopy and 3D reconstructions, immunohistological and biochemical techniques.
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