Molecular and cellular mechanisms of brain and central nervous system plasticity, regeneration, degeneration
About the Project
The aim is to discover and test candidate molecular mechanisms underlying how the central nervous system (CNS) (ie spinal cord and brain) responds to life challenges, for example life experience or injury, driving plasticity, regeneration or degeneration.
We aim to understand why distinct experiences result in adaptation through learning, whilst others can lead to unsurmountable stress, psychiatric and behavioural disorders. We will test the hypothesis that experience results in structural modifications to cells that alter neural circuit connectivity patterns that in turn modify behaviour. Synapses and changes in cell shape are made and unmade every day, as we go about our lives. And if cells change, connectivity patterns in the brain change: what are the consequences to behaviour, what we do, how we feel? The brain is plastic: structural plasticity enable us to form new synapses and connectivity patterns as we learn and adapt to life challenges, encoding memory. Structural homeostasis constrains the brain’s ability to change, thus maintaining neural circuits stable. Exercise and learning increase structural plasticity, whilst homeostatic meachanism can lead to degeneration underlying neurodegenerative diseases (e.g. Alzheimer’s and Parkinson’s), neuro-inflammation and psychiatric disorders (e.g. depression). The cellular processes underlying structural brain change include neurogenesis and gliogenesis, cell loss, changes in cell shape, synapse formation and loss, modifying circuits an behaviour. As behaviour is a source of experience, we aim to find out how cycles of experience and behaviour modify our brain throughout life.
On the other hand, the human central nervous system does not regenerate after injury (for example to the spinal cord) or disease. Injury triggers an inflammatory reaction leading to further cell loss. However, some animals can regenerate their CNS. Furthermore, the human brain is plastic, meaning it can undergo change, enabling neurogenesis, gliogenesis, formation of new synapses and connections in response to challenges. This means that regeneration of cells and connections in the spinal cord or brain after damage could be possible. Animals that can regenerate their CNS do so by inducing de novo neurogenesis followed by integration of new neurons into functional neural circuits. In humans, new neurons are made daily during learning, and these new neurons also integrate into functional circuits. This means that cells can ‘know’ how to re-establish cell populations and circuits. It may possible to tap into the regenerative potential of the CNS to direct regeneration after injury and damage.
We will use the fruit-fly Drosophila as a model organism, for its unparalleled, powerful genetics.
We will investigate the molecular and cellular mechanisms that drive inflammatory and degenerative responses versus plastic and regenerative responses to life experience or injury. The approach will combine a wide range of techniques including: advanced genetics to manipulate genes and cells, molecular cell biology including CRISPR/Cas9 gene editing technology and transgenesis, microscopy, including laser scanning confocal microscopy and calcium imaging in time-lapse, computational imaging approaches for analysis of images and movie recordings, analysis of the connectome to identify neural circuits, stimulating neuronal function with opto- and thermo-genetics in vivo, recording and analysing fruit-fly behaviour, aided by computational data analyses tools.
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