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Structural brain plasticity in health, regeneration and repair

Principal Supervisor: Dr Alicia Hidalgo - School of Biosciences

PhD project title: Structural brain plasticity in health, regeneration and repair

University of Registration: Birmingham

Project outline:

The brain is plastic: neurons and glia make adjustments in cell size and shape (dendrites, axons), in synapses, and in cell number, throughout life. This structural plasticity is necessary for learning and long-term memory, for the brain to change with experience, and for regeneration and repair. But counteracting mechanisms constrain the brain’s ability to change in order to stabilise circuits. The healthy brain is kept in balance between plasticity and homeostasis, resulting in normal behaviour. Exercise and learning increase plasticity, whilst brain diseases are linked to loss of this balance, e.g. brain tumours (e.g. gliomas) or neurodegeneration (eg Alzheimer’s and Parkinson’s disease). Conversely, the homeostatic mechanisms that keep the brain stable also prevent the central nervous system from regenerating upon damage. We want to understand why and how structural plasticity is linked to brain function. Ultimately, this can reveal the fundamental principles of what makes a brain, and how the brain works. Importantly, it will reveal how to enhance and direct structural plasticity and homeostatic to help treat brain disease, brain damage and spinal cord injury.

We tackle this big question by aiming to discover genetic mechanisms of structural plasticity, and investigate the interaction between gene networks, cell biology and neuronal activity in nervous system development, regeneration and repair.

We will use the fruit-fly Drosophila as a model organism, as it is the most powerful genetic model organism. Drosophila genetics has for nearly a century provided groundbreaking discoveries of immense relevance for human health. Drosophila research so far has resulted in five Nobel Prizes, ranging from the discovery of the chromosomal basis of inheritance, to the genetic basis of the body pattern and the universal mechanism of innate immunity. The Drosophila genome was the first complex genome to be sequenced. All the fruit-fly neural circuits are currently being mapped, way ahead of the mapping of human circuits. There are cutting edge genetic tools to visualise and manipulate neurons and glia, neural circuits, genes, and even neuronal activity, in vivo, not in a dish, and visualise how this changes behaviour. It is an extremely exciting time to investigate neuroscience with the fruit-fly Drosophila, to discover fundamental principles about any brain.

Objective:

To investigate molecular and genetic mechanisms of structural brain plasticity in Drosophila

Methods:

We will use a combination of genetics, molecular cell biology including CRISPR/Cas9 technology and transgensis, microscopy, including laser scanning confocal microscopy and calcium imaging of neuronal activity in time-lapse, computational imaging approaches for analysis of images and movies, stimulating and inhibiting neuronal function in vivo, and recording and analysing fruit-fly behaviour.

Ultimately, the findings from our research will have implications beyond Drosophila, with an impact also in understanding how any brain works, in health, injury or disease, including the human brain.

References:

  1. http://www.biosciences-labs.bham.ac.uk/hidalgo/Alicia_Hidalgo_Lab_Home.html
  2. Losada-Perez, Harrison, Hidalgo (2016) Molecular mechanism of central nervous system repair by the Drosophila NG2 homologue kon-tiki. Journal of Cell Biology 214 (5) 587-601.
  3. McIlroy G, Foldi I, Aurikko J, Wentzell JS, Lim MA, Fenton JC, Gay NJ and Hidalgo A (2013) Toll-6 and Toll-7 function as neurotrophin receptors in the Drosophila melanogaster CNS. Nature Neuroscience 16, 1248-1256
  4. Kato K, Forero MG, Fenton JC and Hidalgo A (2011) The glial regenerative response to central nervous system injury is enabled by Pros-Notch and Pros-NFkB feedback. PLoS Biology 9: e1001133
  5. Zhu, Pennack, McQuilton, Forero, Mizuguchi, Gu, Fenton and Hidalgo (2008) Drosophila neurotrophins reveal a common mechanism of nervous system formation. PLoS Biology 6, e284.

BBSRC Strategic Research Priority: Molecules, cells and systems

Techniques that will be undertaken during the project:

Molecular biology: cloning, PCR, CRISPR/Cas9

Genetics: transgenesis, generation of mutants, knock-outs and knock-ins, reporter lines to visualise cells eg with GFP, etc.

Cell biology: to test for protein-protein interactions, eg co-immunoprecipitations Microscopy: laser scanning confocal microscopy, epi-fluorescence microscopy, time-lapse including calcium imaging using GcAMP reporters

Opto and thermogenetics to manipulate neuronal activity: increase or inhibit neuronal activity and see the consequences with cell biology, GcAMP and behaviour

Behaviour: locomotion, optomotor response, learning and memory

Contact: Dr Alicia Hidalgo, University of Birmingham