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Molecular mechanisms of brain plasticity, degeneration and regeneration

Principal Supervisor: Professor Alicia Hidalgo

Secondary Supervisor(s): Dr Jack Rogers

University of Registration: University of Birmingham

BBSRC Research Themes:

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Deadline: 4 January, 2024


Project Outline

The aim of the project is to discover and test candidate molecular mechanisms underlying structural brain plasticity, degeneration and regeneration. We aim to understand how the brain responds to environmental challenge, how it changes as we go through life, how experience shapes the brain, why does the brain degenerate as we age, how can we promote regeneration after injury. The human brain is plastic: it changes as we learn, enabling adaptation and memory, and then it degenerates as we age. The brain and spinal cord can also respond to stressors and injury. The human central nervous system (CNS) does not regenerate after injury or disease, but some animals can regenerate their CNS and this generally involves cell reprogramming, de novo neurogenesis followed by integration of new neurons into functional neural circuits.

This means that cells can ‘know’ how to re-establish cell populations and circuits. In fact, the healthy brain is kept in balance between structural plasticity and homeostasis, resulting in normal behaviour. Structural plasticity enables change as we learn and adapt to environmental change, encoding memory. Structural homeostasis constrains the brain’s ability to change, thus maintaining neural circuits stable. Exercise and learning increase structural plasticity, sleep promotes homeostasis, whilst brain diseases are linked to loss of this balance, such as brain tumours (e.g. gliomas), neurodegenerative diseases (e.g. Alzheimer’s and Parkinson’s), neuro-inflammation and psychiatric disorders (e.g. depression).

Conversely, the homeostatic mechanisms that keep the brain stable also slow down learning and prevent the brain from recovering in injury and disease. The cellular processes underlying structural CNS change include neurogenesis and gliogenesis, cell death and cell loss, cellular reprogramming, changes in cell shape (generation or loss or axons, dendrites, glial projections), synapse formation and loss, altogether leading to neural circuit modification and modification of behaviour. We will investigate how experience, stressors and injury modify cellular processes and circuits and how this modifies behaviour. The molecular mechanisms underlying structural brain change are scarcely known.

Discovering them will help answer how the brain works, how we can maintain brain health, promote regeneration after injury and treat brain disease.

Methods

We will use the fruit-fly Drosophila as a model organism, combining a wide range of techniques including: genetics, 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 movies, stimulating neuronal function with opto- and thermos-genetics in vivo, and recording and analysing fruit-fly behaviour.

References

Visit our lab website: https://more.bham.ac.uk/hidalgo/

Sun et al (2022 and under review) Structural circuit plasticity by a neurotrophin with a Toll modifies dopamine-dependent behaviour. BioRxiv https://doi.org/10.1101/2023.01.04.522695

Harrison N, Connolly E, Gascón Gubieda A, Yang Z, Altenhein B, Losada-Perez M, Moreira M, Hidalgo A (2021) Regenerative neurogenesis is induced from glia by Ia-2 driven neuron-glia communication. eLife10:e58756 DOI: 10.7554/eLife.58756

Li G and Hidalgo A (2020) Adult neurogenesis in the Drosophila brain: the evidence and the void. International Journal of Molecular Sciences 21(18), 6653

Guiyi Li and Alicia Hidalgo (2021) The Toll route to structural brain plasticity. Frontiers in Physiology. Frontiers in Physiology DOI: 10.3389/fphys.2021.679766

Li G, Forero MG, Wentzell JS, Durmus I, Wolf R, Anthoney NC, Parker M, Jiang R, Hasenauer J, Strausfeld NJ, Heisenberg M, Hidalgo A (2020) A Toll-receptor map underlies structural brain plasticity eLife, 9: e52743 DOI: 10.7554/eLife.52743
eLife Digest article 17 March 2020 dedicated to our paper: “How experience shapes the brain” https://elifesciences.org/digests/52743/how-experience-shapes-the-brain

Losada-Perez M, Harrison N, Hidalgo A. (2016) Molecular mechanism of central nervous system repair by the Drosophila NG2 homologue kon-tiki. Journal of Cell Biology 214, 587

Kato, Forero and Hidalgo (2011) The glial regenerative response to CNS injury is enabled by Pros-Notch ad Pros-NFkB feed-back. PLoS Biology 9, e1001133

Techniques

Molecular biology: cloning, PCR, CRISPR/Cas9 gene editing.

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

Cell biology and 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 imaging

Behaviour: locomotion, learning and memory, custom-made set ups, etc.