Molecular and cellular mechanisms of brain and central nervous system plasticity, regeneration, degeneration

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 (2024) Structural circuit plasticity by a neurotrophin with a Toll modifies dopamine-dependent behaviour. eLife https://doi.org/10.7554/eLife.102222.1 

• Singh et al (under revision). Fungi activate Toll-1 dependent immune evasion to induce cell loss in the host brain. bioRxiv DOI https://doi.org/10.1101/2024.04.29.591341 

• 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, 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