Developmental robustness - critical periods of brain development

Heliconius Butterflies

Supervisor: Matthias Landgraf

Project Summary (PhD):

How does nature enable robustness in developmental processes, in the face of unpredictable (seasonal) environmental changes? For example, temperature affects all biological processes, and in insects dictates developmental speed. We focus on the nervous system, which are particularly sensitive to environmental changes.  For example, transient heat stress during a few hours of embryonic development (termed a 'critical period') leads to a change in developmental trajectory, with unstable nervous systems that are prone to seizures and reduced locomotion. 

Working with Drosophila, we discovered that temperature changes trigger metabolic signals in the mitochondria, transmitted to the nucleus by the highly conserved metabolic reprogramming factor, Hypoxia-inducible factor 1 alpha (HIF-1alpha). 

We can now study how metabolic changes cause altered neuronal properties, how a transient stimulus is made permanent, and how resultant mal-adaptations might be reversed.

Type of Work:

This project will use a range of techniques, including opto- and thermo-genetics for targeted manipulations, as well as pharmacological manipulations; RNA seq and metabolomics, confocal imaging and behavioural assays to study the consequences of critical period manipulations.

Importance of the area of research concerned:

How nerve cells acquire their properties during development, especially during so-called critical periods, is not well understood. This project takes a novel, metabolic perspective, which could radically change our understanding of the underlying mechanisms. 

This knowledge should contribute toward developing therapeutic approaches that might enable re-programming neuronal properties, e.g. to ameliorate hyper-excitability of cells that causes epilepsy. 

References: 

Sobrido-Cameán D, Coulson B, Miller M, Oswald MCW, Pettini T, Bailey DMD, Baines RA, Landgraf M. Mitochondrial ROS and HIF-1α signaling mediate synaptic plasticity in the critical period (2026). PLoS Biol. 2025 Aug 13;23(8):e3003338. doi: 10.1371/journal.pbio.3003338. Epub ahead of print. PMID: 40802851.  Drummond-Barbosa D, Tennessen JM  (2020). Reclaiming Warburg: using developmental biology to gain insight into human metabolic diseases. Development. 147(11):dev189340. doi: 10.1242/dev.189340.  Coulson B, Hunter I, Doran S, Parkin J, Landgraf M, Baines RA  (2022). Critical periods in Drosophila neural network development: Importance to network tuning and therapeutic potential. Front Physiol. 2022 Dec 2;13:1073307. doi: 10.3389/fphys.2022.1073307. Hunter I, Coulson B, Pettini T, Davies JJ, Parkin J, Landgraf M, Baines RA  (2024). Balance of activity during a critical period tunes a developing network. Elife. 12:RP91599. doi: 10.7554/eLife.91599.