Developmental robustness of neuronal networks
Supervisor
Most animals are not warm-blooded and therefore have to buffer their development against biophysical impacts, e.g. as come with changes in temperature. This perhaps most affects the developing nervous system, where transient exposure to sub-optimal temperatures during the brief critical period (in late embryogenesis) permanently alters neuronal properties, changing behaviour and making animals seizure-prone. This is concerning as we face climate change.
What are the developmental, cellular and molecular mechanisms that endow developing nervous systems with stability?
We identified critical periods of development as windows during which cellular properties (of growth, excitability, etc) are set, instructed by metabolic signals. Excitingly, we find that different parts of the developing locomotor network have distinct critical periods, suggesting sequential assembly which could endow reliability.
Using super-resolution microscopy, paired with state-of-the-art genetic expression systems, we can investigate how changes in developmental conditions lead to changes in synaptic connectivity. By working with a well characterised network, that of the Drosophila larva, we are in the unique position of being able to explore how patterns of connectivity change across the network. Questions we can now ask include:
Are there specific ‘tuning points’ within the network? Are neurons that differentiated at different times or that have opposing functions differentially affected? How is connectivity ‘corrected’ if we re-open the critical period in later life?
In this project you will use a combination of opto-and thermo-genetics for targeted manipulations. Super-resolution imaging (e.g. ExM and STED) and electrophysiology (2-electrode voltage clamp) allows us to characterise the consequences of critical period manipulations, with synaptic resolution, complemented by behavioural assays.
References
1. Giachello CNG, Hunter I, Pettini T, Coulson B, Knüfer A, Cachero S, Winding M, Arzan Zarin A, Kohsaka H, Fan YN, Nose A, Landgraf M, Baines RA (2022). Electrophysiological validation of monosynaptic connectivity between premotor interneurons and the aCC motoneuron in the Drosophila larval CNS. J Neurosci. 42(35):6724–38. doi: 10.1523/JNEUROSCI.2463-21.2022.
2. Oswald MCW, Brooks PS, Zwart MF, Mukherjee A, West RJH, Giachello, CNG, Morarach K, Baines RA, Sweeney ST and Landgraf M. (2018). Reactive Oxygen Species Regulate Activity-Dependent Neuronal Structural Plasticity. eLife, 7. http://doi.org/10.7554/eLife.39393
3. Giachello CNG, Fan YN, Landgraf M, Baines RA (2021). Nitric oxide mediates activity-dependent change to synaptic excitation during a critical period in Drosophila. Sci Rep. 2021 Oct 13;11(1):20286. doi: 10.1038/s41598-021-99868-8.
4. Zwart, M. F. et al. Selective Inhibition Mediates the Sequential Recruitment of Motor Pools. Neuron (2016). doi:10.1016/j.neuron.2016.06.031
5. Couton L., Mauss A.S., Yunusov T., Diegelmann S., Evers JF., Landgraf M. Development of connectivity in a motoneuronal network in Drosophila larvae. Curr Biol. 25:568-76 (2015). doi: 10.1016/j.cub.2014.12.056.
Image: Left: pre-motor interneuron (orange) in context of axon tracts (blue). Right: motorneuron (yellow) with postsynaptic sites (cyan); inset showing magnified view of dendrites.