Ca2+ is an essential cellular signal that regulates diverse processes in neurons, including synaptic plasticity, excitability or gene expression, and operates with vastly different spatial and temporal dynamics. Dysregulation of Ca2+ plays a pivotal role in degeneration and death of brain cells after ischemic strokes, in long-term neurodegeneration such as Alzheimer's disease, and also in inflammatory processes, bipolar disorder or schizophrenia. Understanding the molecular processes regulating Ca2+ homeostasis is critical for the development of novel therapeutic strategies for these disorders and ensuring health across an individual’s lifespan.
We have established oxygen responses in the nematode model organism C. elegans as a powerful paradigm to tease apart the mechanisms underpinning calcium function and dysfunction in neural circuits. We found that ambient oxygen evokes a strong and sustained but instantly reversible rise of Ca2+ in the O2-sensing neurons, which controls behavioural state of C. elegans in the long term. It is sustained by calcium influx through ion channels, Ca2+ release from intracellular stores and IP3 signalling.
Strikingly, we found that these O2 responses are reprogrammed by experience: Animals show very different tuning of O2-evoked responses when raised at different oxygen levels. This plasticity depends on prolonged changes of neuronal [Ca2+] in the sensory neurons themselves and it changes their excitability, showing hallmarks of long-term memory. We have identified and started to characterise candidate genes that control the stability and plasticity of Ca2+ responses, and therefore behavioural state, throughout the lifespan.
In this project, we will bring together in silico and in vivo analyses in C. elegans to build a model of the biochemical and cellular mechanisms that control the long-term regulation and plasticity of calcium in neurons. The project will be performed in collaboration between the Busch lab, which studies sensory neural circuit function in C. elegans, and the Stefan lab, which uses computational models and simulations to study the molecular and cellular basis of memory.
Combining the power of computational modelling with in vivo studies, you will characterise the signalling factors that control Ca2+ dynamics in the circuit mediating O2 responses. You will mechanistically characterise them using genetics, behavioural assays and functional neuronal imaging. You will also use chemical kinetic models to simulate time courses of biochemical interactions in various conditions. The model will also give us the opportunity to dissect the effects of environmental changes, mutations or other malfunctions on neuronal Ca2+ function.
Most genes known to regulate Calcium signalling are highly conserved in evolution, including between C. elegans and humans. We therefore anticipate that molecular and cellular mechanisms we will identify in C. elegans are applicable to humans.
- Busch KE , Laurent P, Soltesz Z, Murphy RJ, Faivre O, Hedwig B, Thomas M, Smith HL, de Bono M (2012) Tonic signaling from O₂ sensors sets neural circuit activity and behavioral state. Nat Neurosci. 15, 581-591. doi: 10.1038/nn.3061.
Li L, Stefan MI, Le Novère, N (2012) Calcium Input Frequency, Duration and Amplitude Differentially Modulate the Relative Activation of Calcineurin and CaMKII. PLoS One 7, e43810. doi: 10.1371/journal.pone.0043810