Precision Medicine DTP - Using modelling and C. elegans to target the molecular mechanisms governing Ca2+-linked cognitive decline

Background
One of the most feared aspects of age is that as we get older, the brain functionally deteriorates and there is an increased risk of neurodegeneration and dementia. An early hallmark of cognitive decline is the loss of the ability to learn. Increasing evidence shows that Ca2+ signalling, a universal signal required for the plasticity and functional stability of neurons, plays a key role in this decline. Ca2+ becomes chronically elevated in neurons with age, impairing neural plasticity and contributing to long-term neurodegeneration such as Alzheimer’s disease. The mechanisms how chronically high Ca2+ affects downstream pathways to impair neural plasticity remain elusive, and understanding them is critical to develop novel therapeutic strategies for neurodegenerative disorders.
We have established Caenorhabditis elegans as a powerful paradigm to understand the mechanisms underpinning calcium function and functional decline in neural circuits. We found that ambient oxygen evokes a strong and sustained rise of Ca2+ in the O2-sensing neurons, which control the long-term behavioural state of C. elegans. O2 responses are reprogrammed by experience, representing long-term cellular memory. Tantalisingly, we find that chronically elevated [Ca2+] induced by high ambient O2 causes these neurons to lose their ability to adapt and learn new information within days, while previously learned responses are maintained. Persistent reduction of their activity restores plasticity of these neurons. In particular, the differential expression of neuronal genes that modulate Ca2+ homeostasis plays a central role in mediating the age-dependent cognitive decline.

Aims
In this project, we aim to gain an understanding of the pathways that underlie Ca2+-induced cognitive decline. 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 Ca2+-linked decline of plasticity in neurons.

The project will be performed in collaboration between the Stefan lab, which uses computational models and simulations to study the molecular and cellular basis of memory, and the Busch lab, which studies sensory neural circuit function in C. elegans.

The specific research aims are to:
1. Create a computational model of Ca2+ signalling in the C. elegans O2-sensing neurons and integrate the experimentally determined roles of genes linked to Ca2+ signalling.
2. Identify and characterise the key pathways that govern the decline of neural plasticity with age in response to chronically elevated Ca2+.
3. Elucidate how these pathways act in concert to bring about the decline of neural plasticity, by making interaction predictions in silico and testing them in vivo.

You will build on a chemical kinetic model of the C. elegans neurons that we developed previously to simulate time courses of biochemical interactions in various conditions, and use this to implement an in silico equivalent of neuronal plasticity governed by the long-term activity state of the neuron. You will also use chemical kinetic models to simulate time courses of biochemical interactions in various conditions. The model will then give you the opportunity to dissect the effects of environmental changes, mutations or other malfunctions on neuronal Ca2+ function.
Our data pinpoint three highly conserved intersecting pathways in the decline of plasticity downstream from Ca2+, namely calcineurin, mTOR and AMPK signalling. You will implement each pathway in the model, characterise interactions between them in silico and quantify their contribution to the dynamic Ca2+ response under varying conditions. The model can be used to generate hypotheses about the role of how these pathways interact in synaptic plasticity and ageing. You can then test these hypotheses in vivo by targeting components of one or more pathways and conducting plasticity assays in ageing C. elegans.
The pathways regulated by Ca2+ signalling are highly conserved in evolution and can be pharmacologically targeted, and we anticipate that the physiological mechanisms we will identify are applicable to humans.

Training outcomes
This project will provide you with multidisciplinary experience at the interface between computational and biomedical science, focusing on computational biology and pathway modelling, functional neural and behavioural assays, genetics and transcriptomics. You will employ computational methods to model data generated from basic science, then translate and connect these models to in vivo contexts to set the stage for future prediction-based pharmacological treatments. You will learn to use a specialised software for chemical kinetics modelling, as well as how to construct, validate, and run a chemical kinetics model.