Computational models of interactions between developmental and homeostatic processes during nervous system development
Lead Research Organisation:
University of Edinburgh
Department Name: Inst for Adaptive and Neural Computation
Abstract
Nervous system development is a complicated process of growth, specialisation and refinement. Once neurons have formed connections, intrinsically generated spontaneous electrical activity has a critical role of controlling and maintaining the stability of immature neural circuits. If this regulation fails, circuits can not develop properly, and neurological disorders such as epilepsy can develop as a result. Currently, we are only beginning to understand these regulatory processes. A challenge for this research is that often multiple cellular mechanism act simultaneously, resulting in complicated mutual interactions between neural physiology and circuits. In this project, state of the art computational and mathematical modelling will be used to address these questions. Models of neural circuits and regulatory processes will be combined to interpret experimental results and to develop novel, experimentally testable hypotheses. These methods will also be used to study the regulation of neural activity in the developing retina, an important model system for neural development and neurodegenerative disorders. This project will therefore not only advance our basic understanding of regulation of neural activity during development, but also help to understand the origins of developmental and degenerative neurological disorders. Additionally, computational models can help to reduce the number of animals required for research.
Technical Summary
Developing neural circuits are constantly changing during nervous system development. Yet, despite this potential source of variability and instability, they display a remarkable functional robustness once mature. Homeostatic processes, which stabilise and shape immature neural circuits and depend on spontaneous neural activity during early development, are thought to critically contribute to this robustness. How developmental and homeostatic processes interact is currently not well understood and the topic of this project.
Approaching this question experimentally is challenging because neurons have a potentially large repertoire of simultaneously operating homeostatic processes affecting different aspects of their physiology. Moreover, homeostatic processes often compensate for experimental manipulations, complicating their characterisation. This project will address these challenges by means of computational and mathematical modelling of developing neural circuits, and by combining methods from computational neuroscience and systems biology to integrate models of neural activity and activity-dependent molecular regulatory pathways. Models of neurons and activity-dependent pathways will be combined, and integrated into models of developing neural circuits to explore the interactions between the development of cellular excitability, network connectivity and the dynamical regulation of these properties, and to develop and test functional hypotheses regarding their roles in shaping neural circuits.
These methods will also be employed to specifically study activity-dependent mechanisms during retinal development, a well characterised model system for neural development. Spontaneous activity in the developing retina has the form of propagating activity, termed retinal waves, which are implicated in visual system development. Using a recently developed model and a rich set of experimental multi-electrode recordings as a starting point, the maintenance and development of retinal waves will be investigated against the background of retinal circuit maturation. This work will also investigate the properties of retinal waves in CRX knockout mice, which serve as a model system for retinal degenerative disorders. Simulation results will be directly compared with experimental data and contribute to the design of new experiments.
In summary, this project will advance the understanding of the interactions between developmental and activity-dependent homeostatic processes, and explore how they contribute to robust nervous system development. There is now evidence that these processes are involved in the aetiology of developmental brain disorders, in particular in epilepsy, and are also relevant during recovery from brain injury and circuit reorganisation in neurodegenerative disorders. The models developed in this project will therefore also allow to gain a better understanding such pathological conditions.
Approaching this question experimentally is challenging because neurons have a potentially large repertoire of simultaneously operating homeostatic processes affecting different aspects of their physiology. Moreover, homeostatic processes often compensate for experimental manipulations, complicating their characterisation. This project will address these challenges by means of computational and mathematical modelling of developing neural circuits, and by combining methods from computational neuroscience and systems biology to integrate models of neural activity and activity-dependent molecular regulatory pathways. Models of neurons and activity-dependent pathways will be combined, and integrated into models of developing neural circuits to explore the interactions between the development of cellular excitability, network connectivity and the dynamical regulation of these properties, and to develop and test functional hypotheses regarding their roles in shaping neural circuits.
These methods will also be employed to specifically study activity-dependent mechanisms during retinal development, a well characterised model system for neural development. Spontaneous activity in the developing retina has the form of propagating activity, termed retinal waves, which are implicated in visual system development. Using a recently developed model and a rich set of experimental multi-electrode recordings as a starting point, the maintenance and development of retinal waves will be investigated against the background of retinal circuit maturation. This work will also investigate the properties of retinal waves in CRX knockout mice, which serve as a model system for retinal degenerative disorders. Simulation results will be directly compared with experimental data and contribute to the design of new experiments.
In summary, this project will advance the understanding of the interactions between developmental and activity-dependent homeostatic processes, and explore how they contribute to robust nervous system development. There is now evidence that these processes are involved in the aetiology of developmental brain disorders, in particular in epilepsy, and are also relevant during recovery from brain injury and circuit reorganisation in neurodegenerative disorders. The models developed in this project will therefore also allow to gain a better understanding such pathological conditions.
