The Bloomsbury Colleges | PhD Studentships | Studentships 2018 | Development and plasticity of structural and functional networks in the mouse brain
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Development and plasticity of structural and functional networks in the mouse brain

Principal Supervisor: Helen Stolp (Royal Veterinary College)

Co-Supervisor: Michael Thomas (Birkbeck)

Project description

Early life events have long-term consequences for brain development, e.g. hypoxia-ischemia and inflammation during gestation resulting in high incidence of neurodevelopmental disorders. There are an increasing number of children with mild pathology that can only be diagnosed based on the detection of cognitive or behavioural deficits in later life (e.g. Attention deficit hyperactivity disorder, Autism spectrum disorder). In these cases, the mechanism of injury is unclear and likely due to a complex interaction between normal developmental processes, genetic background and environmental insult. In order to make progress in understanding the injury process, and to recognise at risk patients, it is necessary to have a better understanding of the relationship between structural and functional development in the brain. In particular, it is essential to better comprehend the inherent plasticity within the system that varies over the developmental period. As the brain develops there is increasing complexity of local cellular structure (e.g. cell density and arborisation), connectivity (local and long-range) and functional activity (cell specific, local networks and globally).

Advanced computational models such as graph theory have been applied to MRI data to assess network density, efficiency and strength over human development. Recent work has shown region-specific maturations rates and local connectivity can be affected by premature birth (Batalle et al., 2017). One aim of the present study is to determine whether changes of this type in early life remain present throughout the remainder of development, and the kinetics and mechanisms of changes and whether correction is facilitated by the plasticity of the developing brain. For this we will be using mouse models of brain development that allow this greater degree of assessment and intervention. In the rodent there is the possibility to correlate these global measures of network strength and efficiency over development (e.g. Calabrese et al., 2015) with microstructural analysis of cellular maturation (structural and functional). The availability of these additional data will allow an understanding of the biological underpinning of the global metrics.

In this study we will combine the assessment of normal development with acute pharmacological intervention to assess the plasticity of these structural and functional networks at different stages of brain development. Assessments will be made correlating behaviour to macrostructural assessment of the brain with diffusion MRI, and microstructural parameters of cellular number and arborisation, for both the glutamatergic and GABAergic cell populations in the brain.

Mice will be treated with the a GABAA agonist at a number of early postnatal ages and assessment of the structural development of the brain will be assessed in the first week of life, and as juvenile, young adult and adult ages. Assessments will include behaviour, diffusion MRI and cellular microstructure. The project will generate multiple sources of brain data from micro to macros scales, as well as behavioural data across development. It is challenging to link these levels within a causal account, or indeed to establish a theoretical framework to formulate hypotheses. Multi-scale computational modelling provides one framework to generate causal accounts. Artificial neural networks are a computational formulism in which low-level properties of neural systems can be linked to global behaviour through experience-dependent learning processes (Thomas et al., 2016; Thomas, 2016). The project will include a limited computational element, using Matlab to construct a simple network of integrate-and-fire neurons. The model will implement a regime of exuberant connectivity growth following by pruning, as well as experience-dependent plasticity. Under different assumptions of early pathology, the framework will simulate the network’s ability acquire and maintain input-output functions. The modelling component will therefore provide a formal language to generate hypotheses to understand the relation between structural and functional mouse model observations and high-level changes in behaviour.

This work will enable the assessment of microstructural features and their natural variability over the course of development, and following a disruption to the excitatory-inhibitory balance to the brain. The use of behavioural testing will allow a functional correlation to be made from microstructural data. The data will lead to a greater understanding of the basic relationship between structure and function in the developing brain, the relative plasticity of the system to alterations in these parameters at different stages of development, and the utility of a global assessment technique (diffusion MRI) for probing brain structural plasticity.

Subject areas/ keywords

Developmental neuroscience, plasticity, excitatory-inhibitory balance, neuropathology, MRI, computational modelling

Candidate requirements

This role would ideally suit a candidate with a background in cellular and/or computational neuroscience, medical imaging or biomedical engineering.
The candidate should be familiar with Matlab, computational modelling, microscopy, cellular neuroscience, diffusion MRI acquisition and analysis, and be willing to undertake a home office licence for work with mice. Training will be given in all methods, but the candidate should be confident with advanced analytical techniques.

Key References

  • Stolp HB, Ball G, So P-W, Tournier JD, Jones M, Thornton C, Edwards AD. Voxel-wise comparison of cellular microstructure and diffusion –MRI in mouse hippocampus using 3D Bridging of Optically-clear histology with Neuroimaging Data (3D-BOND). Scientific reports, under review (available on request).
  • Batalle D, Hughes EJ, Zhang H, Tournier JD, Tusor N, Aljabar P, Wali L, Alexander DC, Hajnal JV, Nosarti C, Edwards AD, Counsell SJ (2017). Early development of structural networks and the impact of prematurity on brain connectivity. NeuroImage, 149: 379.
  • Salari & Amani (2017). Neonatal blockade of GABA-A receptors alters behavioural and physiological phenotypes in adult mice. International Journal of Developmental Neuroscience, 57: 62.
  • Thomas, M. S. C. (2016). Do more intelligent brains retain heightened plasticity for longer in development? A computational investigation. Developmental Cognitive Neuroscience, 19, 258–269.
  • Thomas, M. S. C., Forrester, N. A., & Ronald, A. (2016). Multi-scale modeling of gene-behavior associations in an artificial neural network model of cognitive development. Cognitive Science, 40(1), 51-99.

Further information

Further information about PhDs at the Royal Veterinary College is available here.

The successful student will be registered at: The Royal Veterinary College

How to apply

Instructions for applicants

Applications should be made to the RVC via UKPASS – information on how to apply can be found here.

Queries about the application process should be sent to:

The closing date for applications is: 15th April 2018