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An integrated approach to understanding effects of Candida albicans on cerebral functions

Primary Supervisor: Dr Martine Hamann, Department of Neuroscience, Psychology and Behaviour

Secondary Supervisor: Professor Nick Hartell

PhD project title: An integrated approach to understanding effects of Candida albicans on cerebral functions.

University of Registration: University of Leicester

Project outline:

General Background

Candida albicans is a common member of the human gut flora detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. A higher carriage rate for oral Candida albicans is observed in children and in elderly subjects. Candida albicans can switch to a fungal pathogen playing a critical role in various inflammatory conditions. Its virulence is determined by the lifestyle and the health of the host as predisposing factors to candida invasion include carbohydrate-rich diets, smoking, alcohol or diabetes. A recent study showed that Candida albicans produces a significant brain infection and affects synaptic function and short-term memory 1, demonstrating the direct relationship between the gut microbiota and the central nervous system (CNS). Candida is also releasing toxins that target and destroy CNS oligodendrocytes, resulting in axonal degeneration and demyelination. Despite the recognized relationship between gut flora and cerebral functions, the complex interplay between Candida albicans and synaptic function in the CNS remains poorly understood.

Studies suggest that an addiction to sugar or cheese can lead to excessive Candida albicans that may affect the perception of sounds. Our previous studies demonstrated that accurate auditory perception relies on the myelination of auditory nerve fibres projecting to the central auditory system 2 and the occurrence of synaptic plasticity in the dorsal cochlear nucleus 3, the first relay of the central auditory pathway. The project aims at investigating the central effects of Candida albicans on the myelination of auditory nerve fibres and the synaptic function in the dorsal cochlear nucleus.

Experimental model

Professor Hartell engineered a unique transgenic mouse referred to as SyG37 that expresses a ratiometric calcium sensor selectively in presynaptic terminals and used this model to show that ageing is associated with an increase in presynaptic calcium concentration, affecting synaptic transmission and plasticity at hippocampal synapses 4. Syg37 transgenic mice will be topically inoculated with Candida albicans and a multidisciplinary approach will be used to address specific objectives.

Objectives and Methods

  1. Anatomical methods (electron microscopy and immunocytochemistry) 2 will assess the effects of Candida albicans on the myelination of auditory nerve fibres
  2. In vitro field potential recordings on auditory nerve fibres and mathematical modelling 2 will assess and predict respectively the functional effects of Candida albicans on auditory nerve axonal properties.
  3. Patch clamp electrophysiology 2,3 and multiphoton Ca2+ imaging 4 will assess the effects of Candida albicans on presynaptic Ca2+, synaptic transmission and synaptic plasticity in the dorsal cochlear nucleus.
  4. Behavioural pre-pulse inhibition of the acoustic startle reflex 5 will assess the effects of Candida albicans on auditory perception.

References

  1. Wu, et al. Nat Commun, 2019, 10, 58.
  2. Tagoe et al. J Neurosci, 2014, 34, 2684-2688.
  3. Tagoe et al. Exp Neurol, 2017, 292, 1-10.
  4. Pereda et al., Aging Cell, 2019, DOI: 10.1111/acel.13008, e13008.
  5. Olsen et al., Neuropharmacology, 2018, 133, 319-333.

BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and behaviour

    Techniques that will be undertaken during the project:

    Techniques that will be undertaken involve electron microscopy and immunocytochemistry, patch clamp electrophysiology and multiphoton Ca2+ imaging, mathematical modelling and behavioural methodologies.

    Contact: Dr Martine Hamann, University of Leicester