Elucidating the neural mechanisms of stress: a 13C-NMR study of glutamate and neuronal-glial interactions
13C-Magnetic Resonance Spectroscopy (13C-MRS) is an emerging imaging modality that allows the measurement of concentrations and synthesis rates of glutamate, glutamine and GABA within precisely defined regions of the brain. The high chemical specificity of 13C can not only distinguish 13C isotope incorporation in different molecules but also into specific carbon positions within the same molecule. This provides a powerful means to follow the fate of non-radioactive 13C molecule through multiple metabolic pathways and separately quantify neuronal and glial metabolic fluxes. Unlike 1H spectroscopy which provides a measure of total glutamate, 13C-MRS allows us to investigate more sophisticated neuronal-glial interactions. There is a tight coupling between cellular energy metabolism and amino acid metabolism and this is exploited to investigate the workings of the glutamate-glutamine metabolic cycle. In addition to obtaining overall measures of metabolic fluxes between neuronal and glial compartments, the 13C-MRS technique allows the detection of metabolic end products specific to neuronal and glial metabolism which allows the delineation of glutamate concentration for the neuronal, glial and extracellular compartments separately.
The metabolism of brain glutamate is tightly coupled to a substrate cycle between neurons and glia and recently the regulation of these systems have been implicated in the pathophysiology of several psychiatric conditions including major depression. There is converging preclinical evidence that suggests that glutamate may be an important mediator of stress related neurobiological changes and it has been posited that glutamate excess may contribute to the observed cell changes. Whilst early studies of glutamate in depression have yielded inconclusive findings, numerous studies now paint a very different picture as to the role glutamate assumes in this condition. Recent studies show that acute stress results in a rapid efflux of glutamate into the extrasynaptic space in the hippocampus and prefrontal cortex in animals. Other studies report that glucocorticoid excess increases glutamate release in the CA1 region of the hippocampus and chronic stress increases extracellular levels in the CA3 region. Surprisingly, whilst numerous studies have investigated the relationship between stress and brain structure, there is a paucity of studies investigating the effect of stress on in vivo glutamate neurotransmission in humans.This PhD project seeks to investigate neurobiological changes associated with stress in humans, using in vivo 13C-Magnetic Resonance Spectroscopy and will explore key questions relating to the stress-diathesis model.
This project will be conducted at the Brain and Mind Research Institute. Ideally, PhD candidates should have a background in science, psychology, medicine, biomedical engineering, or other related neuroscience field. Experience with MRS acquisitions and analyses would be an advantage.
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The opportunity ID for this research opportunity is: 689
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