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MRC DTP 4 Year PhD Programme: The impact of novel, fast-acting antidepressants on hippocampal dysfunction resulting from early-life adversity in rodents.


About This PhD Project

Project Description

This project is part of our exciting and challenging University of Dundee 4-year MRC DTP Programme in Quantitative and Interdisciplinary approaches to biomedical science. This PhD programme brings together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science. Further information on the programme structure and training can be found at https://www.dundee.ac.uk/study/pg/phds/dtp/mrc-dtp/

According to the WHO, depression is now the leading cause of poor health and disability worldwide. Currently available drugs have limited and variable efficacy, and typically take weeks to improve mood and behaviour. The problem stems, in part, from our lack of understanding of the brain mechanisms underlying depression, and uncertainty surrounding the ways in which antidepressants work. Although drug-discovery efforts have typically focussed on the actions of neuromodulators such as serotonin (e.g. Prozac), there is growing evidence that the brain’s principal excitatory neurotransmitter, glutamate, plays a central role in depression. For example, we and others find that the antidepressant tianeptine, and HNK (a metabolite of ketamine), both enhance AMPA-receptor-mediated transmission at glutamatergic synapses (1; Mariano and Lambert, unpublished observations). Both drugs have rapid-onset antidepressant properties—within hours for HNK. These findings may fundamentally change the landscape of antidepressant therapy.

A key target for potential antidepressants is the hippocampus, part of a network of regions implicated in depression. Hippocampal dysfunction may contribute to abnormalities in the processing of reward and punishment information and the cognitive impairment that is often observed in human patients with depression (2). This project will utilise a ‘limited-bedding’ mouse model of early-life adversity in which a reduced quantity of nesting material during early postnatal development leads to a temporary fragmentation of maternal care, but long-lasting changes in the brain and behaviour of the offspring that mimic many of the symptoms of depression (3). You will study the long-term consequences of this manipulation using a combination of techniques in which you will receive extensive training; these include behavioural testing (Martin, Langston), in vivo electrophysiological recording using multi-channel arrays (Martin, Langston), and in vitro recording from hippocampal slices (Lambert). A particular focus will be abnormalities in hippocampal oscillations and/or single-unit firing during tasks involving 1) memory, and 2) the processing of reward or punishment information. This approach will generate large, complex datasets necessitating a cross-disciplinary machine-learning approach to map electrophysiological measures onto behavioural responses (Steele; Division of Imaging Science and Technology). The goal is to characterise abnormalities in hippocampal physiology and function caused by early-life adversity, and to study their possible reversal by drugs that enhance glutamatergic transmission.

References

1. Zhang H, Etherington LA, Hafner AS, Belelli D, Coussen F, Delagrange P, Chaouloff F, Spedding M, Lambert JJ, Choquet D, & Groc L. (2013) Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule. Mol Psychiatry 18: 471-484.



2. Johnston BA, Tolomeo S, Gradin V, Christmas D, Matthews K, & Steele JD. (2015) Failure of hippocampal deactivation during loss events in treatment-resistant depression. Brain 138: 2766-2776.

3. Mitchell SJ, Maguire EP, Cunningham L, Gunn BG, Linke M, Zechner U, Dixon CI, King SL, Stephens DN, Swinny JD, Belelli D, & Lambert JJ. (2018) Early-life adversity selectively impairs α2-GABAA receptor expression in the mouse nucleus accumbens and influences the behavioral effects of cocaine. Neuropharmacology 141: 98-11.

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