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MRC DTP 4 Year PhD Programme: Early life adversity and hippocampal dysfunction in rodents: the impact of novel, fast-acting antidepressants


About This PhD Project

Project Description

This project is offered as part of the University of Dundee 4-year MRC DTP Programme “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. The outstanding biomedical research at the University of Dundee was recognised by its very high rankings in REF 2014, with Dundee rated as the top University for Biological Sciences in the UK. A wide range of projects are available within this programme crossing exceptional strengths in four key areas: Infection and Disease; Responses to Cellular Stresses; Development, Stem Cells and Neurobiology; and Big Data and Translation. All students on this programme will receive training in computational biology, mathematical biology and statistics to equip with the quantitative skills in tackling complex biological questions. In the 1st year, students will carry out 3 rotation projects prior to selection of the final PhD project.

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of ketamine), both enhance AMPA-receptor-mediated transmission at glutamatergic synapses (1; Mariano and Lambert, unpublished observations).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.

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.

References

Recent work from the lab can be found in the following references:

Dixon CI, Walker SE, Swinny J, Belelli D, Lambert JJ, King SL, & Stephens DN (2019) Early-life stress influences acute and sensitized responses of adult mice to cocaine by interacting with GABAA α2 receptor expression. Behav Pharmacol 30: 272-281.

Geugies H, Mocking RJT, Figueroa CA, Groot PFC, Marsman JC, Servaas MN, Steele JD, Schene AH, Ruhé HG. (2019) Impaired reward-related learning signals in remitted unmedicated patients with recurrent depression. Brain 142: 2510-2522.

Sakae DY & Martin SJ (2019) Formation of a morphine-conditioned place preference does not change the size of evoked potentials in the ventral hippocampus – nucleus accumbens projection. Sci Rep 9: 5206.

Bjerknes TL, Langston RF, Kruge IU, Moser EI, & Moser MB (2015) Coherence among head direction cells before eye opening in rat pups. Curr Biol 25:103-108.

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