Project Synopsis: This project will use dietary manipulations in mice and look at behavioural effects on memory alongside electrophysiological changes in synaptic plasticity and changes in receptor expression in the brain. It will investigate the question of whether GABA-A receptor alpha-5 subunits, a target for cognitive enhancing drugs, are upregulated by a high fat diet and whether this is linked to inflammatory cytokine activation. It aims to define a mechanistic link between fat consumption and memory loss.
Background: Cognitive deficits in mice appear within days of initiating high fat feeding. This models cognitive decline seen in Type II diabetics and in fact in healthy young subjects with a high BMI (1). We have previously demonstrated that a high-fat diet (HFD), in mice, rapidly and dramatically impacts on complex associative episodic-like memory, which incorporates information about specific events, including spatial locations and the contextual features of the environment in which the event took place (2). Episodic memory is one of the memories initially compromised in Alzheimer’s disease and is located in the hippocampus. These cognitive deficits could be caused by the activation of inflammatory cytokines such as the interleukins, which are thought to modulate GABA-A receptor function (3). GABA-A receptors containing the alpha-5 subunit are found in a high density in the hippocampus and are involved in learning and memory. Downregulating these receptors can be a method of cognitive enhancement which has been shown in healthy human volunteers and is currently in clinical trials for Down’s syndrome. Could these receptors could be a link between high fat feeding and cognitive decline, potentially due to their activation by inflammatory cytokines?
1. Show that high fat feeding in mice causes specific and rapid deficits in memory (technique: dietary manipulation and behavioural testing in vivo- Dundee)
2. Investigate whether administration of drugs affecting GABA-A alpha-5 can reverse the cognitive deficits seen with high fat feeding (in vivo neuropharmacology and behaviour- Dundee)
3. Study the expression of alpha-5 and interleukins and their correlation with cognition (in situ hybridization- Aberdeen)
4. Examine hippocampal synaptic plasticity and the role of alpha-5 in the brains of mice who have been high fat fed (in vitro and in vivo electrophysiology- Dundee)
Supervisors: Dr Langston and Prof Williams have recently shown in a joint PhD studentship (EastBio, current) the rapid effects of high fat diet on a suite of sensitive translational behavioural tests for mice. Dr Langston and Prof Lambert currently collaborate on multiple funded projects examining the role of the GABA-A receptor alpha-5 subunit in cognitive decline associated with neurodegenerative disorders. This team of supervisors and their laboratories will provide a range of techniques and experienced mentors to take forward this exciting research area. The behavioural and electrophysiological (in vivo) work will be carried out in Dundee (75%) with molecular pharmacology work in Aberdeen (25%).
(1) Cheke LG, Simons JS, Clayton NS (2016) Higher body mass index is associated with episodic memory deficits in young adults. QJEP 69(11):2305-16
(2) McLean FH, Langston RF, Campbell FM, Lorenzo-Arribas A, Williams LM (2014) Episodic-memory is rapidly compromised by a high-fat diet in C57Bl/6 mice and is associated with markers of hippocampal neuronal damage identified by proteomics. Society for Neuroscience 2014 Abstract
(3) Wang DS1, Zurek AA, Lecker I, Yu J, Abramian AM, Avramescu S, Davies PA, Moss SJ, Lu WY, Orser BA (2012) Memory deficits induced by inflammation are regulated by α5-subunit-containing GABAA receptors. Cell Rep 2(3):488-96