BackgroundPopulation studies on neurodegeneration (ND) have shown that mid-life obesity (BMI>30; 40-65 yrs old) increases dementia risk while later life obesity (>65 yrs old) decreases dementia risk. The melanocortin (MC) system has a key role in food intake and metabolism. Mutations in melanocortin-4-receptor (MC4R) are the most common cause of monogenic obesity in humans. MCs, ligands for MC4R, have been shown to protect against ND. The effect of MC4R deficiency on ND is less well known. Moreover, studies have shown that weight loss precedes dementia onset and patients with dementia lose appetite. This points to disruption of neuronal feeding circuits prior to dementia onset, in keeping with our preliminary data. The essence of the proposal is to study food behaviour/MC system in an Alzheimer’s disease (AZ) zebrafish line and the effect of MC4R deficiency on cognition. This study will provide mechanistic insights into appetite regulation in ND and the effects of MC4R deficiency on cognition.
AimsThe overarching aim of the project is to explore the relationship between neuronal control of appetite and ND. We hypothesise that feeding dysregulation directly affects cognition and perturbation of the MC system will alter cognitive outcomes. The specific aims are (1) Assessment of an AD zebrafish line at early and late time points (2) Determination of the effects of fasting and feeding on cognition in AD zebrafish (3) Study of cognition in MC4R deficient zebrafish at early and late stages (4) Modelling of the impact of MC4R deficiency in AD zebrafish. With each specific aim, we will study (a) food intake (b) motivation (c) cognition (d) CNS and hypothalamic morphology (e) hypothalamic microarchitecture (f) expression and function of MC system. We anticipate that feeding dysregulation seen in AD is due to perturbation of the MC system, in which case we aim to rescue this with pharmacological activation of the MC system to hopefully reverse the cognitive phenotypes.
ImportanceUnderstanding the neuronal control of food intake and its consequences in ND is currently limited. This project will greatly enhance knowledge in this field. The study of food regulation in obesity, mainly in mice, is an expanding area. The proposed project will utilise zebrafish as a model to study feeding and ND. It brings together the expertise of Dr Chan and Dr Brennan. Dr Brennan is an expert in the assessment of zebrafish neurobiology and behaviour, a relatively new and expanding field, whilst Dr Chan has over the years developed expertise in the MC system. Together, they have developed feeding and behavioural assays as part of funding from the Wellcome Trust. Both the MC4R-/- zebrafish and AD zebrafish are in house. The project will lay the groundwork for future research grant applications as well as establish a model of AD and MC deficiency that could be utilized for small molecule screens in the future.
ImpactAnorexia is a normal animal acute response to physiological disturbance requiring energy conservation during recovery. However, prolonged anorexia is associated with cachexia, a wasting condition occurring in chronic, life-threatening conditions including AD and other types of ND. This directly affects outcomes. For example, in cancer, more than 30% of cancer patients die due to cachexia. The effect size is unclear in ND. Weight loss often precedes dementia symptoms for several years and patients with established AD have poor appetite. Weight loss and reduced appetite may have a multifactorial etiology in AD. An understanding of the mechanisms that govern food intake in ND is lacking. If our hypothesis is true then we would be able to highlight the importance of food intake and the MC system in cognition and ND. We hope this would prompt future studies, possibly pharmacological, on tackling this issue in patients with early dementia.
This project is open to applicants with or intending to apply for external funding.
Candidatses should have or, expect to receive a first or upper-second class honours degree in an area relevant to the project. Applicants from outside of the UK are required to provide evidence of their English language ability. Please see our English language requirements page for details: https://www.qmul.ac.uk/international-students/englishlanguagerequirements/postgraduateresearch/
Interested candidates are welcome to contact Dr Li Chan (email@example.com) or Professor Caroline Brennan (firstname.lastname@example.org) to express an interest in the project before submitting a formal application.