Masters project in translational neuroscience hos University of Copenhagen

Background: Genome-wide association studies (GWAS) have identified numerous loci associated with substance abuse disorders. Whilst addiction is viewed as a disease of the brain, we propose an extension to this, that liver hormones and their receptors in the central nervous system can play a major role in the aetiology of addiction.

Both human genetics and rodent physiology support the role of the liver secreted hormone fibroblast growth factor 21 (FGF21) and it’s co-receptor beta-klotho (KLB) in regulating preference for hedonic nutrients such as sucrose. FGF21 knockout mice over-consume sucrose whilst FGF21 treatment reduces preference of sucrose by signalling to KLB+ neurons in the ventromedial hypothalamus (PMID: 26724861 and 32640184). Similarly, humans with FGF21 variants have an increased preference for sweet foods (PMID: 28467924).

Genome-wide associations studies (GWAS) have also highlighted a key role for this pathway in alcohol use disorder (AUD). Variants in KLB are consistently associated with self-reported alcohol intake and scores of alcohol dependence whilst FGF21 reduces drinking in alcohol preferring non-human primates by ~50% (PMID: 30940813, PMID: 35108517). Mechanistically, FGF21 acts on dopaminergic pathways whilst KLB signalling in the brain, in particular the nucleus accumbens and basolateral amygdala, is critical for the regulation of alcohol intake, and preference, in mice (PMID: 27911795, 26724861 and 35108517).

More recently, it was shown that FGF21 overexpressing mice have a reduced preference for morphine (PMID: 34715121). As such, we propose that the KLB-FGF21 signalling pathway represents a strong pharmaceutical target for abuse disorders.

This project: For this project, the student will work with post-mortem human brain samples (i.e. hypothalamus, amygdala etc) from control patients and those diagnosed with alcohol use disorder obtained from the NIH Neurobiobank in the US as part of a recently funded Lundbeck Experiment grant investigating the role of FGF21 in addiction. The student will focus on understanding the distribution of KLB expression in the human brain, in addition to other genes involved in the FGF21-KLB signaling pathway. Further, using advanced histological techniques (i.e. RNAscope) the student will determine the localization of KLB RNA molecules in different neuronal cell types using neuron specific probes.

The student: The student will work in the group of Assoc. Prof. Matt Gillum and be mentored by Dr. Peter Aldiss, a postdoc in the lab who will train and assist you with directing the research project. We are looking for a highly motivated Master Student who is enthusiastic about research, has the ability to learn and work independently and has a keen interest in translational neuroscience.

Contact: Dr. Peter Aldiss (peter.aldiss@sund.ku.dk)

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