Characterizing the Mesolimbic Dopamine Reward Pathway in a Magel2-null Mouse, a Model of Prader-Willi Syndrome

• Author / Creator

  Luck Gibson, Chloe

• Prader-Willi Syndrome (PWS) is a genetic disorder characterized by extreme hyperphagia that can lead to severe obesity. The abnormal motivation to eat in PWS suggests a disruption in the hedonic feeding pathway, which is feeding based on reward as opposed to physiological need. Hedonic feeding is controlled by dopaminergic neurons in the ventral tegmental area (VTA) and other regions of the brain, forming a reward circuit. Magel2 is one of the genes inactivated in PWS, and mice lacking Magel2 have phenotypes that resemble those seen in people with PWS. The aim of this research project is to characterize the dopamine reward circuitry in a mouse model of PWS lacking the Magel2 gene. Regions important for motivative behaviour and reward processing were assessed. Immunohistochemistry, high-performance liquid chromatography (HPLC), and immunoblot analyses were used to identify the baseline differences within the reward pathway of Magel2-null mice. The responses to changes in diet which are similar to biochemical responses observed with drugs of abuse, were also measured by subjecting the mice to a high-fat diet, then withdrawing them from the high fat diet back to a standard diet. Specific molecular changes including the phosphorylation of ERK, AKT and CREB within brain regions that form the reward circuit were identified and measured in response to changes in diet. The levels of biogenic amines within the nuclei of the reward pathway were also assessed by HPLC, in response to the changes in diet. Binge feeding behavior was assessed by exposing the mice to a limited time access of high-fat food. There was no difference between the Magel2-null and wildtype mice in the number of dopamine-producing cells within the nuclei of the reward pathway. However, the HPLC analysis showed a global reduction in the dopaminergic and serotonergic metabolites in the Magel2-null mice. The level of neurofilament was significantly increased in the hypothalamus of Magel2-null mice, and the axonal calibre of forebrain projections from the VTA was significantly smaller in the Magel2-null animals. This could influence how much dopamine is reaching the target nuclei in response to rewarding behaviours. Magel2-null mice consume consistently less high-fat food when given limited access to a high-fat diet. This suggests an impaired bingeing response. This behavioural response suggests decreased dopaminergic responses to the exposure. Magel2-null mice show a loss of HPLC-detected differences between mice fed a chronic high-fat diet or a standard diet. Magel2-null also have an attenuated feeding response to the initial exposure of a HF-diet. This also suggests a decrease in dopamine signaling in response to a palatable food source. In conclusion, Magel2-null mice show deficits throughout the dopamine reward pathway that indicate reduced dopamine-related activity. Deficits were observed both under baseline conditions, and in response to both acute and chronic exposure to a rewarding food source. This is consistent with the attenuated locomotive response to cocaine previously observed in mice lacking Magel2. This phenotype resembles the increased threshold for dopamine signaling and the subsequent feeling of reward that is observed in pathological drug users, driving the compulsive need to obtain the drug. Understanding how the loss of Magel2 influences dopamine signaling and the molecular mechanisms driving the pathology of Prader-Willi Syndrome. This knowledge will be useful for the development or potential treatments for individuals with PWS and other forms of binge eating disorder.

• Subjects / Keywords

  • Obesity
  • Prader-Willi syndrome
  • Magel2
  • Leptin
  • Dopamine

• Graduation date

  Fall 2016

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R3PV6BF98

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.