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Pathogenic mechanisms
A25 Psychiatric and metabolic changes in the BACHD mouse model of Huntington's disease
  1. S Hult1,
  2. R Soylu1,
  3. D Kirik2,
  4. Å Petersén1
  1. 1Translational Neuroendocrine Research Unit (TNU), Department of Experimental Medical Science, Lund University, Lund, Sweden
  2. 2Brain Repair and Imaging in Neural Systems (BRAINS), Department of Experimental Medical Science, Lund University, Lund, Sweden

Abstract

Background Psychiatric symptoms and metabolic changes occur early in Huntington's disease (HD) and may be a result of hypothalamic dysfunction. The hypothalamus has emerged as an important site of pathology, but a causative relationship between hypothalamic dysfunction and non-motor features in HD remain to be established. Cre-recombinase (cre) mediated excision allows inactivation of mutant huntingtin (htt) in the BACHD mouse and it is therefore a useful tool to study structure to functional relationships.

Aims The aim of this study was to investigate whether the BACHD mouse displays psychiatric and metabolic disturbances. As hypothalamus regulates metabolism, we also tested whether inactivation of mutant htt in the hypothalamus could prevent the development of metabolic alterations.

Methods The psychiatric profile was assessed with Porsolt forced swim test and elevated plus maze. The metabolic phenotype was determined with DEXA, indirect calorimetry, glucose and insulin tolerance tests and ELISA.

Results We found that BACHD mice developed both depressive-like and anxiety-like behaviours at an early age. They also displayed enhanced accumulation of fat, impaired glucose tolerance as well as insulin and leptin resistance. The increase in body weight was due to increased appetite. Inactivation of mutant htt in the hypothalamus in young BACHD mice using adeno associated viral vectors expressing cre prevented the development of the metabolic phenotype.

Conclusions Our data demonstrate that BACHD mice display early depressive and anxiety-like behaviours as well as a metabolic phenotype. The metabolic disturbances in this model are caused by hypothalamic dysfunction.

  • hypothalamus
  • metabolism
  • depression

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