Background The clinical manifestations of Huntington's disease (HD) include depression and anxiety as well as metabolic dysfunction. Recent studies have suggested that these aspects of HD could be related to pathology in the hypothalamus. Neuronal loss including reduced expression of oxytocin and vasopressin, two neuropeptides involved in the regulation of emotion and metabolism, have been reported in the paraventricular nucleus (PVN) of the hypothalamus in HD. The BACHD mouse displays both psychiatric-like features and a metabolic phenotype. As this mouse model is generated with loxP sites flanking exon1 of the mutant HD gene, it enables studies aiming at assessing effects of deletion of mutant huntingtin (htt) in specific cells by the use of the enzyme Cre recombinase.
Aim The aim of this study was to investigate if selective deletion of mutant htt in PVN neurons would reverse the metabolic and psychiatric-like phenotype in the BACHD mouse model of HD.
Methods We crossed BACHD mice with mice expressing Cre recombinase under a critical transcription factor for PVN neuropeptides, Sim 1 (Single-minded 1), in order to delete mutant htt expression in these neurons. Only F1 offspring was included in the study. Mice were assessed for body weight changes and percentage of body fat composition. The behavioural and motor phenotypes were assessed by using Porsolt forced swim test, the elevated plus maze, the sucrose preference test and the open field test.
Results We confirmed the activity of Cre recombinase in PVN neurons by crossing the BACHDSim1Δ mice with ROSA-EYFP mice. Mice were followed for up to 8 months of age. Preliminary results showed no major effects on the body weight in BACHD female mice after inactivation of mutant htt in Sim1 neurons. Further analyses are ongoing.
Conclusion The BACHD mouse model is an elegant tool to study whether inactivation of mutant HTT in specific cells plays a role for the development of the phenotype.
- paraventricular nucleus (PVN)
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