Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, BMC D11, SE-22184 Lund, Sweden.
Sci Rep. 2016 Jun 23;6:28322. doi: 10.1038/srep28322.
Hypothalamic pathology, metabolic dysfunction and psychiatric symptoms are part of Huntington disease (HD), which is caused by an expanded CAG repeat in the huntingtin (HTT) gene. Inactivation of mutant HTT selectively in the hypothalamus prevents the development of metabolic dysfunction and depressive-like behavior in the BACHD mouse model. The hypothalamic paraventricular nucleus (PVN) is implicated in metabolic and emotional control, therefore we here tested whether inactivation of mutant HTT in the PVN affects metabolic and psychiatric manifestations of HD in BACHD mice. BACHD mice were crossed with mice expressing Cre-recombinase under the Sim1 promoter (Sim1-Cre) to inactivate mutant HTT in Sim1 expressing cells, i.e. the PVN of the hypothalamus. We found that inactivation of mutant HTT in Sim1 cells had a sex-specific effect on both the metabolic and the psychiatric phenotype, as these phenotypes were no longer different in male BACHD/Sim1-Cre mice compared to wild-type littermates. We also found a reduced number of GnRH neurons specifically in the anterior hypothalamus and an increased testes weight in male BACHD mice compared to wild-type littermates. Taken together, expression of mutant HTT in Sim1 cells may play a role for the development of metabolic dysfunction and depressive-like behavior in male BACHD mice.
下丘脑病理学、代谢功能障碍和精神症状是亨廷顿病（HD）的一部分，该病由亨廷顿（HTT）基因中 CAG 重复序列的扩增引起。在 BACHD 小鼠模型中，选择性地使突变 HTT 在下丘脑失活可防止代谢功能障碍和抑郁样行为的发展。下丘脑室旁核（PVN）与代谢和情绪控制有关，因此我们在此测试了在 PVN 中失活突变 HTT 是否会影响 BACHD 小鼠的 HD 代谢和精神表现。将 BACHD 小鼠与在 Sim1 启动子（Sim1-Cre）下表达 Cre 重组酶的小鼠杂交，以在表达 Sim1 的细胞中失活突变 HTT，即下丘脑的 PVN。我们发现，在 Sim1 细胞中失活突变 HTT 对代谢和精神表型具有性别特异性影响，因为与野生型同窝仔相比，雄性 BACHD/Sim1-Cre 小鼠的这些表型不再存在差异。我们还发现，与野生型同窝仔相比，雄性 BACHD 小鼠的 GnRH 神经元数量减少，而睾丸重量增加。总之，Sim1 细胞中表达的突变 HTT 可能对雄性 BACHD 小鼠代谢功能障碍和抑郁样行为的发展起作用。
