Effects of Deletion of Mutant Huntingtin in Steroidogenic Factor 1 Neurons on the Psychiatric and Metabolic Phenotype in the BACHD Mouse Model of Huntington Disease

Psychiatric and metabolic features appear several years before motor disturbances in the neurodegenerative Huntington’s disease (HD), caused by an expanded CAG repeat in the huntingtin (HTT) gene. Although the mechanisms leading to these aspects are unknown, dysfunction in the hypothalamus, a brain region controlling emotion and metabolism, has been suggested. A direct link between the expression of the disease causing protein, huntingtin (HTT), in the hypothalamus and the development of metabolic and psychiatric-like features have been shown in the BACHD mouse model of HD. However, precisely which circuitry in the hypothalamus is critical for these features is not known. We hypothesized that expression of mutant HTT in the ventromedial hypothalamus, an area involved in the regulation of metabolism and emotion would be important for the development of these non-motor aspects. Therefore, we inactivated mutant HTT in a specific neuronal population of the ventromedial hypothalamus expressing the transcription factor steroidogenic factor 1 (SF1) in the BACHD mouse using cross-breeding based on a Cre-loxP system. Effects on anxiety-like behavior were assessed using the elevated plus maze and novelty-induced suppressed feeding test. Depressive-like behavior was assessed using the Porsolt forced swim test. Effects on the metabolic phenotype were analyzed using measurements of body weight and body fat, as well as serum insulin and leptin levels. Interestingly, the inactivation of mutant HTT in SF1-expressing neurons exerted a partial positive effect on the depressive-like behavior in female BACHD mice at 4 months of age. In this cohort of mice, no anxiety-like behavior was detected. The deletion of mutant HTT in SF1 neurons did not have any effect on the development of metabolic features in BACHD mice. Taken together, our results indicate that mutant HTT regulates metabolic networks by affecting hypothalamic circuitries that do not involve the SF1 neurons of the ventromedial hypothalamus.神经退行性疾病亨廷顿舞蹈症（Huntington’s disease, HD）由亨廷顿（huntingtin, HTT）基因CAG重复序列扩增引发，其运动症状出现前数年，患者即可出现精神与代谢相关特征。尽管介导此类表现的机制尚未阐明，但有研究提出，调控情绪与代谢的脑区下丘脑（hypothalamus）功能异常可能与此相关。在HD的BACHD小鼠模型中，已有研究证实下丘脑内致病蛋白亨廷顿（HTT）的表达，与代谢及类精神特征的发生发展存在直接关联。然而，下丘脑内究竟哪些神经环路对上述特征至关重要，目前仍不明确。 我们提出如下假说：腹内侧下丘脑（该脑区参与代谢与情绪调控）中突变型HTT的表达，对这类非运动特征的发展具有关键作用。为此，我们基于Cre-loxP重组酶系统（Cre-loxP system），通过杂交育种的方式，在BACHD小鼠腹内侧下丘脑中表达转录因子类固醇生成因子1（steroidogenic factor 1, SF1）的特定神经元群体内，灭活突变型HTT。 我们采用高架十字迷宫（elevated plus maze）与新奇诱导抑制进食实验（novelty-induced suppressed feeding test）评估小鼠的类焦虑样行为；采用Porsolt强迫游泳实验（Porsolt forced swim test）评估其类抑郁样行为；通过检测体重、体脂含量，以及血清胰岛素与瘦素（leptin）水平，分析小鼠的代谢表型变化。 有趣的是，在4月龄的雌性BACHD小鼠中，于表达SF1的神经元内灭活突变型HTT，对其类抑郁样行为产生了部分正向改善作用。在该小鼠队列中，未检测到类焦虑样行为。而在表达SF1的神经元中删除突变型HTT，并未对BACHD小鼠的代谢特征发展产生任何影响。 综上，本研究结果表明，突变型HTT通过影响不涉及腹内侧下丘脑SF1神经元的下丘脑神经环路，来调控机体代谢网络。