Changes in striatal activity and functional connectivity in a mouse model of Huntington's disease

Hereditary Huntington’s disease (HD) is associated with progressive motor, cognitive and psychiatric symptoms. A primary consequence of the HD mutation is the preferential loss of medium spiny projection cells with relative sparing of local interneurons in the striatum. In addition, among GABAergic striatal projection cells, indirect pathway cells expressing D2 dopamine receptors are lost earlier than direct pathway cells expressing D1 receptors. To test in vivo the functional integrity of direct and indirect pathways as well as interneurons in the striatum of male R6/1 transgenic mice, we assessed their c-Fos expression levels induced by a striatal-dependent cognitive task and compared them with age-matched wild-type littermates. We found a significant increase of c-Fos+ nuclei in the dorsomedial striatum, and this only at 2 months, when our HD mouse model is still pre-motor symptomatic, the increase disappearing with symptom manifestation. Contrary to our expectation, the indirect pathway projection neurons did not undergo any severer changes of c-Fos expression regardless of age in R6/1 mice. We also found a decreased activation of interneurons that express parvalbumin in the dorsomedial striatum at both presymptomatic and symptomatic ages. Finally, analysis of c-Fos expression in extended brain regions involved in the cognitive learning used in our study, demonstrates, throughout ages studied, changes in the functional connectivity between regions in the transgenic mice. Further analysis of the cellular and molecular changes underlying the transient striatal hyperactivity in the HD mice may help to understand the mechanisms involved in the disease onset.

遗传性亨廷顿舞蹈症（HD）与进行性运动、认知及精神症状密切相关。亨廷顿突变引发的核心病理改变之一，是纹状体中中等棘突投射神经元的选择性丢失，而局部中间神经元则相对得以保留。此外，在γ-氨基丁酸能（GABAergic）纹状体投射神经元中，表达D2型多巴胺受体的间接通路神经元，其丢失时间早于表达D1型多巴胺受体的直接通路神经元。
为在活体状态下检测雄性R6/1转基因小鼠纹状体直接通路、间接通路以及中间神经元的功能完整性，我们评估了纹状体依赖性认知任务诱导的c-Fos表达水平，并将其与同月龄野生型同窝小鼠进行对照。我们发现，仅在2月龄阶段，背内侧纹状体中的c-Fos阳性细胞核数量出现显著升高——此时我们的HD小鼠模型仍处于运动前症状期，该升高现象会随症状出现而逐渐消失。与我们的预期相悖的是，无论处于哪个年龄段，R6/1小鼠的间接通路投射神经元的c-Fos表达均未出现更为显著的变化。
我们还发现，在症状前及症状期两个年龄段，背内侧纹状体中表达小白蛋白（parvalbumin）的中间神经元的激活水平均出现下降。最后，对本研究中认知学习任务所涉及的扩展脑区的c-Fos表达进行分析后发现，在所有研究的年龄段中，转基因小鼠的脑区间功能连接均存在异常改变。进一步分析HD小鼠中这种一过性纹状体过度激活背后的细胞与分子机制，或有助于阐明疾病发病的核心机制。