Institut des Neurosciences Paris-Saclay (Neuro-PSI), UMR 9197, Université Paris Sud, CNRS, Université Paris Saclay, Orsay, 91405, France.
Department of Medical Genetics, University of Tuebingen, Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, Tuebingen, Germany.
Neuropharmacology. 2017 Sep 1;123:136-147. doi: 10.1016/j.neuropharm.2017.05.032. Epub 2017 Jun 3.
In Huntington's disease (HD), dysfunctional affective processes emerge as key symptoms of disturbances. In human HD and transgenic rat models of the disease, the amygdala was previously shown to have a reduced volume and to carry a high load of mutant huntingtin (mHTT) aggregates. In search of the pathophysiology of affective dysregulation in HD, we hypothesized a specific role of the central amygdala (CeA), known to be particularly involved in emotional regulation. Using transgenic BACHD rats carrying full-length human mHTT, we compared behavioral consequences of pharmacological modulation of CeA function by infusing GABA receptor (GABAR) antagonist picrotoxin into ∼4.5 month old BACHD and WT rats before confronting them to potentially threatening situations. Our results show that disinhibition of the CeA induced differential behaviors in WT and BACHD rats in our tasks: it increased social contacts and responses to the threatening warning signal in an avoidance task in BACHD rats but not in WT animals. At the cellular level, analyzes of amygdala alteration/dysfunction showed (1) an age-dependent increase in number and size of mHTT aggregates specifically in the CeA of BACHD rats; (2) no alteration of GABA and GABAR expression level, but (3) an increased neuronal reactivity (Arc labelling) to a threatening stimulus in the medial part of this nucleus in 4.5 months old BACHD rats. These results suggest a basal pathological hyper-reactivity in the CeA (in particular its medial part) in the transgenic animals. Such amygdala dysfunction could account, at least in part, for affective symptoms in HD patients.
在亨廷顿病（HD）中，功能失调的情感过程作为紊乱的关键症状出现。在人类 HD 和疾病的转基因大鼠模型中，先前已经表明杏仁核体积减小并且携带大量突变亨廷顿蛋白（mHTT）聚集体。为了寻找 HD 中情感失调的病理生理学，我们假设中央杏仁核（CeA）具有特定作用，已知其特别参与情感调节。使用携带全长人 mHTT 的转基因 BACHD 大鼠，我们比较了在将它们暴露于潜在威胁情况下之前，通过将 GABA 受体（GABAR）拮抗剂印防己毒素注入约 4.5 个月大的 BACHD 和 WT 大鼠的 CeA 功能的药理学调节对行为的影响。我们的结果表明，CeA 的去抑制在 WT 和 BACHD 大鼠的任务中引起了不同的行为：它增加了 BACHD 大鼠的社交接触和对回避任务中威胁警告信号的反应，但在 WT 动物中没有。在细胞水平上，对杏仁核改变/功能障碍的分析表明：（1）在 BACHD 大鼠的 CeA 中，mHTT 聚集体的数量和大小呈年龄依赖性增加；（2）GABA 和 GABAR 表达水平没有改变，但（3）在 4.5 个月大的 BACHD 大鼠的该核中部对威胁刺激的神经元反应性（Arc 标记）增加。这些结果表明，在转基因动物中，CeA（特别是其内侧部分）存在基础病理性高反应性。这种杏仁核功能障碍至少可以部分解释 HD 患者的情感症状。
