Estrada-Sánchez Ana María, Blake Courtney L, Barton Scott J, Howe Andrew G, Rebec George V
Program in Neuroscience and Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana.
Departmento de Biología Molecular, Instituto Potosino De Investigación Científica y Tecnológica, San Luis Potosí, Mexico.
J Neurophysiol. 2019 Dec 1;122(6):2621-2629. doi: 10.1152/jn.00777.2018. Epub 2019 Nov 6.
Abnormal communication between cerebral cortex and striatum plays a major role in the motor symptoms of Huntington's disease (HD), a neurodegenerative disorder caused by a mutation of the huntingtin gene (). Because cortex is the main driver of striatal processing, we recorded local field potential (LFP) activity simultaneously in primary motor cortex (M1) and dorsal striatum (DS) in BACHD mice, a full-length HD gene model, and in a conditional BACHD/Emx-1 Cre (BE) model in which is suppressed in cortical efferents, while mice freely explored a plus-shaped maze beginning at 20 wk of age. Relative to wild-type (WT) controls, BACHD mice were just as active across >40 wk of testing but became progressively less likely to turn into a perpendicular arm as they approached the choice point of the maze, a sign of HD motor inflexibility. BE mice, in contrast, turned as freely as WT throughout testing. Although BE mice did not exactly match WT in LFP activity, the reduction in alpha (8-13 Hz), beta (13-30 Hz), and low-gamma (30-50 Hz) power that occurred in M1 of turning-impaired BACHD mice was reversed. No reversal occurred in DS. In fact, BE mice showed further reductions in DS theta (4-8 Hz), beta, and low-gamma power relative to the BACHD model. Coherence analysis indicated a dysregulation of corticostriatal information flow in both BACHD and BE mice. Collectively, our results suggest that in cortical outputs drives the dysregulation of select cortical frequencies that accompany the loss of behavioral flexibility in HD. BACHD mice, a full-length genetic model of Huntington's disease (HD), express aberrant local field potential (LFP) activity in primary motor cortex (M1) along with decreased probability of turning into a perpendicular arm of a plus-shaped maze, a motor inflexibility phenotype. Suppression of the mutant huntingtin gene in cortical output neurons prevents decline in turning and improves alpha, beta, and low-gamma activity in M1. Our results implicate cortical networks in the search for therapeutic strategies to alleviate HD motor signs.
大脑皮层与纹状体之间的异常通信在亨廷顿舞蹈病（HD）的运动症状中起主要作用，HD是一种由亨廷顿基因（）突变引起的神经退行性疾病。由于皮层是纹状体处理的主要驱动因素，我们在BACHD小鼠（一种全长HD基因模型）以及条件性BACHD/Emx-1 Cre（BE）模型（其中在皮质传出神经中被抑制）的初级运动皮层（M1）和背侧纹状体（DS）中同时记录了局部场电位（LFP）活动，这些小鼠从20周龄开始自由探索十字迷宫。相对于野生型（WT）对照，BACHD小鼠在超过40周的测试中同样活跃，但随着它们接近迷宫的选择点，转向垂直臂的可能性逐渐降低，这是HD运动不灵活性的一个迹象。相比之下，BE小鼠在整个测试过程中转向与WT一样自由。尽管BE小鼠在LFP活动方面与WT并不完全匹配，但在转向受损的BACHD小鼠的M1中出现的α（8 - 13 Hz）、β（13 - 30 Hz）和低γ（30 - 50 Hz）功率降低得到了逆转。DS中未发生逆转。事实上，相对于BACHD模型，BE小鼠的DS中θ（4 - 8 Hz）、β和低γ功率进一步降低。相干分析表明，BACHD和BE小鼠的皮质纹状体信息流均失调。总体而言，我们的结果表明，皮质输出中的驱动了HD中行为灵活性丧失时伴随的特定皮质频率的失调。BACHD小鼠是亨廷顿舞蹈病（HD）的全长遗传模型，在初级运动皮层（M1）中表现出异常的局部场电位（LFP）活动，同时转向十字迷宫垂直臂的概率降低，这是一种运动不灵活性表型。在皮质输出神经元中抑制突变的亨廷顿基因可防止转向能力下降，并改善M1中的α、β和低γ活动。我们的结果表明皮质网络在寻找缓解HD运动症状的治疗策略中具有重要意义。
