Department of Psychology and Neuroscience, Duke University, Durham, North Carolina 27708.
Department of Psychology and Neuroscience, Duke University, Durham, North Carolina 27708
J Neurosci. 2023 Nov 22;43(47):7967-7981. doi: 10.1523/JNEUROSCI.0734-23.2023.
The subthalamic nucleus (STN) is a common target for deep brain stimulation (DBS) treatments of Parkinsonian motor symptoms. According to the dominant model, the STN output can suppress movement by enhancing inhibitory basal ganglia (BG) output via the indirect pathway, and disrupting STN output using DBS can restore movement in Parkinson's patients. But the mechanisms underlying STN DBS remain poorly understood, as previous studies usually relied on electrical stimulation, which cannot selectively target STN output neurons. Here, we selectively stimulated STN projection neurons using optogenetics and quantified behavior in male and female mice using 3D motion capture. STN stimulation resulted in movements with short latencies (10-15 ms). A single pulse of light was sufficient to generate movement, and there was a highly linear relationship between stimulation frequency and kinematic measures. Unilateral stimulation caused movement in the ipsiversive direction (toward the side of stimulation) and quantitatively determined head yaw and head roll, while stimulation of either STN raises the head (pitch). Bilateral stimulation does not cause turning but raised the head twice as high as unilateral stimulation of either STN. Optogenetic stimulation increased the firing rate of STN neurons in a frequency-dependent manner, and the increased firing is responsible for stimulation-induced movements. Finally, stimulation of the STN's projection to the brainstem mesencephalic locomotor region was sufficient to reproduce the behavioral effects of STN stimulation. These results question the common assumption that the STN suppresses movement, and instead suggest that STN output can precisely specify action parameters via direct projections to the brainstem. Our results question the common assumption that the subthalamic nucleus (STN) suppresses movement, and instead suggest that STN output can precisely specify action parameters via direct projections to the brainstem.
底丘脑核（STN）是深部脑刺激（DBS）治疗帕金森运动症状的常见靶点。根据主导模型，STN 输出可以通过间接途径增强抑制性基底神经节（BG）输出来抑制运动，而使用 DBS 破坏 STN 输出可以恢复帕金森病患者的运动。但是，STN-DBS 的机制仍知之甚少，因为以前的研究通常依赖于电刺激，电刺激不能选择性地靶向 STN 输出神经元。在这里，我们使用光遗传学选择性地刺激 STN 投射神经元，并使用 3D 运动捕捉技术在雄性和雌性小鼠中量化行为。STN 刺激导致潜伏期短（10-15ms）的运动。单个光脉冲足以产生运动，并且刺激频率与运动学测量之间存在高度线性关系。单侧刺激导致向刺激侧（对侧）的运动，并定量确定头部俯仰和头部滚动，而 STN 的单侧刺激都会导致头部抬起（俯仰）。双侧刺激不会导致转向，但会使头部抬起高度是单侧 STN 刺激的两倍。光遗传学刺激以频率依赖性方式增加 STN 神经元的放电率，而增加的放电率是刺激诱导运动的原因。最后，刺激 STN 投射到脑干中脑运动区的投射足以重现 STN 刺激的行为效应。这些结果质疑了 STN 抑制运动的常见假设，而是表明 STN 输出可以通过直接投射到脑干来精确指定动作参数。
