Institute of Neurophysiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Institute of Integrative Neuroanatomy, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany, and.
J Neurosci. 2019 Mar 27;39(13):2470-2481. doi: 10.1523/JNEUROSCI.1642-18.2019. Epub 2019 Jan 30.
Adaptive motor control critically depends on the interconnected nuclei of the basal ganglia in the CNS. A pivotal element of the basal ganglia is the subthalamic nucleus (STN), which serves as a therapeutic target for deep brain stimulation (DBS) in movement disorders, such as Parkinson's disease. The functional connectivity of the STN at the microcircuit level, however, still requires rigorous investigation. Here we combine multiple simultaneous whole-cell recordings with extracellular stimulation and neuroanatomical analysis to investigate intrinsic and afferent connectivity and synaptic properties of the STN in acute brain slices obtained from rats of both sexes. Our data reveal an absence of intrinsic connectivity and an afferent innervation with low divergence, suggesting that STN neurons operate as independent processing elements driven by upstream structures. Hence, synchrony in the STN, a hallmark of motor processing, exclusively depends on the interactions and dynamics of GABAergic and glutamatergic afferents. Importantly, these inputs are subject to differential short-term depression when stimulated at high, DBS-like frequencies, shifting the balance of excitation and inhibition toward inhibition. Thus, we present a mechanism for fast yet transient decoupling of the STN from synchronizing afferent control. Together, our study provides new insights into the microcircuit organization of the STN by identifying its neurons as parallel processing units and thus sets new constraints for future computational models of the basal ganglia. The observed differential short-term plasticity of afferent inputs further offers a basis to better understand and optimize DBS algorithms. The subthalamic nucleus (STN) is a pivotal element of the basal ganglia and serves as target for deep brain stimulation, but information on the functional connectivity of its neurons is limited. To investigate the STN microcircuitry, we combined multiple simultaneous patch-clamp recordings and neuroanatomical analysis. Our results provide new insights into the synaptic organization of the STN identifying its neurons as parallel processing units and thus set new constraints for future computational models of the basal ganglia. We further find that synaptic dynamics of afferent inputs result in a rapid yet transient decoupling of the STN when stimulated at high frequencies. These results offer a better understanding of deep brain stimulation mechanisms, promoting the development of optimized algorithms.
适应性运动控制严重依赖中枢神经系统基底节的核团相互连接。基底节的一个关键组成部分是丘脑底核（STN），它是运动障碍（如帕金森病）深部脑刺激（DBS）的治疗靶点。然而，STN 的微电路水平的功能连接仍需要严格的研究。在这里，我们结合了多个同时的全细胞膜片钳记录与细胞外刺激和神经解剖学分析，以研究从两性大鼠获得的急性脑切片中 STN 的内在和传入连接以及突触特性。我们的数据表明，不存在内在连接，传入神经支配具有低发散性，这表明 STN 神经元作为由上游结构驱动的独立处理元件运作。因此，STN 的同步性，运动处理的标志，完全依赖于 GABA 能和谷氨酸能传入的相互作用和动力学。重要的是，当以高 DBS 样频率刺激时，这些输入会经历不同的短期抑制，从而将兴奋和抑制的平衡转向抑制。因此，我们提出了一种快速但短暂地将 STN 与同步传入控制解耦的机制。总的来说，我们的研究通过将其神经元鉴定为并行处理单元，为 STN 的微电路组织提供了新的见解，从而为基底节的未来计算模型设定了新的限制。观察到传入输入的差异短期可塑性进一步提供了更好地理解和优化 DBS 算法的基础。丘脑底核（STN）是基底节的关键组成部分，是深部脑刺激的靶点，但关于其神经元的功能连接信息有限。为了研究 STN 的微电路，我们结合了多个同时的膜片钳记录和神经解剖学分析。我们的结果提供了 STN 突触组织的新见解，将其神经元鉴定为并行处理单元，从而为基底节的未来计算模型设定了新的限制。我们进一步发现，当以高频刺激时，传入输入的突触动力学导致 STN 的快速但短暂的解耦。这些结果提供了对深部脑刺激机制的更好理解，促进了优化算法的发展。
