Carannante Ilaria, Scolamiero Martina, Hjorth J J Johannes, Kozlov Alexander, Bekkouche Bo, Guo Lihao, Kumar Arvind, Chachólski Wojciech, Kotaleski Jeanette Hellgren
Science for Life Laboratory, Department of Computer Science, KTH Royal Institute of Technology, Stockholm, Sweden.
Department of Mathematics, KTH Royal Institute of Technology, Stockholm, Sweden.
Netw Neurosci. 2024 Dec 10;8(4):1149-1172. doi: 10.1162/netn_a_00394. eCollection 2024.
Striatum, the input stage of the basal ganglia, is important for sensory-motor integration, initiation and selection of behavior, as well as reward learning. Striatum receives glutamatergic inputs from mainly cortex and thalamus. In rodents, the striatal projection neurons (SPNs), giving rise to the direct and the indirect pathway (dSPNs and iSPNs, respectively), account for 95% of the neurons, and the remaining 5% are GABAergic and cholinergic interneurons. Interneuron axon terminals as well as local dSPN and iSPN axon collaterals form an intricate striatal network. Following chronic dopamine depletion as in Parkinson's disease (PD), both morphological and electrophysiological striatal neuronal features have been shown to be altered in rodent models. Our goal with this in silico study is twofold: (a) to predict and quantify how the intrastriatal network connectivity structure becomes altered as a consequence of the morphological changes reported at the single-neuron level and (b) to investigate how the effective glutamatergic drive to the SPNs would need to be altered to account for the activity level seen in SPNs during PD. In summary, we predict that the richness of the connectivity motifs in the striatal network is significantly decreased during PD while, at the same time, a substantial enhancement of the effective glutamatergic drive to striatum is present.
纹状体作为基底神经节的输入阶段，对于感觉运动整合、行为的发起和选择以及奖赏学习都很重要。纹状体主要从皮层和丘脑接收谷氨酸能输入。在啮齿动物中，产生直接通路和间接通路的纹状体投射神经元（分别为直接通路投射神经元和间接通路投射神经元）占神经元总数的95%，其余5%是GABA能和胆碱能中间神经元。中间神经元的轴突终末以及局部直接通路投射神经元和间接通路投射神经元的轴突侧支形成了一个复杂的纹状体网络。在帕金森病（PD）中，如长期多巴胺耗竭后，啮齿动物模型中的纹状体神经元在形态和电生理特征上均已显示发生改变。我们这项计算机模拟研究的目标有两个：（a）预测和量化由于在单神经元水平报道的形态变化，纹状体内网络连接结构如何改变；（b）研究为了适应帕金森病期间直接通路投射神经元的活动水平，需要如何改变对直接通路投射神经元的有效谷氨酸能驱动。总之，我们预测在帕金森病期间，纹状体网络中连接基序的丰富度显著降低，而与此同时，对纹状体的有效谷氨酸能驱动大幅增强。
