Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102.
Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102
J Neurosci. 2019 Jun 12;39(24):4727-4737. doi: 10.1523/JNEUROSCI.2913-18.2019. Epub 2019 Apr 5.
The main excitatory inputs to the striatum arising from the cortex and the thalamus innervate both striatal spiny projection neurons and interneurons. These glutamatergic inputs to striatal GABAergic interneurons have been suggested to regulate the spike timing of striatal projection neurons via feedforward inhibition. Understanding how different excitatory inputs are integrated within the striatal circuitry and how they regulate striatal output is crucial for understanding basal ganglia function and related behaviors. Here, using VGLUT2 mice from both sexes, we report the existence of a glutamatergic projection from the mesencephalic locomotor region to the striatum that avoids the spiny neurons and selectively innervates interneurons. Specifically, optogenetic activation of glutamatergic axons from the pedunculopontine nucleus induced monosynaptic excitation in most recorded striatal cholinergic interneurons and GABAergic fast-spiking interneurons. Optogenetic stimulation in awake head-fixed mice consistently induced an increase in the firing rate of putative cholinergic interneurons and fast-spiking interneurons. In contrast, this stimulation did not induce excitatory responses in spiny neurons but rather disynaptic inhibitory responses and a decrease in their firing rate , suggesting a feedforward mechanism mediating the inhibition of spiny projection neurons through the selective activation of striatal interneurons. Furthermore, unilateral stimulation of pedunculopontine nucleus glutamatergic axons in the striatum induced ipsilateral head rotations consistent with the inhibition of striatal output neurons. Our results demonstrate the existence of a unique interneuron-specific midbrain glutamatergic input to the striatum that exclusively recruits feedforward inhibition mechanisms. Glutamatergic inputs to the striatum have been shown to target both striatal projection neurons and interneurons and have been proposed to regulate spike timing of the projection neurons in part through feedforward inhibition. Here, we reveal the existence of a midbrain source of glutamatergic innervation to the striatum, originating in the pedunculopontine nucleus. Remarkably, this novel input selectively targets striatal interneurons, avoiding the projection neurons. Furthermore, we show that this selective innervation of interneurons can regulate the firing of the spiny projection neurons and inhibit the striatal output via feedforward inhibition. Together, our results describe a unique source of excitatory innervation to the striatum which selectively recruits feedforward inhibition of spiny neurons without any accompanying excitation.
纹状体的主要兴奋性输入来自皮层和丘脑，它们既支配纹状体的棘突投射神经元，也支配中间神经元。这些谷氨酸能输入到纹状体 GABA 能中间神经元，被认为通过前馈抑制来调节纹状体投射神经元的尖峰时间。了解不同的兴奋性输入如何在纹状体回路中整合，以及它们如何调节纹状体输出，对于理解基底神经节的功能和相关行为至关重要。在这里，我们使用来自雌雄两性的 VGLUT2 小鼠，报告了从中脑运动区到纹状体的谷氨酸能投射的存在，该投射避开了棘突神经元，选择性地支配中间神经元。具体来说，pedunculopontine 核谷氨酸能轴突的光遗传学激活诱导了大多数记录的纹状体内胆碱能中间神经元和 GABA 能快棘突中间神经元的单突触兴奋。在清醒的头部固定小鼠中，光遗传学刺激一致地增加了推定的胆碱能中间神经元和快棘突中间神经元的放电率。相比之下，这种刺激不会诱导棘突神经元产生兴奋性反应，而是产生双突触抑制反应，并降低其放电率，这表明通过选择性激活纹状体中间神经元，存在一种前馈机制来介导对棘突投射神经元的抑制。此外，单侧刺激纹状体 pedunculopontine 核谷氨酸能轴突会诱导同侧头部旋转，这与纹状体输出神经元的抑制一致。我们的结果表明，纹状体存在一种独特的中间神经元特异性中脑谷氨酸能传入，它专门募集前馈抑制机制。已经表明，纹状体的谷氨酸能输入既靶向纹状体的投射神经元，也靶向中间神经元，并被提出部分通过前馈抑制来调节投射神经元的尖峰时间。在这里，我们揭示了中脑纹状体谷氨酸能传入的一个来源，起源于 pedunculopontine 核。值得注意的是，这种新的输入选择性地靶向纹状体中间神经元，避开了投射神经元。此外，我们表明，这种中间神经元的选择性支配可以通过前馈抑制调节棘突投射神经元的放电并抑制纹状体的输出。总之，我们的结果描述了一种独特的纹状体兴奋性传入源，它专门募集棘突神经元的前馈抑制，而没有任何伴随的兴奋。
