Multimodal sensory control of motor performance by glycinergic interneurons of the mouse spinal cord deep dorsal horn

Multimodal sensory control of motor performance by glycinergic interneurons of the mouse spinal cord deep dorsal hornRepository containing MoSeq datasets obtained and analysis for M. Gradwell, N Ozeri-Engelhard, et al. 2024. Neuron. AbstractTo achieve smooth motor performance in a changing sensory environment, motor outputs must be constantly updated in response to sensory feedback. Inhibitory interneurons in the spinal cord play an essential role in shaping motor activity by gating the transmission of sensory information and setting the pattern and rhythm of motor neurons. Here, in mice, we identify the medial deep dorsal horn of the spinal cord as a “hot zone” of convergent proprioceptive and cutaneous information from the hindlimb, where inhibitory neurons show increased responsiveness to sensory input and are more prominently recruited during locomotion in comparison to excitatory neurons. We identify a novel population of glycinergic inhibitory neurons within the deep dorsal horn that express parvalbumin (dPV) and receive convergent proprioceptive and cutaneous input from the paw. We show that dPVs possess intrinsic properties that support spontaneous discharge, even in the absence of synaptic input. However, a drug cocktail mimicking descending input (5-HT, dopamine, NMDA) amplifies dPV output, while cutaneous and proprioceptive inputs shape the temporal dynamics of dPV activity. These findings suggest dPV-mediated inhibition is modulated by behavioral state and can be fine-tuned by sensory input. Using intersectional genetic strategies, we selectively target spinal cord dPVs and demonstrate their capacity to provide widespread ipsilateral inhibition to both pre-motor and motor networks of the ventral horn, thereby gating sensory-evoked muscle activity. Manipulating the activity of dPVs during treadmill locomotion results in altered limb kinematics at the transition of stance to swing and altered step cycle timing at increased speeds. To investigate the effects of manipulating dPV activity on broader sets of motor behaviors, we used depth vision and machine learning to quantify and scale spontaneous behavior. We find that although sub-movements remain stable, the transitions between sub-movements are reduced, suggesting a role in movement switching. In sum, our study reveals a new model by which sensory convergence and inhibitory divergence produce a surprisingly flexible influence on motor networks to increase the diversity of mechanisms by which sensory input facilitates smooth movement and context-appropriate transitions.小鼠脊髓背侧深层角甘氨酸能中间神经元对运动行为的多模态感觉调控 本数据集仓库收纳了M. Gradwell、N·奥泽里-恩格尔哈德（N Ozeri-Engelhard）等人2024年发表于《神经元》（Neuron）期刊的研究中所获取并分析的MoSeq数据集。 摘要：为在动态变化的感觉环境中实现流畅的运动行为，运动输出必须持续响应感觉反馈进行更新。脊髓内的抑制性中间神经元通过门控感觉信息传递、调控运动神经元的活动模式与节律，在塑造运动活动过程中发挥关键作用。本研究以小鼠为模型，鉴定出脊髓内侧背侧深层角为后肢本体感觉与皮肤感觉信息汇聚的“热点区域”，相较于兴奋性神经元，该区域的抑制性神经元对感觉输入的响应性更强，且在运动时被更显著地募集。我们发现脊髓背侧深层角内存在一群表达小白蛋白（parvalbumin）的新型甘氨酸能抑制性神经元（dPVs），它们接收来自后肢足部的本体感觉与皮肤感觉汇聚输入。实验结果表明，dPVs具备支持自发放电的内在特性，即便在无突触输入的情况下也可产生自发放电。然而，模拟下行输入的药物组合（5-羟色胺、多巴胺、N-甲基-D-天冬氨酸（NMDA））可增强dPV的输出活性，同时皮肤与本体感觉输入会塑造dPV活动的时间动态特征。上述发现提示，dPV介导的抑制作用受行为状态调控，并可通过感觉输入进行精细调节。我们采用交叉遗传策略选择性靶向脊髓dPVs，证实其能够向脊髓腹角的运动前网络与运动网络提供广泛的同侧抑制，从而门控感觉诱发的肌肉活动。在跑步机运动过程中操控dPV的活性，会导致站立相向摆动相转换时的肢体运动学特征发生改变，并在运动速度提升时改变步周期时序。为探究操控dPV活性对更广泛运动行为的影响，我们采用深度视觉与机器学习技术对自发行为进行量化与标准化分析。结果发现，尽管子运动本身保持稳定，但子运动之间的转换次数显著减少，这提示dPVs在运动切换过程中发挥重要作用。综上，本研究揭示了一种全新的调控模型：感觉汇聚与抑制性发散可对运动网络产生出人意料的灵活影响，从而拓展了感觉输入促进流畅运动与情境适配性转换的机制多样性。