Auer Franziska, Nardone Katherine, Matsuda Koji, Hibi Masahiko, Schoppik David
Depts. of Otolaryngology, Neuroscience & Physiology, and the Neuroscience Institute, NYU Grossman School of Medicine, New York, United States.
Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Japan.
Elife. 2025 Apr 24;13:RP97614. doi: 10.7554/eLife.97614.
Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells - the output neurons of the cerebellar cortex - as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.
小脑功能障碍会导致姿势不稳。最近在自由活动啮齿动物身上开展的研究改变了对小脑在姿势控制方面作用的研究。然而,陆地运动和啮齿动物小脑的综合复杂性促使人们采用新方法在更简单的脊椎动物中干扰小脑功能。在此,我们采用一种经过验证的化学遗传学工具(TRPV1/辣椒素)来描述浦肯野细胞(小脑皮质的输出神经元)在斑马鱼幼体自由进行深度游动时所起的作用。在对姿势和运动进行定量高通量评估的同时,我们实现了对浦肯野细胞的双向控制(激活和消融)。激活改变了俯仰(头朝上/头朝下)轴上的姿势控制。同样,消融破坏了俯仰轴姿势以及负责攀爬的鳍与身体的协调。姿势紊乱在较年长的幼体中更为普遍,为发育中的小脑在姿势控制中新兴作用提供了一个窗口。最后,我们发现浦肯野细胞的活动能够单独和共同编码倾斜方向,这是姿势控制神经元的一个关键特征。我们的研究结果阐明了小脑在斑马鱼幼体姿势控制和前庭感觉中的预期作用,确立了TRPV1/辣椒素介导的干扰在一种简单的、具有遗传易处理性的脊椎动物中的有效性。此外,通过比较浦肯野细胞消融在不同时间对姿势的影响,我们揭示了整个早期发育过程中小脑对姿势控制作用逐渐显现的特征。这项工作朝着理解小脑在调节姿势成熟方面的原始作用迈出了重要一步。