Department of Neuroscience, and.
MD-PhD Program, Washington University School of Medicine, St. Louis, Missouri 63110.
J Neurosci. 2019 Aug 21;39(34):6626-6643. doi: 10.1523/JNEUROSCI.0086-19.2019. Epub 2019 Jun 24.
The vermal cerebellum is a hub of sensorimotor integration critical for postural control and locomotion, but the nature and developmental organization of afferent information to this region have remained poorly understood Here, we use two-photon calcium imaging of the vermal cerebellum in awake behaving male and female mice to record granule neuron responses to diverse sensorimotor cues targeting visual, auditory, somatosensory, and motor domains. Use of an activity-independent marker revealed that approximately half (54%) of vermal granule neurons were activated during these recordings. A multikernel linear model distinguished the relative influences of external stimuli and co-occurring movements on neural responses, indicating that, among the subset of activated granule neurons, locomotion (44%-56%) and facial air puffs (50%) were more commonly and reliably encoded than visual (31%-32%) and auditory (19%-28%) stimuli. Strikingly, we also uncover populations of granule neurons that respond differentially to voluntary and forced locomotion, whereas other granule neurons in the same region respond similarly to locomotion in both conditions. Finally, by combining two-photon calcium imaging with birth date labeling of granule neurons via electroporation, we find that early- and late-born granule neurons convey similarly diverse sensorimotor information to spatially distinct regions of the molecular layer. Collectively, our findings elucidate the nature and developmental organization of sensorimotor information in vermal granule neurons of the developing mammalian brain. Cerebellar granule neurons comprise over half the neurons in the brain, and their coding properties have been the subject of theoretical and experimental interest for over a half-century. In this study, we directly test long-held theories about encoding of sensorimotor stimuli in the cerebellum and compare the coding properties of early- and late-born granule neurons. Strikingly, we identify populations of granule neurons that differentially encode voluntary and forced locomotion and find that, although the birth order of granule neurons specifies the positioning of their parallel fiber axons, both early- and late-born granule neurons convey a functionally diverse sensorimotor code. These findings constitute important conceptual advances in understanding the principles underlying cerebellar circuit development and function.
小脑绒球是感觉运动整合的关键枢纽，对姿势控制和运动至关重要，但该区域传入信息的性质和发育组织仍知之甚少。在这里，我们使用在清醒行为的雄性和雌性小鼠的小脑绒球进行双光子钙成像，记录颗粒神经元对针对视觉、听觉、躯体感觉和运动域的各种感觉运动线索的反应。使用非活性依赖性标记物显示，在这些记录中，大约有一半（54%）的绒球颗粒神经元被激活。多核线性模型区分了外部刺激和同时发生的运动对神经反应的相对影响，表明在被激活的颗粒神经元亚群中，运动（44%-56%）和面部空气吹（50%）比视觉（31%-32%）和听觉（19%-28%）刺激更常见且更可靠地编码。引人注目的是，我们还发现了一些颗粒神经元群体，它们对自愿和强制运动的反应不同，而同一区域的其他颗粒神经元对两种条件下的运动反应相似。最后，通过将双光子钙成像与通过电穿孔对颗粒神经元进行的出生日期标记相结合，我们发现早期和晚期出生的颗粒神经元以类似的方式将感觉运动信息传递到分子层的空间上不同的区域。总的来说，我们的研究结果阐明了发育中的哺乳动物大脑小脑绒球颗粒神经元中感觉运动信息的性质和发育组织。小脑颗粒神经元构成大脑中神经元的一半以上，其编码特性是半个多世纪以来理论和实验研究的主题。在这项研究中，我们直接检验了关于小脑中感觉运动刺激编码的长期理论，并比较了早期和晚期出生的颗粒神经元的编码特性。引人注目的是，我们确定了对自愿和强制运动有不同编码的颗粒神经元群体，并发现尽管颗粒神经元的出生顺序决定了它们平行纤维轴突的定位，但早期和晚期出生的颗粒神经元都传递了功能多样的感觉运动编码。这些发现是理解小脑回路发育和功能的基本原理的重要概念进展。
