The relationship between birth timing, circuit wiring, and physiological response properties of cerebellar granule cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 23; pp. 1 - 11
• Main Authors: Shuster, S. Andrew, Wagner, Mark J., Pan-Doh, Nathan, Ren, Jing, Grutzner, Sophie M., Beier, Kevin T., Kim, Tony Hyun, Schnitzer, Mark J., Luo, Liqun
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08.06.2021
• Subjects: Animals; Animals, Newborn; Axons; Biological Sciences; Birth; Calcium imaging; Calcium ions; Cerebellar Cortex - growth & development; Cerebellar Cortex - virology; Cerebellum; Granular materials; Granule cells; Lyssavirus; Mice; Mice, Transgenic; Motor nuclei; Nerve Fibers - metabolism; Nerve Fibers - virology; Nuclei (cytology); Parallel processing; Rabies; Rabies virus - metabolism; Reinforcement; Representations; Stimuli; Timer circuits; Viruses; Wiring; birth timing; rabies tracing; granule cells; two-photon Ca2+ imaging; cerebellum
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/PNAS.2101826118

Cerebellar granule cells (GrCs) are usually regarded as a uniform cell type that collectively expands the coding space of the cerebellum by integrating diverse combinations of mossy fiber inputs. Accordingly, stable molecularly or physiologically defined GrC subtypes within a single cerebellar region have not been reported. The only known cellular property that distinguishes otherwise homogeneous GrCs is the correspondence between GrC birth timing and the depth of the molecular layer to which their axons project. To determine the role birth timing plays in GrC wiring and function, we developed genetic strategies to access early- and late-born GrCs. We initiated retrograde monosynaptic rabies virus tracing from control (birth timing unrestricted), early-born, and late-born GrCs, revealing the different patterns of mossy fiber input to GrCs in vermis lobule 6 and simplex, as well as to early- and late-born GrCs of vermis lobule 6: sensory and motor nuclei provide more input to early-born GrCs, while basal pontine and cerebellar nuclei provide more input to late-born GrCs. In vivo multidepth two-photon Ca2+ imaging of axons of early- and late-born GrCs revealed representations of diverse task variables and stimuli by both populations, with modest differences in the proportions encoding movement, reward anticipation, and reward consumption. Our results suggest neither organized parallel processing nor completely random organization of mossy fiber→GrC circuitry but instead a moderate influence of birth timing on GrC wiring and encoding. Our imaging data also provide evidence that GrCs can represent generalized responses to aversive stimuli, in addition to recently described reward representations.