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

Abstract

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.

Novel Cerebello-Amygdala Connections Provide Missing Link Between Cerebellum and Limbic System

“…The circuit, which could account for the previously observed short-latency cerebello-amygdala responses (Heath and Harper, 1974), could convey cerebellar information about prediction, salience, and/or valence to BLA, shaped by the intrinsic, synaptic, and integrative properties of the nodes. Indeed, the cerebellum is known to encode such information (Ohmae and Medina, 2015;Wagner et al, 2017;Hull, 2020;Ma et al, 2020;Bina et al, 2021;Shuster et al, 2021), which is also seen in BLA (Paton et al, 2006;Adolphs, 2010;Janak and Tye, 2015;Sengupta et al, 2018;Zhang and Li, 2018;Gründemann et al, 2019;Brockett et al, 2021), and which is thought to be used by CM and PF during aversive conditioning, observational learning and reward-seeking behavior (Jeon et al, 2010;Sengupta and McNally, 2014;Vertes et al, 2015;Xiao et al, 2018;Cover and Mathur, 2021;Rizzi et al, 2021).…”

Cerebellum Directly Modulates the Substantia Nigra Dopaminergic Activity

“…Intriguingly, several recent studies have shown that the cerebellum contains reward related information 88,[96][97][98][99][100][101][102][103] . In addition to the recently described direct projection of cerebellum to one of the major reward processing brain regions, the ventral tegmental area 104 , the Cb-SNc pathway described here may also serve as a medium through which information about reward and other non-motor behaviors might be conveyed from the cerebellum to the basal ganglia.…”

Novel cerebello-amygdala connections provide missing link between cerebellum and limbic system

“…The circuit, which could account for the previously observed short-latency cerebello-amygdala responses 37 , could convey cerebellar information about prediction, salience and/or valence to BLA, shaped by the intrinsic, synaptic and integrative properties of the nodes. Indeed, the cerebellum is known to encode such information 8,[69][70][71][72][73] , which is also seen in BLA 35,[74][75][76][77][78][79] , and which is thought to be used by CM and PF during aversive conditioning, observational learning and reward-seeking behavior 30,46,[80][81][82][83] .…”