Cerebellar granule cells constitute the majority of neurons in the brain and are the primary conveyors of sensory and motor-related mossy fiber information to Purkinje cells. The functional capability of the cerebellum hinges on whether individual granule cells receive mossy fiber inputs from multiple precerebellar nuclei or are instead unimodal; this distinction is unresolved. Using cell-type-specific projection mapping with synaptic resolution, we observed the convergence of separate sensory (upper body proprioceptive) and basilar pontine pathways onto individual granule cells and mapped this convergence across cerebellar cortex. These findings inform the long-standing debate about the multimodality of mammalian granule cells and substantiate their associative capacity predicted in the Marr-Albus theory of cerebellar function. We also provide evidence that the convergent basilar pontine pathways carry corollary discharges from upper body motor cortical areas. Such merging of related corollary and sensory streams is a critical component of circuit models of predictive motor control.DOI: http://dx.doi.org/10.7554/eLife.00400.001

Highlights d DN/IPN thalamocortical activity conveys a reliable feedforward motor timing signal d Silencing DN/IPN or recipient regions of thalamus blocks movement initiation d Photostimulation of the DN/IPN thalamocortical pathway triggers movement d Thalamocortical activation drives behavioral contextdependent movement initiation

Itch and pain are refractory symptoms of many ocular conditions. Ocular itch is generated mainly in the conjunctiva and is absent from the cornea. In contrast, most ocular pain arises from the cornea. However, the underlying mechanisms remain unknown. Using genetic axonal tracing approaches, we discover distinct sensory innervation patterns between the conjunctiva and cornea. Further genetic and functional analyses in rodent models show that a subset of conjunctival-selective sensory fibers marked by MrgprA3 expression, rather than corneal sensory fibers, mediates ocular itch. Importantly, the actions of both histamine and nonhistamine pruritogens converge onto this unique subset of conjunctiva sensory fibers and enable them to play a key role in mediating itch associated with allergic conjunctivitis. This is distinct from skin itch, in which discrete populations of sensory neurons cooperate to carry itch. Finally, we provide proof of concept that selective silencing of conjunctiva itch-sensing fibers by pruritogen-mediated entry of sodium channel blocker QX-314 is a feasible therapeutic strategy to treat ocular itch in mice. Itch-sensing fibers also innervate the human conjunctiva and allow pharmacological silencing using QX-314. Our results cast new light on the neural mechanisms of ocular itch and open a new avenue for developing therapeutic strategies.

Tel. +44 131 650 3113 53 Email: Ian.Duguid@ed.ac.uk 54 65 Stimulating the MThDN/IPN thalamocortical pathway in the absence of the cue recapitulated cue-66 evoked M1 membrane potential dynamics and forelimb behavior in the learned behavioral 67 context, but generated semi-random movements in an altered behavioral context. Thus, 68 cerebellar-recipient motor thalamocortical input to M1 is indispensable for the generation of 69 motor commands that initiate goal-directed movement, refining our understanding of how the 70 cerebellar-thalamocortical pathway contributes to movement timing. 71 72 129 ( Figure 1c and Video S1). Mice rapidly learned to execute the task (mean = 7.5 days, 95% CI 130 [6.3, 8.6], N = 16 mice, all data, unless otherwise stated, are presented as mean, 131 [bootstrapped 95% confidence interval]; last session task success, mean = 0.64 rewards per 132 cue presentation, 95% CI [0.56, 0.72]), displaying relatively fast reaction times (last session, 133 median = 0.32s [0.30, 0.34]) and reproducible forelimb kinematic trajectories (Figures 1d-1f, 134 Video S1).135 136

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Activation of TRPA1 by isoflurane negatively affects anesthetic induction latency by altering respiratory patterns and impairing pulmonary compliance.