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Rubrocerebellar Feedback Loop Isolates the Interposed Nucleus As an Independent Processor of Corollary Discharge Information in Mice

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Rubrocerebellar Feedback Loop Isolates the Interposed Nucleus As an Independent Processor of Corollary Discharge Information in Mice This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Systems/Circuits Rubrocerebellar feedback loop isolates the interposed nucleus as an independent processor of corollary discharge information in mice Christy S. Beitzel1, Brenda D. Houck2, Samantha M. Lewis2 and Abigail L. Person2 1Neuroscience Graduate Program, University of Colorado School of Medicine, Aurora, CO 80045 2Department of Physiology & Biophysics, University of Colorado School of Medicine, Aurora, CO 80045 DOI: 10.1523/JNEUROSCI.1093-17.2017 Received: 23 April 2017 Revised: 1 September 2017 Accepted: 12 September 2017 Published: 15 September 2017 Author contributions: C.S.B. and A.L.P. designed research; C.S.B., B.D.H., S.M.L., and A.L.P. performed research; C.S.B. and A.L.P. analyzed data; C.S.B. and A.L.P. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. Work was supported by NIH R01 NS084996, the Klingenstein and McKnight Foundations to ALP and F31 NS096887 to CSB. Light microscopy was performed in the University of Colorado Anschutz Medical Campus Advance Light Microscopy Core. Optogenetics support was provided by the University of Colorado Optogenetics and Neural Engineering Core. Both cores are supported in part by Rocky Mountain Neurological Disorders Core Grant Number P30NS048154 and by NIH/NCRR Colorado CTSI Grant Number UL1 RR025780. We also thank Mr Jesse Gilmer for advice on cerebellar volume measurements and Cristin Welle and colleagues for advice on the manuscript. Corresponding author: Abigail L Person, 12800 E 19th Ave RC1 North Room 7402K, Aurora, CO 80045, Phone, 303-724-4514, email: [email protected] Cite as: J. Neurosci ; 10.1523/JNEUROSCI.1093-17.2017 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2017 the authors 1 2 3 4 5 Rubrocerebellar feedback loop isolates the interposed nucleus as an 6 independent processor of corollary discharge information in mice 7 8 9 Christy S. Beitzel1, Brenda D. Houck2*, Samantha M. Lewis2, Abigail L. Person2 10 11 1. Neuroscience Graduate Program, University of Colorado School of Medicine, Aurora, CO 12 80045 13 2. Department of Physiology & Biophysics, University of Colorado School of Medicine, Aurora, 14 CO 80045 15 16 Running title: A feedback loop between cerebellum and brainstem 17 18 Pages: 28 19 Figures: 8 20 Tables: 0 21 Abstract: 218 22 Introduction: 615 23 Significance Statement:105 24 Discussion: 1463 25 26 Conflict of Interest: None. 27 Acknowledgements:Work was supported by NIH R01 NS084996 , the Klingenstein and 28 McKnight Foundations to ALP and F31 NS096887 to CSB. Light microscopy was performed in 29 the University of Colorado Anschutz Medical Campus Advance Light Microscopy Core. 30 Optogenetics support was provided by the University of Colorado Optogenetics and Neural 31 Engineering Core. Both cores are supported in part by Rocky Mountain Neurological Disorders 32 Core Grant Number P30NS048154 and by NIH/NCRR Colorado CTSI Grant Number UL1 33 RR025780. We also thank Mr Jesse Gilmer for advice on cerebellar volume measurements and 34 Cristin Welle and colleagues for advice on the manuscript. 35 * Current address: Department of Biology, Hendrix College, Conway, AR 72032 36 37 38 Corresponding author: 39 Abigail L Person 40 12800 E 19th Ave RC1 North Room 7402K 41 Aurora, CO 80045 42 Phone, 303-724-4514 43 email: [email protected] 44 1 45 Abstract 46 Understanding cerebellar contributions to motor coordination requires deeper insight into how 47 the output structures of the cerebellum, the cerebellar nuclei, integrate their inputs and influence 48 downstream motor pathways. The magnocellular red nucleus (RNm), a brainstem premotor 49 structure, is a major target of the interposed nucleus (IN), and has also been described in 50 previous studies to send feedback collaterals to the cerebellum. Because such a pathway is in a 51 key position to provide motor efferent information to the cerebellum, satisfying predictions about 52 the use of corollary discharge in cerebellar computations, we studied it in mice of both sexes. 53 Using anterograde viral tracing, we show that innervation of cerebellum by rubrospinal neuron 54 collaterals is remarkably selective for the IN compared to the cerebellar cortex. Optogenetic 55 activation of the pathway in acute mouse brain slices drove IN activity despite small amplitude 56 synaptic currents, suggesting an active role in IN information processing. Monosynaptic 57 transsynpatic rabies tracing indicated the pathway contacts multiple cell types within the IN. By 58 contrast, IN inputs to the RNm targeted a region that lacked inhibitory neurons. Optogenetic 59 drive of IN inputs to the RNm revealed strong, direct excitation but no inhibition of RNm 60 neurons. Together, these data indicate that the cerebellar nuclei are under afferent control 61 independent of the cerebellar cortex, potentially diversifying its roles in motor control. 62 63 Significance Statement 64 The common assumption that all cerebellar mossy fibers uniformly collateralize to the cerebellar 65 nuclei and cortex underlies classic models of convergent Purkinje influence on cerebellar output. 66 Specifically, mossy fibers are thought to both directly excite nuclear neurons and drive 67 polysynaptic feedforward inhibition via Purkinje neurons, setting up a fundamental 68 computational unit. Here we present data that challenge this rule. A dedicated cerebellar nuclear 69 afferent comprised of feedback collaterals from premotor rubrospinal neurons can directly 70 modulate IN output independent of Purkinje cell modulation. In contrast to the IN-RNm 71 pathway, the RNm-IN feedback pathway targets multiple cell types, potentially influencing both 72 motor output pathways and nucleoolivary feedback. 73 74 75 2 76 Introduction 77 Prominent theories of cerebellar contributions to motor control propose that the cerebellum 78 computes a prediction of body kinematics, termed a forward model (Wolpert et al., 1998; 79 Kawato and Gomi, 1992). Because sensory feedback is too slow to guide most fast movements, 80 forward models provide a framework for online motor corrections, facilitating fast and accurate 81 movements. Evidence that the cerebellum is a source of predictive coding has accumulated in 82 recent years (Herzfeld et al., 2015; Pasalar et al., 2006), raising the question of how this 83 computation is made. Outgoing motor commands, communicated via corollary discharge 84 pathways, are essential to compute a forward model (Wolpert, 1997). Many inputs to the 85 cerebellum are thought to convey a mix of both sensory and motor information. However, 86 cerebellar inputs arising from the magnocellular region of the red nucleus (RNm) are an 87 interesting candidate likely to provide the cerebellum with real time motor information (Eccles et 88 al., 1975; Anderson, 1971; Huisman et al., 1983; Courville and Brodal, 1966; Brodal and 89 Gogstad, 1954). 90 91 The RNm is a premotor structure that projects directly to motor neurons and premotor pools in 92 the spinal cord that innervate limb musculature (Huisman et al., 1981; Murray and Gurule, 1979; 93 Gibson et al., 1985; Kohlerman et al., 1982). Dual-color retrograde dye injections into the spinal 94 cord and cerebellar interposed nucleus (IN) revealed co-labeled neurons in the RNm, suggesting 95 that RNm projections to the cerebellum are collaterals of the rubrospinal tract, potentially 96 providing the cerebellum with another source of corollary discharge information (Huisman et al., 97 1983). However, there is debate whether RNm projects mainly to the cerebellar cortex, the IN or 98 both (Huisman et al., 1983; Walberg and Dietrichs, 1986; Naus et al.,1984; Courville, 1968; 99 Courville and Brodal, 1966; Hineman and Carpenter, 1959). Indeed, if RNm projects mainly to 100 the cerebellar nuclei it would be in a position to facilitate computations independent of the 101 cerebellar cortex, potentially setting up a comparator circuit with convergent Purkinje afferents. 102 Since the rubrocerebellar pathway has only been examined using retrograde tracing, this debate 103 has gone largely unresolved. While it is often assumed that excitatory innervation of the 104 cerebellar nuclei is dominated by collaterals of precerebellar afferents producing either mossy 105 fibers or climbing fibers, the literature on single cell fills of mossy fibers reveals large 3 106 heterogeneity in the degree of collateralization of mossy fibers to the nuclei (Quy et al., 2011; 107 Wu et al., 1999; Luo and Sugihara, 2014). 108 109 Of course, RNm is also a major target of cerebellar output. Therefore, a projection back to the IN 110 would form a reciprocal loop between these two structures. Previous studies have shown that 111 ablation of cerebellar cortical inhibition causes prolonged depolarization of IN neurons, 112 suggestive of a reverberating circuit between IN and its targets (Tsukahara et al., 1983). 113 Moreover, excitatory feedback loops are seen throughout the motor system and are important for 114 models of neural control of movement (Anastasio and Robinson, 1981; Cannon et al., 1983; 115 Houk et al., 1993). However, because the IN and RNm contain multiple cell types, including 116 both excitatory and inhibitory
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