Cerebellospinal Neurons Regulate Motor Performance and Motor Learning

I'm sure someone can make sense out of this because it seems to me that knowing exactly how this works would help us recover motor movement. WHOM DO WE ASK TO TRANSLATE THIS INTO A STROKE PROTOCOL? This is the complete problem in stroke. NO LEADERSHIP, NO STRATEGY.  This does seem to be in mice since they are talking about forelimbs. So even more important is research in humans.

Cerebellospinal Neurons Regulate Motor Performance and Motor Learning

Author links open overlay panelAnupamaSathyamurthy¹ArnabBarik²Courtney I.Dobrott¹⁴Kaya J.E.Matson¹StefanStoica¹RandallPursley³Alexander T.Chesler²Ariel J.Levine¹⁵

https://doi.org/10.1016/j.celrep.2020.107595Get rights and content

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open access

Highlights

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Cerebellospinal (CeS) neurons constitute approximately 5%–10% of excitatory deep cerebellar neurons

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Ipsilateral CeS neurons to the cervical cord are necessary for skilled forelimb movement

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Contralateral CeS neurons (CeS^cer-contra) are necessary for skilled locomotor learning

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CeS^cer-contra neurons target local and long-range neurons in the cervical cord

Summary

To understand the neural basis of behavior, it is important to reveal how movements are planned, executed, and refined by networks of neurons distributed throughout the nervous system. Here, we report the neuroanatomical organization and behavioral roles of cerebellospinal (CeS) neurons. Using intersectional genetic techniques, we find that CeS neurons constitute a small minority of excitatory neurons in the fastigial and interpositus deep cerebellar nuclei, target pre-motor circuits in the ventral spinal cord and the brain, and control distinct aspects of movement. CeS neurons that project to the ipsilateral cervical cord are required for skilled forelimb performance, while CeS neurons that project to the contralateral cervical cord are involved in skilled locomotor learning. Together, this work establishes CeS neurons as a critical component of the neural circuitry for skilled movements and provides insights into the organizational logic of motor networks.

Graphical Abstract

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Keywords

deep cerebellar nuclei

interpositus

cerebellospinal

spinal cord

fastigial

descending pathways

motor control

cerebellum

Introduction

Seamless movements are accomplished by the concerted action of diverse motor areas, including the cortex, basal ganglia, red nucleus, brainstem, cerebellum, and spinal cord. Over the past century, there have been great strides toward defining the neural computations of each of these areas and their contribution to motor control. However, to truly understand the neural basis of behavior, it is essential to reveal how individual motor areas are bound into coordinated networks to accomplish purposeful movement. All neural information must flow through the “final common pathway” of spinal motoneurons to drive movement (Sherrington, 1911). While motor areas in the brain may encode discrete aspects of movement such as the neural commands for the initiation, speed, and direction of movement, the spinal cord integrates and transforms these complementary motor commands into precise patterns of muscle contractions (Armstrong, 1986, Shik and Orlovsky, 1976). The intricate processing capabilities of the cord are sustained by a diverse array of functionally specialized interneurons, which serve as rich substrates for finetuning, diversifying, and coordinating motor output (Jankowska, 1992). Therefore, deconstructing motor circuits with reference to their terminal targets among spinal networks can provide a powerful framework for decoding the neural mechanisms underlying motor control.

To exert precise temporal and spatial control over the body’s musculature, it is essential to accurately time the neural activity of multiple motor areas, a task that is thought to be served by the cerebellum (Arshavsky et al., 1983). Indeed, loss of motor coordination or ataxia is a hallmark of cerebellar damage (Holmes, 1917, Sprague and Chambers, 1953, Carrea and Mettler, 1947). This critical role for the cerebellum in motor coordination is attributed to its ability to learn and predict errors and to ultimately transform error predictions into corrected motor commands (Wolpert et al., 1998). However, the organizational logic of efferent cerebellar pathways that convey cerebellar computations to the appropriate spinal segments for movement are not clear (Thach et al., 1992). Nearly all cerebellar output flows from Purkinje neurons to the rest of the nervous system via the deep cerebellar nuclei (DCN): the dentate, fastigial, and interpositus nuclei (Thach et al., 1992). Rather than acting as passive relays, these nuclei integrate sensori-motor information and play essential roles in motor control (Becker and Person, 2019, Brooks et al., 2015, Chabrol et al., 2019, Low et al., 2018, Martin et al., 2000, Mason et al., 1998, Mori et al., 1999, Perciavalle et al., 2013, Sprague and Chambers, 1953, Strick et al., 2009, Yu and Eidelberg, 1983). DCN neurons project to the thalamus, red nucleus, and brainstem nuclei, sites where cerebellar instructions are likely integrated with other sensori-motor information and relayed to spinal circuits that execute movements. (Angaut and Bowsher, 1965, Asanuma et al., 1983, Batton et al., 1977, Brodal and Szikla, 1972, Courville, 1966, Kelly and Strick, 2003, Tolbert et al., 1980). Accordingly, most contemporary and classic studies of motor control have posited that the cerebellum influences movement only through indirect, poly-synaptic relays in these brain areas (Kandel, 2013, Perciavalle et al., 2013, Ruigrok, 2012). However, a direct projection from the DCN to the spinal cord has been reported.

Beginning with anatomical circuit tracing studies over a century ago, direct cerebellospinal (CeS) neurons have been observed in a wide variety of tetrapod animals (Asanuma et al., 1980, Cajal, 2012, Carrea and Mettler, 1954, Fukushima et al., 1977, Gray, 1926, Jakob, 1942, Liang et al., 2011, Matsushita and Hosoya, 1978, Nudo and Masterton, 1988, Thomas et al., 1956, Wang et al., 2018, Wilson et al., 1978), but their initial descriptions were debated (Barker, 1901, Gray, 1918). Nevertheless, anatomical descriptions of the CeS pathway were corroborated by electrophysiological recordings (Alstermark et al., 1987, Orioli, 1961, Wilson et al., 1978). Notably, despite the potential importance of CeS neurons in mediating movement, these neurons remain poorly characterized and have not been incorporated into the framework for studies of motor control.

Here, we investigated the anatomy, function, and targets of CeS neurons in the adult mouse and reveal that they play critical roles in motor performance and motor learning. We first defined three groups of excitatory CeS neurons based on their location within the DCN and their pattern of connectivity with the spinal cord. Next, we found that CeS neurons that project to the ipsilateral cervical spinal cord are critical for skilled forelimb movement, while those that project to the contralateral cervical spinal cord are important for skilled locomotor learning. Finally, we found that CeS neurons target segmental and long-range intersegmental neurons in the cervical cord, thereby providing a direct link between the cerebellum and spinal substrates for motor coordination. Together, this work establishes CeS neurons as important players in the descending control of movement.

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