Control of mammalian locomotion by ventral spinocerebellar tract neurons

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FROM: https://phys.org/news/2022-01-mice-n...ocomotion.html Research in mice identifies neurons that control locomotion by Cell Press (2022-01-20) For more than a century, scientists have known that while the commands that initiate movement come from the brain, the neurons that control locomotion once movement is underway reside within the spinal cord. In a study published January 20 in the journal Cell, researchers report that, in mice, they have identified one particular type of neuron that is both necessary and sufficient for regulating this type of movement. These neurons are called ventral spinocerebellar tract neurons (VSCTs). "We hope that our findings will open up new avenues toward understanding how complex behaviors like locomotion come about and give us new insight into the mechanisms and biological principles that control this essential behavior," says the paper's senior author George Mentis, associate professor of pathology and cell biology in the Department of Neurology at Columbia University. "It's also possible that our findings will lead to new ideas for therapeutic avenues, whether they involve treatments for spinal cord injury or neurodegenerative diseases that affect movement and motor control." VSCTs were discovered in the 1940s, but researchers have long believed that their main function was to relay messages about neuronal activity from the spinal cord to the cerebellum. The new study reports that instead they control locomotor behavior both during development and in adulthood. "These findings were a huge surprise," Mentis says. "One of the key discoveries in our study was that apart from their connection to the cerebellum, these neurons make connections with other spinal neurons that are also involved in locomotor behavior via their axon collaterals." The research involved several novel experimental approaches. One part of the research used optogenetics, employing LED light to regulate certain proteins that were expressed selectively in VSCTs to either activate or suppress the neuronal activity. Another set of experiments used chemogenetics, a process by which a chemical compound is used to activate or suppress synthetic ligands expressed artificially in these neurons, controlling their activity... (SNIP)

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FROM: https://www.cell.com/cell/fulltext/S...674(21)01452-5 Control of mammalian locomotion by ventral spinocerebellar tract neurons Joshua I. Chalif, María de Lourdes Martínez-Silva, John G. Pagiazitis, Andrew J. Murray, George Z. Mentis VOLUME 185, ISSUE 2, P328-344.E26 (2022-01-20) Summary Locomotion is a complex behavior required for animal survival. Vertebrate locomotion depends on spinal interneurons termed the central pattern generator (CPG), which generates activity responsible for the alternation of flexor and extensor muscles and the left and right side of the body. It is unknown whether multiple or a single neuronal type is responsible for the control of mammalian locomotion. Here, we show that ventral spinocerebellar tract neurons (VSCTs) drive generation and maintenance of locomotor behavior in neonatal and adult mice. Using mouse genetics, physiological, anatomical, and behavioral assays, we demonstrate that VSCTs exhibit rhythmogenic properties and neuronal circuit connectivity consistent with their essential role in the locomotor CPG. Importantly, optogenetic activation and chemogenetic silencing reveals that VSCTs are necessary and sufficient for locomotion. These findings identify VSCTs as critical components for mammalian locomotion and provide a paradigm shift in our understanding of neural control of complex behaviors. Introduction Locomotion is an essential animal behavior that is critical for survival. Overground locomotion is defined as the alternating, rhythmic motor activity between opposing limbs, as well as between antagonistic muscles of the same limb. Although sensory feedback and supraspinal commands are important for modulating locomotion, a network of spinal interneurons—known as the central pattern generator (CPG)—is thought to be responsible for the genesis of locomotor activity (Guertin, 2012; Kiehn, 2016) without relying on sensory or descending inputs (Graham Brown, 1911). These neurons are thought to activate spinal motor neurons (MNs) in a patterned manner. Subsequently, MNs convey their motor commands to peripheral muscles, resulting in limb movement. Recent studies have begun to unravel the organization of the spinal neuronal circuits underlying left-right and flexor-extensor alternation (Crone et al., 2008; Gosgnach et al., 2006; Talpalar et al., 2013; Zhang et al., 2014), demonstrating the modularity and speed-dependency of these circuits. However, it is unknown whether a single neuronal population is necessary and sufficient for the generation and maintenance of locomotor activity. Here, using mice as an experimental model, we identify ventral spinocerebellar tract neurons (VSCTs) as an essential population of spinal neurons for mammalian locomotion. In rodents, locomotor behavior is evident at early postnatal periods, since intact ex vivo spinal cord preparations can produce locomotor-like behavior following sensory fiber stimulation or application of a cocktail of drugs (Mentis et al., 2005; Talpalar et al., 2013; Whelan et al., 2000). This behavior is characterized by alternating rhythmic oscillations of MN activity between the left and right sides of the spinal cord and between rostral (L1/L2) and caudal (L4/L5) lumbar segments (Bonnot et al., 2002). Traditionally, CPG networks are thought to reside upstream of MNs (Goulding and Pfaff, 2005; Kiehn and Butt, 2003), whereas MNs act as the spinal output to convey motor commands to muscles. However, we have previously shown that stimulation of MN axons results in locomotor activity (Mentis et al., 2005). Additionally, manipulation of MN activity can alter ongoing locomotor behavior (Falgairolle et al., 2017) and zebrafish MNs can influence premotor excitatory CPG elements (Song et al., 2016). These observations implicate MNs in the regulation of locomotor rhythmogenesis via a local spinal neuron that is activated by MN axon collaterals. Although previous studies have provided evidence that the neural circuits encompassing CPG elements reside in the ventral spinal cord (Grillner and Wallén, 1985; Kiehn, 2016), the only spinal neurons that are contacted by MN axon collaterals known to date are Renshaw cells (Alvarez and Fyffe, 2007; Eccles et al., 1954; Mentis et al., 2005; Renshaw, 1946) and Sim1+ interneurons (Chopek et al., 2018). However, Renshaw cells do not affect the locomotor CPG (Enjin et al., 2017; Noga et al., 1987), and Sim1+ neurons regulate the speed of vertebrate locomotion and contribute to vigor and coordination but are not involved in locomotor rhythmogenesis (Zhang et al., 2008). Thus, MNs may contact another yet-to-be-defined neuron that resides within the ventral spinal cord and mediates locomotor rhythmogenesis... (SNIP)

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