A Cluster of Cholinergic Premotor Interneurons Modulates Mouse Locomotor Activity

Zagoraiou, Laskaro; Akay, Turgay; Martin, James F.; Brownstone, Robert M.; Jessell, Thomas M.; Miles, Gareth B.

doi:10.1016/j.neuron.2009.10.017

Cited by 381 publications

(546 citation statements)

References 97 publications

(134 reference statements)

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“…CST connections with ChAT interneurons and C boutons are sensitive to afferent fiber manipulations ChAT ϩ spinal interneurons include a distinctive class based on Pitx2 ϩ gene expression during development (Zagoraiou et al, 2009). Although these cells cannot be identified definitively in the rat, their neurotransmitter phenotype and location suggest that at least some of these interneurons are of the Pitx2 group.…”

Section: Discussionmentioning

confidence: 99%

“…Because ϳ5% of motoneuron soma membrane is occupied by 1a afferent terminals (Ichiyama et al, 2006), freeing up this space after DRX could contribute directly to this C bouton increase. Changes in C bouton density would not only affect the capacity of the CST to activate muscle but also that of other descending pathways and spinal interneurons because cholinergic interneurons have a variety of input sources and output targets (Zagoraiou et al, 2009), Moreover, many other interneurons in spinal motor circuits receive direct CS and/or afferent fiber innervation, such as Ia inhibitory interneurons in proprioceptive sensorimotor circuits (Hultborn and Santini, 1972) and recently defined dI3 excitatory interneurons in cutaneous sensorimotor circuits (Bui et al, 2013). Competition from afferent fibers would thus not only drive dynamic reconstruction of CST axons but also induce rewiring of spinal motor circuits, which could affect motor function.…”

Section: Discussionmentioning

confidence: 99%

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Competition with Primary Sensory Afferents Drives Remodeling of Corticospinal Axons in Mature Spinal Motor Circuits

2016

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Injury to the mature motor system drives significant spontaneous axonal sprouting instead of axon regeneration. Knowing the circuitlevel determinants of axonal sprouting is important for repairing motor circuits after injury to achieve functional rehabilitation. Competitive interactions are known to shape corticospinal tract axon outgrowth and withdrawal during development. Whether and how competition contributes to reorganization of mature spinal motor circuits is unclear. To study this question, we examined plastic changes in corticospinal axons in response to two complementary proprioceptive afferent manipulations: (1) enhancing proprioceptive afferents activity by electrical stimulation; or (2) diminishing their input by dorsal rootlet rhizotomy. Experiments were conducted in adult rats. Electrical stimulation produced proprioceptive afferent sprouting that was accompanied by significant corticospinal axon withdrawal and a decrease in corticospinal connections on cholinergic interneurons in the medial intermediate zone and C boutons on motoneurons. In contrast, dorsal rootlet rhizotomy led to a significant increase in corticospinal connections, including those on cholinergic interneurons; C bouton density increased correspondingly. Motor cortex-evoked muscle potentials showed parallel changes to those of corticospinal axons, suggesting that reciprocal corticospinal axon changes are functional. Using the two complementary models, we showed that competitive interactions between proprioceptive and corticospinal axons are an important determinant in the organization of mature corticospinal axons and spinal motor circuits. The activity-and synaptic space-dependent properties of the competition enables prediction of the remodeling of spared corticospinal connection and spinal motor circuits after injury and informs the target-specific control of corticospinal connections to promote functional recovery.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Competition with Primary Sensory Afferents Drives Remodeling of Corticospinal Axons in Mature Spinal Motor Circuits

2016

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“…One notable difference, however, does appear to exist. In mice, ipsilaterally projecting cholinergic (V0c) neurons that are labeled by Pitx2 develop from the p0 domain (Zagoraiou et al, 2009). In zebrafish V0c-corresponding neurons seem to be absent, as Evx2-and Pax2-positive neurons appear to account for all the population of V0 neurons, and Pitx2 is not expressed in V0 neurons (our unpublished observation).…”

Section: V0 Neurons In Zebrafishmentioning

confidence: 99%

Generation of Multiple Classes of V0 Neurons in Zebrafish Spinal Cord: Progenitor Heterogeneity and Temporal Control of Neuronal Diversity

Satou

Kimura²,

Higashijima³

2012

J. Neurosci.

147

207

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The developing spinal cord is subdivided into distinct progenitor domains, each of which gives rise to different types of neurons. However, the developmental mechanisms responsible for generating neuronal diversity within a domain are not well understood. Here, we have studied zebrafish V0 neurons, those that derive from the p0 progenitor domain, to address this question. We find that all V0 neurons have commissural axons, but they can be divided into excitatory and inhibitory classes. V0 excitatory neurons (V0-e) can be further categorized into three groups based on their axonal trajectories; V0-eA (ascending), V0-eB (bifurcating), and V0-eD (descending) neurons. By using time-lapse imaging of p0 progenitors and their progeny, we show that inhibitory and excitatory neurons are produced from different progenitors. We also demonstrate that V0-eA neurons are produced from distinct progenitors, while V0-eB and V0-eD neurons are produced from common progenitors. We then use birth-date analysis to reveal that V0-eA, V0-eB, and V0-eD neurons arise in this order. By perturbing Notch signaling and accelerating neuronal differentiation, we predictably alter the generation of early born V0-e neurons at the expense of later born ones. These results suggest that multiple types of V0 neurons are produced by two distinct mechanisms; from heterogeneous p0 progenitors and from the same p0 progenitor, but in a time-dependent manner.

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“…En1-Cre/ Tau-loxP-STOP-loxP-mEGFP-IRES-INLacZ express, upon Cre recombination, a bicistronic transcript encoding a modified β-galactosidase (β-gal) with a nuclear localization signal (nls) and a modified membrane-bound enhanced green fluorescent protein (mEGFP) designed to best depict neurite morphology and surfaces (DePaola et al, 2003). In these (Liu et al, 2003;Zagoraiou et al, 2009). …”

Section: Animalsmentioning

confidence: 99%

“…VAChT, which packages acetylcholine into synaptic vesicles for exocytosis, is an effective synaptic marker of motor axon synapses on RCs but there are additional sources of VAChT-IR synapses in the ventral horn Mentis et al, 2005;Miles et al, 2007;Zagoraiou et al, 2009). Some VAChT-IR contacts were observed on V1-IaIN dendrites at P20 ; therefore, we investigated their origins and the possibility that this input, similar to the VGLUT1 input on RCs, was initially stronger in neonatal V1-IaINs and then deselected ( Fig.…”

Section: Vacht-ir Bouton Density On V1-iains Is Lower Than On Rcs Of mentioning

confidence: 99%

Target selection of proprioceptive and motor axon synapses on neonatal V1‐derived Ia inhibitory interneurons and Renshaw cells

Siembab

Smith

Zagoraiou

et al. 2010

J of Comparative Neurology

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The diversity of premotor interneurons in the mammalian spinal cord is generated from a few phylogenetically conserved embryonic classes of interneurons (V0, V1, V2, V3). Their mechanisms of diversification remain unresolved, although these are clearly important to understand motor circuit assembly in the spinal cord. Some Ia inhibitory interneurons (IaINs) and all Renshaw cells (RCs) derive from embryonic V1 interneurons; however, in adult they display distinct functional properties and synaptic inputs, for example proprioceptive inputs preferentially target IaINs, while motor axons target RCs. Previously, we found that both inputs converge on RCs in neonates, raising the possibility that proprioceptive (VGLUT1-positive) and motor axon synapses (VAChT-positive) initially target several different V1 interneurons populations and then become selected or deselected postnatally. Alternatively, specific inputs might precisely connect only with predefined groups of V1 interneurons. To test these hypotheses we analyzed synaptic development on V1-derived IaINs and compared them to RCs of the same age and spinal cord levels. V1-interneurons were labeled using genetically encoded lineage markers in mice. The results show that although neonatal V1-derived IaINs and RCs are competent to receive proprioceptive synapses, these synapses preferentially target the proximal somato-dendritic regions of IaINs and postnatally proliferate on IaINs, but not on RCs. In contrast, cholinergic synapses on RCs are specifically derived from motor axons, while on IaINs they originate from Pitx2 V0c interneurons. Thus, motor, proprioceptive, and even some interneuron inputs are biased toward specific subtypes of V1-interneurons. Postnatal strengthening of these inputs is later superimposed on this initial preferential targeting. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe development of spinal cord local interneuronal circuits is currently poorly understood. Recent work has defined a relatively small number of cardinal interneurons in embryo that generates the much larger diversity of adult interneurons (Goulding, 2009). In the ventral horn just four embryonic subgroups (V0, V1, V2, V3) generate most adult premotor interneurons by diversification mechanisms that are currently largely unknown. Each group displays common properties that generally include origins from one type of progenitor cell (p0, p1, p2, p3), the direction taken by the primary axon, their cell migration and final location in the ventral horn with relation to motor pools, and their neurotransmitter phenotype. For example, V1 interneurons have common origins in the p1 progenitor area and are characterized by expression of the engrailed-1 (En-1) transcription factor. They migrate ventrolaterally, positioning themselves adjacent to motor pools, extend ascending axons that target ipsilateral motoneurons, and have an inhibitory phenotype (Matise and Joyner, 1997; Ericsson et al., 1997;Saueressig et al., 1999;Sapir et al., 2004;Alvarez et a...

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A Cluster of Cholinergic Premotor Interneurons Modulates Mouse Locomotor Activity

Cited by 381 publications

References 97 publications

Competition with Primary Sensory Afferents Drives Remodeling of Corticospinal Axons in Mature Spinal Motor Circuits

Competition with Primary Sensory Afferents Drives Remodeling of Corticospinal Axons in Mature Spinal Motor Circuits

Generation of Multiple Classes of V0 Neurons in Zebrafish Spinal Cord: Progenitor Heterogeneity and Temporal Control of Neuronal Diversity

Target selection of proprioceptive and motor axon synapses on neonatal V1‐derived Ia inhibitory interneurons and Renshaw cells

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