Glutamatergic neurons of the gigantocellular reticular nucleus shape locomotor pattern and rhythm in the freely behaving mouse

Lemieux, Maxime; Bretzner, Frédéric

doi:10.1371/journal.pbio.2003880

Cited by 33 publications

(52 citation statements)

References 66 publications

(84 reference statements)

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“…MLR glutamatergic neurons control locomotor speed from basal vertebrates to mammals (e.g., lamprey: Sirota et al, 2000 ; Brocard and Dubuc, 2003 ; Le Ray et al, 2003 ; salamanders: Cabelguen et al, 2003 ; mice: Lee et al, 2014 ; Roseberry et al, 2016 ; Capelli et al, 2017 ; Josset et al, 2018 ; Caggiano et al, 2018 ). A key function of the MLR is to elicit forward symmetrical locomotion by sending bilateral glutamatergic inputs to reticulospinal neurons that project to the spinal central pattern generator for locomotion (cat: Orlovski, 1970 ; lamprey: Buchanan and Grillner, 1987 ; Brocard et al, 2010 ; zebrafish: Kinkhabwala et al, 2011 ; Kimura et al, 2013 ; salamander: Ryczko et al, 2016a ; mouse: Hägglund et al, 2010 ; Bretzner and Brownstone, 2013 ; Capelli et al, 2017 ; Lemieux and Bretzner, 2019 ; for review Grillner and El Manira, 2020 ). In mammals, the MLR sends descending projections to the gigantocellular nucleus (Gi), gigantocellular reticular nucleus, alpha part (GiA), gigantocellular reticular nucleus, ventral part (GiV), lateral paragigantocellular nucleus (LPGi), caudal raphe nuclei, intermediate reticular nucleus and medullary reticular nucleus, which all contain reticulospinal neurons (cat: Edwards, 1975 ; Steeves and Jordan, 1984 ; mouse: Bretzner and Brownstone, 2013 ; Capelli et al, 2017 ; Caggiano et al, 2018 ; for review Ryczko and Dubuc, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Freely Behaving Mice Can Brake and Turn During Optogenetic Stimulation of the Mesencephalic Locomotor Region

Zouwen

Boutin

Fougère

et al. 2021

Front. Neural Circuits

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A key function of the mesencephalic locomotor region (MLR) is to control the speed of forward symmetrical locomotor movements. However, the ability of freely moving mammals to integrate environmental cues to brake and turn during MLR stimulation is poorly documented. Here, we investigated whether freely behaving mice could brake or turn, based on environmental cues during MLR stimulation. We photostimulated the cuneiform nucleus (part of the MLR) in mice expressing channelrhodopsin in Vglut2-positive neurons in a Cre-dependent manner (Vglut2-ChR2-EYFP) using optogenetics. We detected locomotor movements using deep learning. We used patch-clamp recordings to validate the functional expression of channelrhodopsin and neuroanatomy to visualize the stimulation sites. In the linear corridor, gait diagram and limb kinematics were similar during spontaneous and optogenetic-evoked locomotion. In the open-field arena, optogenetic stimulation of the MLR evoked locomotion, and increasing laser power increased locomotor speed. Mice could brake and make sharp turns (~90°) when approaching a corner during MLR stimulation in the open-field arena. The speed during the turn was scaled with the speed before the turn, and with the turn angle. Patch-clamp recordings in Vglut2-ChR2-EYFP mice show that blue light evoked short-latency spiking in MLR neurons. Our results strengthen the idea that different brainstem neurons convey braking/turning and MLR speed commands in mammals. Our study also shows that Vglut2-positive neurons of the cuneiform nucleus are a relevant target to increase locomotor activity without impeding the ability to brake and turn when approaching obstacles, thus ensuring smooth and adaptable navigation. Our observations may have clinical relevance since cuneiform nucleus stimulation is increasingly considered to improve locomotion function in pathological states such as Parkinson’s disease, spinal cord injury, or stroke.

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Section: Introductionmentioning

confidence: 99%

Freely Behaving Mice Can Brake and Turn During Optogenetic Stimulation of the Mesencephalic Locomotor Region

Zouwen

Boutin

Fougère

et al. 2021

Front. Neural Circuits

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“…the same neurons that induce turning when activated unilaterally [29, 30, 31] (see also [57]). Locomotor pauses and rhythm resetting were also reported when photoactivating Vglut2-positive neurons in the Gi in mice [60]. At the MLR level, local GABAergic neurons could stop locomotion likely by inhibiting MLR glutamatergic neurons [9, 12].…”

Section: Discussionmentioning

confidence: 99%

“…The Ai32 mouse [31] has been widely used to activate cells expressing the Cre-recombinase using optogenetics (e.g. [33, 34]). When exposed to Cre-recombinase, the floxed STOP cassette is removed, and this results in the expression of the ChR2(H134R)-EYFP fusion protein under control of CAG promoter.…”

Section: Supplementary Materialsmentioning

confidence: 99%

Freely behaving mice can brake and turn during optogenetic stimulation of the Mesencephalic Locomotor Region

Zouwen

Boutin

Fougère

et al. 2020

Preprint

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Background: Stimulation of the Mesencephalic Locomotor Region (MLR) is increasingly considered as a target to improve locomotor function in Parkinson's disease and spinal cord injury. A key function of the MLR is to control the speed of forward symmetrical locomotor movements. However, the ability of freely moving mammals to integrate environmental cues to brake and turn during MLR stimulation is poorly documented. Objective/hypothesis: We investigated whether freely behaving mice could brake or turn based on environmental cues during MLR stimulation. Methods: We stimulated the cuneiform nucleus in mice expressing channelrhodopsin in Vglut2-positive neurons in a Cre-dependent manner (Vglut2-ChR2-EYFP) using optogenetics. We detected locomotor movements using deep learning. We used patch-clamp recordings to validate the functional expression of channelrhodopsin and neuroanatomy to visualize the stimulation sites. Results: Optogenetic stimulation of the MLR evoked locomotion and increasing laser power increased locomotor speed. Gait diagram and limb kinematics were similar during spontaneous and optogenetic-evoked locomotion. Mice could brake and make sharp turns (~90⁰) when approaching a corner during MLR stimulation in an open-field arena. The speed during the turn was scaled with the speed before the turn, and with the turning angle. In a reporter mouse, many Vglut2-ZsGreen neurons were immunopositive for glutamate in the MLR. Patch-clamp recordings in Vglut2-ChR2-EYFP mice show that blue light evoked short latency spiking in MLR neurons. Conclusion: MLR glutamatergic neurons are a relevant target to improve locomotor activity without impeding the ability to brake and turn when approaching an obstacle, thus ensuring smooth and adaptable navigation.

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“…Promoters for either the vesicular glutamate transporter 2 (vGluT2), or Chx10 have been used to drive cre recombinase expression for opto-or chemo-genetic experiments. Using these techniques, it has become clear that excitatory GRN neurons can modulate locomotor activity (Lemieux and Bretzner, 2019), that bilateral activation of Chx10 RF neurons can stop locomotion (Bouvier et al, 2015), and that their unilateral stimulation can lead to turning (Cregg et al, 2020) or neck movements (Capelli et al, 2017) or both (Usseglio et al, 2020). But glutamatergic neurons in this region are also involved in sleep atonia (Saper et al, 2010), suggesting that results from photoactivation experiments could be skewed by the subpopulation(s) of neurons activated.…”

Section: Introductionmentioning

confidence: 99%

Local brainstem circuits contribute to reticulospinal output in the mouse

Chopek

Zhang

Brownstone

2021

Preprint

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Glutamatergic reticulospinal neurons in the gigantocellular reticular nucleus (GRN) of the medullary reticular formation can function as command neurons, transmitting motor commands to spinal cord circuits. Recent advances in our understanding of this neuron-dense region have been facilitated by the discovery of expression of the transcriptional regulator, Chx10, in excitatory reticulospinal neurons. Here, we address the capacity of local circuitry in the GRN to contribute to reticulospinal output. We define two sub-populations of Chx10-expressing neurons in this region, based on distinct electrophysiological properties and somata size (small and large), and show that these correspond to local interneurons and reticulospinal neurons, respectively. Using focal release of caged-glutamate combined with patch clamp recordings, we demonstrated that Chx10 neurons form microcircuits in which the Chx10 interneurons project to and facilitate the firing of Chx10 reticulospinal neurons. We discuss the implications of these microcircuits in terms of movement selection.SIGNIFICANCE STATEMENTReticulospinal neurons in the medullary reticular formation play a key role in movement. The transcriptional regulator Chx10 defines a population of glutamatergic neurons in this region, a proportion of which have been shown to be involved in stopping, steering, and modulating locomotion. While it has been shown that these neurons integrate descending inputs, we asked whether local processing also ultimately contributes to reticulospinal outputs. Here, we define Chx10-expressing medullary reticular formation interneurons and reticulospinal neurons, and demonstrate how the former modulate the output of the latter. The results shed light on the internal organization and microcircuit formation of reticular formation neurons.

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Glutamatergic neurons of the gigantocellular reticular nucleus shape locomotor pattern and rhythm in the freely behaving mouse

Cited by 33 publications

References 66 publications

Freely Behaving Mice Can Brake and Turn During Optogenetic Stimulation of the Mesencephalic Locomotor Region

Freely Behaving Mice Can Brake and Turn During Optogenetic Stimulation of the Mesencephalic Locomotor Region

Freely behaving mice can brake and turn during optogenetic stimulation of the Mesencephalic Locomotor Region

Local brainstem circuits contribute to reticulospinal output in the mouse

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