Hélène Bras’s research while affiliated with Institut de Neurosciences de la Timone and other places

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Publications (48)


Knockdown of calpain1 in lumbar motoneurons reduces spasticity after spinal cord injury in adult rats
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January 2024

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56 Reads

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3 Citations

Molecular Therapy

Marjorie Kerzonkuf

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Hélène Bras
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Calpain role in the pathophysiology of spasticity after spinal cord injury

January 2022

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16 Reads

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1 Citation

Spasticity is a highly impairing condition following spinal cord injury (SCI) that develops in more than 60% of patients as early as one-year postinjury. To date, pharmacological therapy shows limited effectiveness and various systemic side effects. Animal models allow carrying out in-depth investigations on pathophysiological mechanisms of spasticity after SCI to identify innovative and efficacious therapeutic strategies. So far, several maladaptive changes in sublesional motoneurons have been reported, causing an increased excitation (hyperexcitability) and a reduced inhibition (disinhibition) in the spinal cord. We demonstrated that calpains, a family of calcium-dependent proteases, have an upstream role in promoting the excitatory/inhibitory imbalance of spinal motoneurons that leads to spasticity after SCI. On the one hand, calpains cleave voltage-gated sodium channels Nav1.6 up-regulating the sodium persistent inward current(INaP), which evokes huge plateau potentials with self-sustained spiking, lastly causing spinal hyperexcitability contributing to spasticity. On the other hand, calpains down-regulate the potassium-chloride cotransporter KCC2 on motoneuron membranes, depolarizing the chloride equilibrium potential (ECl⁻) and inducing spinal disinhibition also involved in the onset of spasticity. Therefore, calpain inhibition might represent an effective antispastic therapy targeting the main upstream molecule accounting for multiple mechanisms of spasticity, instead of singularly acting on downstream players. Furthermore, this therapeutic strategy can be adopted not only to prevent spasticity after SCI but also to counteract neurological disorders where calpains have a critical role.


Conservation of locomotion-induced oculomotor activity through evolution in mammals

December 2021

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85 Reads

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13 Citations

Current Biology

Efference copies are neural replicas of motor outputs used to anticipate the sensory consequences of a self-generated motor action or to coordinate neural networks involved in distinct motor behaviors.¹ An established example of this motor-to-motor coupling is the efference copy of the propulsive motor command, which supplements classical visuo-vestibular reflexes to ensure gaze stabilization during amphibian larval locomotion.² Such feedforward replica of spinal pattern-generating circuits produces a spino-extraocular motor coupled activity that evokes eye movements, spatiotemporally coordinated to tail undulation independently of any sensory signal.³,⁴ Exploiting the developmental stages of the frog,¹ studies in metamorphing Xenopus demonstrated the persistence of this spino-extraocular motor command in adults and its developmental adaptation to tetrapodal locomotion.⁵,⁶ Here, we demonstrate for the first time the existence of a comparable locomotor-to-ocular motor coupling in the mouse. In neonates, ex vivo nerve recordings of brainstem-spinal cord preparations reveal a spino-extraocular motor coupled activity similar to the one described in Xenopus. In adult mice, trans-synaptic rabies virus injections in lateral rectus eye muscle label cervical spinal cord neurons closely connected to abducens motor neurons. Finally, treadmill-elicited locomotion in decerebrated preparations⁷ evokes rhythmic eye movements in synchrony with the limb gait pattern. Overall, our data are evidence for the conservation of locomotor-induced eye movements in vertebrate lineages. Thus, in mammals as in amphibians, CPG-efference copy feedforward signals might interact with sensory feedback to ensure efficient gaze control during locomotion.


Neurochemical features of SuML neurons innervating the dorsal dentate gyrus (DG) characterized by simultaneous labeling for the rabies virus (RV) retrograde tracer (green), VGAT mRNA (red) and VGLUT2 mRNA (blue) in a coronal section. a–c Coronal sections of a VGLUT2-cre mouse processed for immunodetection of the RV, 38 h after its injection in supragranular and granule cell layers (G) of the dorsal DG. a Photomicrograph showing the track of the micropipette and site of injection (arrows). Sections at two rostro (b)–caudal (c) levels of the SuM showing retrograde-labeled neurons located within the lateral part of the SuM (SuML). Insert in b, c at higher magnification, Golgi-like labeling of the retrograde-labeled neurons. d–l All confocal images were obtained from sequential acquisition of separate wavelength channels, corresponding to the different fluorophores used for the triple labeling, from a single optical slice. This optical slice was acquired in the supramammillary region of the hypothalamus from a coronal section of a VGLUT2-cre mouse that received an injection of RV in supragranular layer of the dorsal DG (a). d Image obtained from the merge of the two confocal images corresponding, respectively, to the labeling of VGLUT2 (blue) and VGAT (red) mRNAs. Many neurons expressing both VGLUT2 and VGAT mRNAs (arrow) were observed in the lateral region of the supramammillary nucleus (SuML). They were located almost exclusively above and around the mammillary tract (mt). Neurons expressing VGLUT2 mRNA only (blue) were observed mainly in the most medial part of the SuM (SuMM) and were numerous in the mammillary nucleus (M). Few neurons containing VGAT mRNA only (red, arrowheads) were distributed in the SuML and SUMM. e Confocal image corresponding to the immunohistochemical labeling of the RV (green) showing that all RV containing neurons in the SuM were located in the region of the SuML surrounded the mt. f Merge of d, e. g–i Higher magnification of region outlined in d–f showing that all these SuML neurons projecting to the DG, labeled for the RV (h, arrows), co-expressed VGLUT2 and VGAT mRNAs (g, i, arrows). j–l RV labeled neuron (k, arrow) co-expressed VGAT mRNA (j, arrow) and VGLUT2 mRNA (l, arrow). Scale bars a 50 μm; b, c, 500 μm; insert, 50 μm; d–f 100 μm; g–l 10 μm
Neurochemical features of axon terminals from SuML neurons innervating the dorsal DG characterized by simultaneous immunohistochemical labeling for the AAV-EYFP anterograde tracer (green), GAD65 or VGAT (red) and VGLUT2 (blue) in coronal sections. a Diagram illustrating the bilateral injections of the viral vector AAV-DIO-ChR2-EYFP within the lateral region of the SuM. Images from a coronal section showing endogenous fluorescence of EYFP observed in the cell body and proximal dendrites of a transfected neuron located within the SuML as well as fibers and axon terminals within the supragranular (arrowheads) and granular layer (G) of the DG. b Image obtained from a single optical slice showing labeling for EYFP (green), GAD65 (red) and VGLUT2 (blue) in the hippocampus. Fibers labeled with the anterograde tracer AAV-DIO-ChR2-EYFP injected within the SUM as illustrate in a were exclusively located in the supragranular (arrowheads) and granule cell (G) layers as well as the CA2 region of the hippocampus. c, d Images corresponding to a maximum intensity z-projection of a stack of 8 optical slices spaced at 370 nm, showing labeling for EYFP (green), VGLUT2 (blue) and GAD65 (c, red) or VGAT (d, red) in the dorsal DG. Axon terminals and fibers, from neurons in the SuML, labeled for the EYFP anterograde tracer (green) were located mainly in the supragranular layer but also in the granule cell layer. Numerous GAD65- (c) or VGAT- (d) containing terminals were present in the molecular layer (M) and granule cell layer (G) of the dorsal DG. VGLUT2-containing terminals were mainly located in the supragranular layer (SG) but were also observed in G. e–l Images of the three different fluorophores used for the triple labeling, obtained by sequential acquisition of separate wavelength channels from a single optical slice, in the SG of the DG demonstrated that many if not all axon terminals labeled for EYFP (b, i, green, arrowheads) contained GAD65 (g, red arrowheads), VGAT (k, red, arrowheads) but also VGLUT2 (f, j blue, arrowheads). h Merge of e–g. l Merge of i–k. Scale bars a, b, 200 μm; c, d, 25 μm and e–l, 3 μm
Pre-embedding immunolabeling for EYFP anterograde tracer in ultrathin coronal sections of the dorsal DG. a–i In the dorsal DG, numerous axon terminals were labeled for EYFP, revealed by electron-dense peroxidase 3.3′-diaminobenzidine tetrahydrochloride product. a A labeled axon terminal (At) making two synaptic contacts (arrow and arrowhead) on unlabeled somata of 2 presumed granule cells (Gr). b Higher magnification of the At illustrated in a showing that these two synaptic contacts were different: one displayed a relatively thin post-synaptic density (arrowhead) characteristic of symmetric synapses on the soma of one Gr; the other one displayed a thick post-synaptic density (arrow) characteristic of asymmetric synapses on the soma of another Gr. c Labeled axon terminal established a synaptic contact displaying a thick synaptic density on a unlabeled dendritic process (D) that differed from the synaptic contact formed by the unlabeled At (arrow). The synaptic contacts illustrated in d–i displayed relatively thin post-synaptic densities (arrowheads) on the soma (d–f, i) or dendrites (g, h) of unlabeled Gr. m mitochondria, Nu nucleus. Scale bar a–i 0.5 μm
Selective stimulation of axonal terminals from SuML neurons innervating the dorsal DG, performed in hippocampal slices of VGLUT2-ChR2-EYFP mice, induced co-release of GABA and glutamate on DG granule cells. a Diagram illustrating the site of the bilateral injections of AAV-DIO-ChR2-EYFP in VGLUT2-cre mice, of light stimulations and of the recorded patch clamp electrode in the DG of the VGLUT2-ChR2-EYFP mice. b Montage illustrating the position within the dentate granule cell layer of the biocytin-filled cells reconstructed after patch clamp recordings and EYFP-labeled terminals originating from SuML neurons. d, f, h, j, n Examples of light induced PSCs recorded in DG cells illustrated in c, e, g, i, m. d Light induced post-synaptic currents (PSCs) recorded at different holding potentials in DG neuron; short black bar above the upper trace shows the time moment and duration of light stimulus. Note at − 70 to − 50 mV holdings the PSCs had negative-going direction (inward) currents. They were positive-going (outward) at − 10 mV and 0 mV but displayed both negative- and positive-going phases when the neuron membrane was clamped at − 30 mV. This suggests that light stimulation induces two types of postsynaptic currents. Indeed, the application of glutamate receptor blockers NBQX and AP5 (f, red traces) inhibited inward (f, negative going) component of PSCs recorded at negative holding potentials (Vh), but had only small effect on outward component (positive going) recorded at positive Vh. Inversely, the outward component of light induced PSCs was sensitive to GABA A receptor inhibitor gabazine (h, green vs blue traces). This suggests that these PSCs are generated by simultaneous activation of glutamate and GABA post-synaptic receptors. Interestingly at − 50 mV holding, PSC was larger without gabazine (h, blue versus green trace), probably because GABA-mediated current hyperpolarizes the membrane potential increasing thus the driving force for the glutamatergic current. In voltage-clamp condition such an interaction is possible if the pool of postsynaptic GABA Rs is close to the postsynaptic Glu R pool. k, l Effect of glutamate and GABA A receptors blockers on the peak amplitude of light pulse evoked PSC recorded at − 70 mV (red circles) and 10 mV (green circles) holding potentials. For each Vh the peak amplitudes of first 10 PSCs were averaged and used then as a normalization factor for all peak amplitude recorded at given potential. Each point and error bars corresponds the mean ± SD of PSC normalized amplitude recorded in 5 DG neurons. In regular ACSF the repetitive light pulses (5 ms, 0.05 Hz) evoked PCS of relatively stable amplitude (1.00 ± 0.26, L left-hand side red trace-an example of averaged response of one neuron). The application of glutamate receptor blockers (10 µM NBQX + 40 µM D-AP5) reduced the peak amplitude by 84% (0.16 ± 0.15, p < 0.01, n = 5, paired Wilcoxon test). The remaining response was seen in 4 from 5 neurons and is probably due to GABA A mediated current because at − 70 mV the driving force for chloride driven currents is close to but not zero (l, red trance in the middle), therefore, in case of GABA massive release some inward current is still possible. Indeed a switch to Vh = 10 mV revealed a huge PSC response to light stimulation (l, green trace in the middle) whose amplitude was stable (1.00 ± 0.20) but progressively reduced to 12% (0.12 ± 0.16, p < 0.01, n = 5, paired Wilcoxon test) by the addition of 10 µM bicuculline to the ACSF already containing GluR blockers (l, green trace at left). In 3 from 5 neurons, 6 min-lasting bicuculline application completely abolished response to light pulses. In two neurons the remaining current is probably due to the competitive character of bicuculline induced inhibition, i.e. in case of high GABA release 10 µM of bicuculline may be not sufficient to all receptors inhibition. m, n The identical light stimulation (5 ms, 10%, 50% 90% max power LED) of fibers and axon terminals expressing EYFP on slices of control VGLUT2-EYFP mice (n = 3) did not evoke any response in the recorded granule cells (n = 5) confirming that ChR2 activation is required to obtain the PSCs. Scale bar c, e, g, i, m, 20 μm
Effects of light stimulation of axonal terminals from SuML neurons innervating the dorsal DG on DG LFP, EEG recordings and behavior of VGLUT2-ChR2-EYFP mice during WK, SWS and PS. a, e, i Examples of raw recording for EMG, LFP recorded in the DG and parietal cortex EEG as well as associated time–frequency analysis of LFP and EEG in a VGLUT2-ChR2-EYFP mouse during WK (a), SWS (e) and PS (i). The blue bar represents the optogenetic stimulation period (20 Hz with pulses of 10 ms for 10 s). b, c, f, g, j, k LFP power spectra between 0 and 18 Hz and 60–100 Hz in VGLUT2-ChR2-EYFP mouse before and during light stimulation (20 Hz 10 s, pulses of 10 ms, during 4 h) during WK (b, c), SWS (f, g) and PS (j, k). An effect was clearly visible on the LFP in all vigilance states. The stimulation induced a slight increase in the theta power during WK (a, b) and a major increase in theta power and frequency during PS (i, j) as well as a clear reduction of slow wave oscillation during SWS (e, f). The stimulation during WK and PS also increased the power of gamma (c, k). Light stimulation during WK increased locomotor activity reflected by an increase of EMG signal in VGLUT2-ChR2-EYFP mice (a, d, blue trace) as compared to control VGLUT2-EYFP mice (d, gray trace). h Light stimulation during SWS induced awakening reflected by a significant increase of the awakening percentage after stimulation in most VGLUT2-ChR2-EYFP mice (range 30–100%) as compared to that observed in control VGLUT2-EYFP mice (range 0–30%). l In contrast no significant difference in the percentage of awakening was observed between VGLUT2-CHR2-EYFP and control VGLUT2-EYFP mice when stimulation was performed during PS

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GABA-glutamate supramammillary neurons control theta and gamma oscillations in the dentate gyrus during paradoxical (REM) sleep

December 2020

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339 Reads

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33 Citations

Brain Structure and Function

Several studies suggest that neurons from the lateral region of the SuM (SuML) innervating the dorsal dentate gyrus (DG) display a dual GABAergic and glutamatergic transmission and are specifically activated during paradoxical (REM) sleep (PS). The objective of the present study is to characterize the anatomical, neurochemical and electrophysiological properties of the SuML-DG projection neurons and to determine how they control DG oscillations and neuronal activation during PS and other vigilance states. For this purpose, we combine structural connectivity techniques using neurotropic viral vectors (rabies virus, AAV), neurochemical anatomy (immunohistochemistry, in situ hybridization) and imaging (light, electron and confocal microscopy) with in vitro (patch clamp) and in vivo (LFP, EEG) optogenetic and electrophysiological recordings performed in transgenic VGLUT2-cre male mice. At the cellular level, we show that the SuML-DG neurons co-release GABA and glutamate on dentate granule cells and increase the activity of a subset of DG granule cells. At the network level, we show that activation of the SuML-DG pathway increases theta power and frequency during PS as well as gamma power during PS and waking in the DG. At the behavioral level, we show that the activation of this pathway does not change animal behavior during PS, induces awakening during slow wave sleep and increases motor activity during waking. These results suggest that the SuML-DG pathway is capable of supporting the increase of theta and gamma power in the DG observed during PS and plays an important modulatory role of DG network activity during this state.


Differential effects of spinal cord transection on glycinergic and GABAergic synaptic signaling in sub-lesional lumbar motoneurons

July 2020

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27 Reads

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5 Citations

Journal of Chemical Neuroanatomy

This review takes stock on the impact of complete spinal cord transection (SCT) on the plasticity of inhibitory synaptic transmission on sub-lesional lumbar motoneurons (MNs), differentiating between studies in neonate and adult rats. After neonatal SCT, normal maturational up-regulation of glycine receptors was observed. On the other hand, the developmental downregulation of the GABA A receptors, as well as the up-regulation of the co-transporter KCC2 were prevented, but not the normal decrease of NKCC1. In adult SCT rats, glycinergic synaptic transmission, which is the major contributor to spinal MNs inhibition in adulthood, had normal control levels 2 months post-injury. On the other hand, the GABAergic transmission was altered through an up-regulation of the pre-signaling levels and a down-regulation in the density of post synaptic receptors. KCC2 membrane expression was down-regulated at all post-injury times tested (24h to 4 months), thereby depolarizing the Cl− equilibrium potential and reducing the strength of postsynaptic inhibition. The preservation of glycinergic pre- and post signaling, is probably a key factor in the success of locomotor rehabilitation programs in adult SCT rats. However, these data highlight the need to develop strategies to restore KCC2 levels in lumbar MNs, to stabilize the excitation/inhibition balance, which is essential to the effective control of skeletal muscle activity.


Figure 2: Longitudinal quantitative immunohistological study of the expression of GlyR and GABAAR at the membrane of tibialis anterior (TA) and gastrocnemius (GS) MNs in intact control and SCT adult rats. (A) double labeling of GlyR (red) and GABAAR (green) on TA and GS MNs in intact rats, and in SCT rats 3 weeks, 8 weeks and 16 weeks post injury, and 3 weeks post injury after treatment with MP. (B) Quantitative study of the membrane
Figure 3: Longitudinal electrophysiological study of the development of spasticity after SCT. (A) Mean relative amplitudes of the H reflex at frequencies of 0.5, 1, 2 and 5 Hz in intact control rats and in SCT rats at 3 weeks (red), 8 weeks (green) and 12 weeks (blue) after SCT and 3 weeks post-SCT, with early treatment with methylprednisolone (MP; yellow). The data of all experiments (dots) are represented together with the one-phase exponential decay fit of these data. Different parameters of the electromyograms were analyzed: (B) Hmax/Mmax at 0.2 Hz, (C and D) H reflex activation threshold and latencies, (E) amplitude of M wave
Alteration of glycinergic receptor expression in lumbar spinal motoneurons is involved in the mechanisms underlying spasticity after spinal cord injury

April 2020

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115 Reads

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11 Citations

Journal of Chemical Neuroanatomy

Spasticity is a disabling motor disorder affecting 70% of people with brain and spinal cord injury. The rate-dependent depression (RDD) of the H reflex is the only electrophysiological measurement correlated with the degree of spasticity assessed clinically in spastic patients. Several lines of evidence suggest that the mechanism underlying the H reflex RDD depends on the strength of synaptic inhibition through GABAA (GABAAR) and glycine receptors (GlyR). In adult rats with spinal cord transection (SCT), we studied the time course of the expression of GABAAR and GlyR at the membrane of retrogradely identified Gastrocnemius and Tibialis anterior motoneurons (MNs) 3, 8 and 16 weeks after injury, and measured the RDD of the H reflex at similar post lesion times. Three weeks after SCT, a significant decrease in the expression of GABAA and GlyR was observed compared to intact rats, and the H-reflex RDD was much less pronounced than in controls. Eight weeks after SCT, GlyR values returned to normal. Simultaneously, we observed a tendency to recover normal RDD of the H reflex at higher frequencies. We tested whether an anti-inflammatory treatment using methylprednisolone performed immediately after SCT could prevent alterations in GABAA/glycine receptors and/or the development of spasticity observed 3 weeks after injury. This treatment restored control levels of GlyR but not the expression of GABAAR, and it completely prevented the attenuation of RDD. These data strongly suggest that alteration of glycinergic inhibition of lumbar MNs is involved in the mechanisms underlying spasticity after SCI.


Electrophysiological and sensorimotor injuries in lead intoxicated rats are restored by curcumin I

Journal of Systems and Integrative Neuroscience

Lead (Pb) is a heavy metal with various adverse effects on human health including mental health (Liu et al., 2017). Is known to cause several damages in the central and peripheral nervous system, which could be manifested by several neurophysiological and behavioral outcomes (Tchounwou et al., 2012). The present study was focused on: (i). the evaluation of the effect of prenatal exposure of rats to lead (3g/l) from neonatal to adult age on the motor/sensory performances, excitability of spinal cord during development. ii). characterization of the neuroprotective potentials of exposure to Curcumin I (175mg / kg BW) upon Pb induced neurotoxicity by means of a behavioral and electrophysiological approaches. Using electrophysiological trial, grasping, cliff avoidance tests and Catwalk dispositive we evaluated, respectively, the impairment of the excitability of spinal neuronal networks implicated in the control of locomotion and the sensorimotor functions in neonatal and young rats exposed prenatally to lead. Our finding showed primarily, an increase in spontaneous and fictive spinal activities in newborn rats at age P1 and P2, secondly, an impairment of locomotor gait from puppy age and until young age. These abnormalities were strongly attenuated by Curcumin I co-administration.


The GABA-Glutamate supramammillary–dorsal Dentate Gyrus pathway controls theta and gamma oscillations in the DG during paradoxical sleep

March 2019

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485 Reads

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4 Citations

Several studies suggest that neurons from the lateral region of the SuM (SuML) innervating the dorsal dentate gyrus (DG) display a dual GABAergic and glutamatergic transmission and are specifically activated during paradoxical (REM) sleep (PS). The objective of the present study is to fully characterize the anatomical, neurochemical and electrophysiological properties of the SuML-DG projection neurons and to determine how they control DG oscillations and neuronal activation during PS and other vigilance states. For this purpose, we combine structural connectivity techniques using neurotropic viral vectors (rabies virus, AAV), neurochemical anatomy (immunohistochemistry, in situ hybridization) and imaging (light, electron and confocal microscopy) with in vitro (patch clamp) and in vivo (LFP, EEG) optogenetic and electrophysiological recordings performed in transgenic VGLUT2-cre male mice. At the cellular level, we show that the SuML-DG neurons co-release GABA and glutamate on dentate granule cells and increase the activity of a subset of DG granule cells. At the network level, we show that activation of the SuML-DG pathway increases theta power and frequency during PS as well as gamma power during PS and waking in the DG. At the behavioral level, we show that the activation of this pathway does not change animal behavior during PS, induces awakening during slow wave sleep and increases motor activity during waking. These results suggest that the SuML-DG pathway is capable of supporting the increase of theta and gamma power in the DG observed during PS and plays an important modulatory role of DG network activity during this state. Significant statement An increase of theta and gamma power in the dentate gyrus (DG) is an hallmark of paradoxical (REM) sleep (PS) and is suggested to promote learning and memory consolidation by synchronizing hippocampal networks and increasing its outputs to cortical targets. However the neuronal networks involved in such control of DG activity during PS are poorly understood. The present study identifies a population of GABA/Glutamate neurons in the lateral supramammllary nucleus (SuML) innervating the DG that could support such control during PS. Indeed, we show that activation of these SuML-DG projections increase theta power and frequency as well as gamma power in the DG specifically during PS and modulate activity of a subset of DG granule cells.


Figure 3. Illustration of 3D kinematics during treadmill locomotion at P65 and footprints in controls and rats that underwent sensorimotor restriction (SMR). A,C. Photographs of the three phases (beginning of the swing, maximal height of the swing-MH swing-and beginning of the stance) to show hind limb joint angles in representative control and SMR rats, respectively. B,D. Stick reconstruction of the right hind limb movements in the lateral plan during three representative swings in the same control and SMR rats as in A and C. E-G. Plots of the main changes in kinematic variables and joint angles induced by SMR during treadmill locomotion. The duration of the swing was longer in SMR rats than in control rats at P30 (t 5 5.54; d.f. 5 20; P < 0.0001) and P65 (t 5 2.69; d.f. 5 21; P < 0.01). At P30, the normalized lengths of the swing (E: t 5 2.99; d.f. 5 20; P < 0.01) and MH swing (F: t 5 4.26; d.f. 5 20; P < 0.001) phases were shorter in SMR rats compared with control rats while only that of the MH swing was still shorter after SMR at P65 (F: t 5 2.79; d.f. 5 21; P < 0.01). The normalized amplitude of the foot during the MH swing was lower in SMR than in control rats whether of the age (F: P30, t 5 2.42; d.f. 5 20; P < 0.05; P65, t 5 1.99; d.f. 5 21; P < 0.05). Velocities showed in E and F were reduced as well in SMR
Early movement restriction leads to enduring disorders in muscle and locomotion: Enduring impact of sensorimotor restriction

February 2018

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366 Reads

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22 Citations

Motor control and body representation in the central nervous system (CNS) as well as musculoskeletal architecture and physiology are shaped during development by sensorimotor experience and feedback, but the emergence of locomotor disorders during maturation and their persistence over time remain a matter of debate in the absence of brain damage. By using transient immobilization of the hind limbs, we investigated the enduring impact of postnatal sensorimotor restriction (SMR) on gait and posture on treadmill, age-related changes in locomotion, musculoskeletal histopathology and Hoffmann reflex in adult rats without brain damage. SMR degrades most gait parameters and induces overextended knees and ankles, leading to digitigrade locomotion that resembles equinus. Based on variations in gait parameters, SMR appears to alter age-dependent plasticity of treadmill locomotion. SMR also leads to small but significantly decreased tibial bone length, chondromalacia, degenerative changes in the knee joint, gastrocnemius myofiber atrophy and muscle hyperreflexia, suggestive of spasticity. We showed that reduced and atypical patterns of motor outputs, and somatosensory inputs and feedback to the immature CNS, even in the absence of perinatal brain damage, play a pivotal role in the emergence of movement disorders and musculoskeletal pathologies, and in their persistence over time. Understanding how atypical sensorimotor development likely contributes to these degradations may guide effective rehabilitation treatments in children with either acquired (i.e., with brain damage) or developmental (i.e., without brain injury) motor disabilities. This article is protected by copyright. All rights reserved.


Graphical abstract
Plasiticity of spinal motor network
Changes in innervation of lumbar motoneurons and organization of premotor network following training of transected adult rats

September 2017

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344 Reads

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34 Citations

Experimental Neurology

Rats with complete spinal cord transection (SCT) can recover hindlimb locomotor function under strategies combining exercise training and 5-HT agonist treatment. This recovery is expected to result from structural and functional re-organization within the spinal cord below the lesion. To begin to understand the nature of this reorganization, we examined synaptic changes to identified gastrocnemius (GS) or tibialis anterior (TA) motoneurons (MNs) in SCT rats after a schedule of early exercise training and delayed 5-HT agonist treatment. In addition, we analyzed changes in distribution and number of lumbar interneurons (INs) presynaptic to GS MNs using retrograde transneuronal transport of rabies virus. In SCT-untrained rats, we found few changes in the density and size of inhibitory and excitatory inputs impinging on cell bodies of TA and GS MNs compared to intact rats, whereas there was a marked trend for a reduction in the number of premotor INs connected to GS MNs. In contrast, after training of SCT rats, a significant increase of the density of GABAergic and glycinergic axon terminals was observed on both GS and TA motoneuronal cell bodies, as well as of presynaptic P-boutons on VGLUT1 afferents. Despite these changes in innervation the number of premotor INs connected to GS MNs was similar to control values although some new connections to MNs were observed. These results suggest that adaptation of gait patterns in SCT-trained rats was accompanied by changes in the innervation of lumbar MNs while the distribution of the spinal premotor circuitry was relatively preserved.


Citations (41)


... Недавно было показано, что у животных с нарушением целостности спинного мозга инактивация гена кальпаина-1, хорошо известной кальций-зависимой цистеиновой протеазы, предотвращает снижение содержания КСС2 и последующую спастичность мышц [21]. Результаты этого исследования позволяют сделать вывод, что именно кальпаин-зависимый протеолиз является основной причиной снижения содержания KCC2 в поясничном отделе спинного мозга. ...

Reference:

SPONTANEOUS ACTIVITY OF THE POSTURAL MUSCLE DURING FUNCTIONAL UNLOADING. NEURONAL MECHANISMS AND SIGNALING EFFECTS (in Russian)
Knockdown of calpain1 in lumbar motoneurons reduces spasticity after spinal cord injury in adult rats

Molecular Therapy

... The results indicated that lower limbs have different motor pattern with the other parts in walking [23]. Studies proved that motor control of lower limbs was based on the function of central pattern generator, different with the other segments [24]. ...

Conservation of locomotion-induced oculomotor activity through evolution in mammals
  • Citing Article
  • December 2021

Current Biology

... The lateral habenula neurons receive glutamate/GABA co-releasing synaptic inputs from the entopeduncular nucleus (EP) (Shabel et al., 2014;Wallace et al., 2017;Root et al., 2018) and ventral tegmental area (VTA) (Root et al., 2014;Yoo et al., 2016;Root et al., 2018). Hypothalamic supramammillary nucleus (SuM) neurons projecting to the DG also co-release glutamate and GABA (Pedersen et al., 2017;Hashimotodani et al., 2018;Billwiller et al., 2020;Chen et al., 2020;Li et al., 2020;Ajibola et al., 2021). To understand how synaptic inputs mediated by the co-release of the excitatory action of glutamate and the inhibitory action of GABA are integrated and impact postsynaptic cells, it is necessary to elucidate how glutamate and GABA are co-released from the synaptic terminals. ...

GABA-glutamate supramammillary neurons control theta and gamma oscillations in the dentate gyrus during paradoxical (REM) sleep

Brain Structure and Function

... The pathophysiology of spasticity involves motoneuron hyperexcitability, 2,4-6 which is associated with increased persistent sodium and calcium currents, along with synaptic disinhibition. [7][8][9][10][11][12][13] This latter aspect is due to changes in glycine receptors and a reduction in the chloride extruder KCC2, [13][14][15][16][17][18][19] which exacerbates spasticity in both humans and rodents. Such an excitatory/inhibitory imbalance leads to self-sustained spiking activity in sublesional motoneurons, causing prolonged muscle contractions that can be either evoked or spontaneous. ...

Differential effects of spinal cord transection on glycinergic and GABAergic synaptic signaling in sub-lesional lumbar motoneurons
  • Citing Article
  • July 2020

Journal of Chemical Neuroanatomy

... An intriguing clinical study postulated that loss of RDD in SCI originates from impaired presynaptic mechanisms as motor-evoked potential responses, purportedly reflecting postsynaptic inhibition, were comparable among subjects with and without RDD [49]. However, the pure presynaptic origin theory of spasticity is not unanimously embraced, as other studies implicate glycinergic inhibition of lumbar motor neurons in the mechanisms underlying spasticity after SCI, which also influences RDD [34,50]. Further mechanistic associations were provided by Boulenguez et al. [34] who reported that blocking KCC2 in healthy rats diminished RDD while RDD was also reduced in both KCC2-deficient mice and intact rats following intrathecal delivery of brain-derived neurotrophic factor (BDNF) injection to downregulate KCC2. ...

Alteration of glycinergic receptor expression in lumbar spinal motoneurons is involved in the mechanisms underlying spasticity after spinal cord injury

Journal of Chemical Neuroanatomy

... In line with these results, it has been shown that the RSC contains a large number of neurons specifically activated during PS and phase-locked with theta (Koike et al., 2017). Then, it has been demonstrated that a projection of PS-on neurons of the lateral supramammillary nucleus (Sum) activates the DG granule cells (GCs) during PS (Billwiller et al., 2019). Further, in vitro and histological studies showed that the DG projection from the Sum release both GABA and glutamate (Billwiller et al., 2020;Pedersen et al., 2017). ...

The GABA-Glutamate supramammillary–dorsal Dentate Gyrus pathway controls theta and gamma oscillations in the DG during paradoxical sleep

... This early sensorimotor restriction (SMR) mainly induced enduring movement disorders, including reduced length and height of the swing, increased foot velocities and joint angles. These movement disorders that persist into adulthood are related to hyperextension of the knee and ankle, corresponding to a digitigrade locomotion that recapitulates "toe walking" or true pes equinus (Delcour, Massicotte, et al., 2018), a symptom frequently observed in patients with ASD (Vilensky et al., 1981) and cerebral palsy (Rodda et al., 2004). SMR also leads to a degradation of the functional organization and neuronal properties in both the primary somatosensory and motor cortices, along with hyperexcitability in the sensorimotor cortex and lumbar spinal cord, indicative of hyperreflexia, spasms and spasticity Delcour, Massicotte, et al., 2018;Strata et al., 2004). ...

Early movement restriction leads to enduring disorders in muscle and locomotion: Enduring impact of sensorimotor restriction

... In the 87 research studies examined, rats were the most commonly utilized animal model, comprising 76 % of research participants [14,17,28,30,. Within this group, the Sprague Dawley strain was the most prevalent (51 %) [ [28,34,37,41,44,46,48,59,72,78], Lewis and Lister Hooded (7 %) [17,55 −57,68,69], and Long-Evans and Fischer344 (5 %) [33,43,87,95] strains. In a small proportion of studies (2 %) [49,67], the rats' strain was not reported. ...

Changes in innervation of lumbar motoneurons and organization of premotor network following training of transected adult rats
  • Citing Article
  • September 2017

Experimental Neurology

... As indicated by the elevated CAT levels, a lower dose of BFCl was able to lessen the effects of lead toxicity, suggesting that the administration of BFCl is dose-dependent. This outcome is in line with the research done by Benammi et al. [28] , who discovered that Curcuma longa is an effective neuroprotective agent against neurotoxicity triggered by lead. ...

Disturbed sensorimotor and electrophysiological patterns in lead intoxicated rats during development are restored by curcumin I

... The advantage of the mouse model in revealing the depth and complexity of VS organization is shown by the ability to use established and validated techniques to track structural and functional development in embryos [e.g., (154,155)] and perinatally (24). Lambert et al. (33) applied a multitude of techniques to identify the morphological connectivity and functional changes in MVST and LVST neurons occurring during postnatal maturation. Like the cat and squirrel monkeys, the mouse cervical spinal cord's medial and lateral motor columns receive differential innervation from the ipsi-and contralateral MVST and LVST neurons. ...

Early postnatal maturation in vestibulospinal pathways involved in neck and forelimb motor control
  • Citing Article
  • January 2016

Developmental Neurobiology