January 2024
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56 Reads
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3 Citations
Molecular Therapy
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January 2024
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56 Reads
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3 Citations
Molecular Therapy
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.
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.
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.
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.
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.
April 2019
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37 Reads
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.
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.
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.
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.
... 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. ...
January 2024
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]. ...
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. ...
December 2020
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. ...
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. ...
April 2020
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). ...
March 2019
... 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). ...
February 2018
... 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. ...
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. ...
March 2017
... 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. ...
January 2016
Developmental Neurobiology