Cholinergic Partition Cells and Lamina X Neurons Induce a Muscarinic-Dependent Short-Term Potentiation of Commissural Glutamatergic Inputs in Lumbar Motoneurons

Acetylcholine and the activation of muscarinic receptors influence the activity of neural networks generating locomotor behavior in the mammalian spinal cord. Using electrical stimulations of the ventral commissure, we show that commissural muscarinic (CM) depolarizations could be induced in lumbar motoneurons. We provide a detailed electrophysiological characterization of the muscarinic receptors and the membrane conductance involved in these responses. Activation of the CM terminals, originating from lamina X neurons and partition cells, induced a pathway-specific short-term potentiation (STP) of commissural glutamatergic inputs in motoneurons. This STP is occluded in the presence of the muscarinic antagonist atropine. During fictive locomotion, the activation of the commissural pathways transiently enhanced the motor output in a muscarinic-dependent manner. This study describes for the first time a novel regulatory mechanism of synaptic strength in spinal locomotor networks. Such cellular mechanisms would endow the locomotor central pattern generators with adaptive processes needed to generate appropriate synaptic inputs to motoneurons during different motor tasks

Left-Right Facial Orientation of Familiar Faces: Developmental Aspects of « the Mere Exposure Hypothesis »

We investigated the developmental aspect of sensitivity to the orientation of familiar faces by asking 38 adults and 72 children from 3 to 12 years old to make a preference choice between standard and mirror images of themselves and of familiar faces, presented side-by-side or successively. When familiar (parental) faces were presented simultaneously, 3- to 5-year-olds showed no preference, but by age 5–7 years an adult-like preference for the standard image emerged. Similarly, the adult-like preference for the mirror image of their own face emerged by 5–7 years of age. When familiar or self faces were presented successively, 3- to 7-year-olds showed no preference, and adult-like preference for the standard image emerged by age 7–12 years. These results suggest the occurrence of a developmental process in the perception of familiar face asymmetries which is retained in memory related to knowledge about faces

Comparison of Trunk Activity during Gait Initiation and Walking in Humans

To understand the role of trunk muscles in maintenance of dynamic postural equilibrium we investigate trunk movements during gait initiation and walking, performing trunk kinematics analysis, Erector spinae muscle (ES) recordings and dynamic analysis. ES muscle expressed a metachronal descending pattern of activity during walking and gait initiation. In the frontal and horizontal planes, lateroflexion and rotation occur before in the upper trunk and after in the lower trunk. Comparison of ES muscle EMGs and trunk kinematics showed that trunk muscle activity precedes corresponding kinematics activity, indicating that the ES drive trunk movement during locomotion and thereby allowing a better pelvis mobilization. EMG data showed that ES activity anticipates propulsive phases in walking with a repetitive pattern, suggesting a programmed control by a central pattern generator. Our findings also suggest that the programs for gait initiation and walking overlap with the latter beginning before the first has ended

Developmentally Regulated Modulation of Lumbar Motoneurons by Metabotropic Glutamate Receptors: A Cellular and Behavioral Analysis in Newborn Mice

The present study explores the impact of metabotropic glutamate receptor (mGluR) activation on activity-dependent synaptic plasticity (ADSP) and the intrinsic membrane properties of lumbar motoneurons (MNs) using a combination of biochemical, pharmacological, electrophysiological and behavioral techniques. Using spinal cord slices from C57BL/6JRJ mice at two developmental stages, 1-3 and 8-12 postnatal days (P1-P3; P8-P12, respectively), we found that ADSP expressed at glutamatergic synapses between axons conveyed in the ventrolateral funiculus (VLF) and MNs, involved mGluR activation. Using specific agonists of the three groups of mGluRs, we observed that mGluR stimulation causes subtype-specific and developmentally regulated modulation of the ADSP and synaptic transmission at VLF-MN synapses as well as the intrinsic membrane properties of MNs. RT-qPCR analysis revealed a downregulation of mGluR gene expression with age in the ventral part of the lumbar spinal cord. Interestingly, the selective harvest by laser microdissection of MNs innervating the Gastrocnemius and Tibialis anterior muscles unraveled that the level of Grm2 expression is higher in Tibialis MNs compared to Gastrocnemius MNs suggesting a specific mGluR gene expression profile in these two MN pools. Finally, we assessed the functional impact of mGluR modulation on electrically induced bouts of fictive locomotion in the isolated spinal cord preparation of P1-P3 mice, and in vivo during spontaneous episodes of swimming activity in both P1-P3 and P8-P12 mouse pups. We observed that the mGluR agonists induced distinct and specific effects on the motor burst amplitudes and period of the locomotor rhythms tested and that their actions are function of the developmental stage of the animals. Altogether our data show that the metabotropic glutamatergic system exerts a complex neuromodulation in the developing spinal lumbar motor networks and provide new insights into the expression and modulation of ADSP in MNs.Bordeaux Region Aquitaine Initiative for Neuroscienc

Serotonergic modulation of sacral dorsal root stimulation-induced locomotor output in newborn rat

International audienceDescending neuromodulators from the brainstem play a major role in the development and regulation of spinal sensorimotor functions. Here, the contribution of serotonergic signaling in the lumbar spinal cord was investigated in the context of the generation of locomotor activity. Experiments were performed on in vitro spinal cord preparations from newborn rats (0–5 days). Rhythmic locomotor episodes (fictive locomotion) triggered by tonic electrical stimulations (2Hz, 30s) of a single sacral dorsal root were recorded from bilateral flexor-dominated (L2) and extensor-dominated (L5) ventral roots. We found that the activity pattern induced by sacral stimulation evolves over the 5 post-natal (P) day period. Although alternating rhythmic flexor-like motor bursts were expressed at all ages, the locomotor pattern of extensor-like bursting was progressively lost from P1 to P5. At later stages, serotonin (5-HT) and quipazine (5-HT2A receptor agonist) at concentrations sub-threshold for direct locomotor network activation promoted sacral stimulation-induced fictive locomotion. The 5-HT2A receptor antagonist ketanserin could reverse the agonist's action but was ineffective when fictive locomotion was already expressed in the absence of 5-HT (mainly before P2). Although inhibiting 5-HT7 receptors with SB266990 did not affect locomotor pattern organization, activating 5-HT1A receptors with 8-OH-DPAT specifically deteriorated extensor phase motor burst activity. We conclude that during the first 5 post-natal days in rat, serotonergic signaling in the lumbar cord becomes increasingly critical for the expression of fictive locomotion. Our findings therefore further underline the importance of both descending serotonergic and sensory afferent pathways in shaping locomotor activity during postnatal development

Brainstem Steering of Locomotor Activity in the Newborn Rat

International audienceControl of locomotion relies on motor loops conveying modulatory signals between brainstem and spinal motor circuits. We investigated the steering control of the brainstem reticular formation over the spinal locomotor networks using isolated brainstem-spinal cord preparations of male and female neonatal rats. First, we performed patch-clamp recordings of identified reticulospinal cells during episodes of fictive locomotion. This revealed that a spinal ascending phasic modulation of reticulospinal cell activity is already present at birth. Half of the cells exhibited tonic firing during locomotion, while the other half emitted phasic discharges of action potentials phase locked to ongoing activity. We next showed that mimicking the phasic activity of reticulospinal neurons by applying patterned electrical stimulation bilaterally at the ventral caudal medulla level triggered fictive locomotion efficiently. Moreover, the brainstem stimuli-induced locomotor rhythm was entrained in a one-to-one coupling over a range of cycle periods (2-6 s). Additionally, we induced turning like motor outputs by either increasing or decreasing the relative duration of the stimulation trains on one side of the brainstem compared to the other. The ability of the patterned descending command to control the locomotor output depended on the functional integrity of ventral reticulospinal pathways and the involvement of local spinal central pattern generator circuitry. Altogether, this study provides a mechanism by which brainstem reticulospinal neurons relay steering and speed commands to the spinal locomotor networks

Noradrenergic Modulation of Intrinsic and Synaptic Properties of Lumbar Motoneurons in the Neonatal Rat Spinal Cord

Although it is known that noradrenaline (NA) powerfully controls spinal motor networks, few data are available regarding the noradrenergic (NAergic) modulation of intrinsic and synaptic properties of neurons in motor networks. Our work explores the cellular basis of NAergic modulation in the rat motor spinal cord. We first show that lumbar motoneurons express the three classes of adrenergic receptors at birth. Using patch-clamp recordings in the newborn rat spinal cord preparation, we characterized the effects of NA and of specific agonists of the three classes of adrenoreceptors on motoneuron membrane properties. NA increases the motoneuron excitability partly via the inhibition of a KIR like current. Methoxamine (α1), clonidine (α2) and isoproterenol (β) differentially modulate the motoneuron membrane potential but also increase motoneuron excitability, these effects being respectively inhibited by the antagonists prazosin (α1), yohimbine (α2) and propranolol (β). We show that the glutamatergic synaptic drive arising from the T13-L2 network is enhanced in motoneurons by NA, methoxamine and isoproterenol. On the other hand, NA, isoproterenol and clonidine inhibit both the frequency and amplitude of miniature glutamatergic EPSCs while methoxamine increases their frequency. The T13-L2 synaptic drive is thereby differentially modulated from the other glutamatergic synapses converging onto motoneurons and enhanced by presynaptic α1 and β receptor activation. Our data thus show that the NAergic system exerts a powerful and complex neuromodulation of lumbar motor networks in the neonatal rat spinal cord

Monoaminergic control of spinal locomotor networks in SOD1G93A newborn mice

Mutations in the gene that encodes Cu/Zn-superoxide dismutase (SOD1) are the cause of approximately 20% of familial forms of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While ALS symptoms appear in adulthood, spinal motoneurons exhibit functional alterations as early as the embryonic and postnatal stages in the murine model of ALS, the SOD1 mice. Monoaminergic - i.e., dopaminergic (DA), serotoninergic (5-HT) and noradrenergic (NA) - pathways powerfully control the spinal networks and contribute significantly to their embryonic and postnatal maturation. Alterations in monoaminergic neuromodulation during development could therefore lead to impairments in the motoneuronal physiology. In this study, we sought to determine whether the monoaminergic spinal systems are modified in the early stages of development in SOD1 mice. Using a post-mortem analysis by High Performance Liquid Chromatography (HPLC), the contents of monoaminergic neuromodulators and their metabolites were quantified in the lumbar spinal cord of SOD1 and wild-type (WT) mice aged one postnatal day (P1) and P10. This analysis underscores an increased content of DA in the SOD1 lumbar spinal cord compared to that of WT mice but failed to reveal any modification of the other monoaminergic contents. In a next step, we compared the efficiency of the monoaminergic compounds in triggering and modulating fictive locomotion in WT and SOD1 mice. This study was performed in P1-P3 SOD1 mice and age-matched control littermates using extracellular recordings from the lumbar ventral roots in the in vitro isolated spinal cord preparation. This analysis revealed that the spinal networks of SOD1G93A mice could generate normal locomotor activity in the presence of NMA-5-HT. Interestingly, we also observed that SOD1 spinal networks have an increased sensitivity to NA compared to WT spinal circuits but exhibited similar DA responses

Sustained Gq-Protein Signaling Disrupts Striatal Circuits via JNK

International audienceThe dorsal striatum is a major input structure of the basal ganglia and plays a key role in the control of vital processes such as motor behavior, cognition, and motivation. The functionality of striatal neurons is tightly controlled by various metabotropic receptors. Whereas the G s /G i-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of G q-protein-dependent signals remain poorly understood. Here, using different experimental approaches, especially designer receptor exclusively activated by designer drug (DREADD) chemogenetic technology, we found that sustained activation of G q-protein signaling impairs the functionality of striatal neurons and we unveil the precise molecular mechanism underlying this process: a phospholipase C/Ca 2ϩ /proline-rich tyrosine kinase 2/cJun N-terminal kinase pathway. Moreover, engagement of this intracellular signaling route was functionally active in the mouse dorsal striatum in vivo, as proven by the disruption of neuronal integrity and behavioral tasks. To analyze this effect anatomically, we manipulated G q-protein-dependent signaling selectively in neurons belonging to the direct or indirect striatal pathway. Acute G q-protein activation in direct-pathway or indirect-pathway neurons produced an enhancement or a decrease, respectively , of activity-dependent parameters. In contrast, sustained G q-protein activation impaired the functionality of direct-pathway and indirect-pathway neurons and disrupted the behavioral performance and electroencephalography-related activity tasks controlled by either anatomical framework. Collectively, these findings define the molecular mechanism and functional relevance of G q-protein-driven signals in striatal circuits under normal and overactivated states