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Projections of sacrocaudal afferents (SCA) onto lumbar pattern generators were studied in isolated spinal cords of neonatal rats. A locomotor-like pattern could be produced by SCA stimulation in the majority of the preparations. The SCA-induced lumbar rhythm was abolished after blocking synaptic transmission in the sacrococcygeal (SC) cord by bathi...
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... the other four, we first interrupted the left and right lateral VF, then the left and right LF-VLF, and then extended the lateral VF lesions to the midline so that most of the ventral funiculi (VF) was discon- nected. The results are essentially similar to those described above and are summarized in Table 1. ...
Citations
... Ascending projections from lumbar and thoracic levels exist and can entrain or drive upper limb function during locomotion (126)(127)(128)(129)(130). In contrast, the ability for descending projections from the upper limb to drive lower limb motor activity is less powerful (127,131). In vitro studies in neonatal rat have also demonstrated that activation of sacral neural circuitry can activate lumbar locomotor circuitry and may preferentially elicit stance or bilateral extensor discharge compared to stimulation at more rostral lumbar sites, demonstrating a strong ascending gradient of excitability in motor systems (132)(133)(134)(135)(136)(137). This is consistent with extensor-dominated discharge with more caudal stimulation in humans as well (43). ...
Spinal cord injury (SCI) results in sensory, motor and autonomic dysfunction. Obesity, cardiovascular and metabolic diseases are highly prevalent after SCI. Although inadequate voluntary activation of skeletal muscle contributes, it is absent or inadequate activation of thoracic spinal sympathetic neural circuitry and sub-optimal activation of homeostatic (cardiovascular, temperature) and metabolic support systems that truly limits exercise capacity, particularly for those with cervical SCI. Thus, when electrical spinal cord stimulation (SCS) studies aimed at improving motor functions began mentioning effects on exercise-related autonomic functions, a potential new area of clinical application appeared. To survey this new area of potential benefit, we performed a systematic scoping review of clinical SCS studies involving these spinally mediated autonomic functions. Nineteen studies were included, 8 used transcutaneous and 11 used epidural SCS. Improvements in BP at rest or in response to orthostatic challenge were investigated most systematically, whereas reports of improved temperature regulation, whole body metabolism and peak exercise performance were mainly anecdotal. Effective stimulation locations and parameters varied between studies, suggesting multiple stimulation parameters and rostrocaudal spinal locations may influence the same sympathetic function. Brainstem and spinal neural mechanisms providing excitatory drive to sympathetic neurons that activate homeostatic and metabolic tissues that provide support for movement and exercise and their integration with locomotor neural circuitry are discussed. A unifying conceptual framework for the integrated neural control of locomotor and sympathetic function is presented which may inform future research needed to take full advantage of SCS for improving these spinally mediated autonomic functions.
... In rodents, the evidence is ambiguous. Stimulation of motor neurons via ventral roots can activate locomotor circuitry (Mentis et al., 2005;Bonnot et al., 2009;Pujala et al., 2016) through relay interneurons projecting through white matter tracts (Strauss and Lev-Tov, 2003;Etlin et al., 2010Etlin et al., , 2013, but the mechanism remains unknown. ...
Pattern generators and the control of movement and locomotion in the spinal cord of vertebrates
... To our knowledge, no studies have determined the type of cutaneous fibers that mediate the excitatory effect on the spinal locomotor CPG. However, stimulating nociceptive or non-nociceptive sacral afferents is known to evoke fictive locomotor-like activity in isolated spinal cord preparations of neonatal mouse and rats Strauss and Lev-Tov, 2003;Etlin et al., 2013;Mandadi et al., 2013). Thus, it is likely that low-and high-threshold afferents from the perineal region facilitate hindlimb locomotion. ...
... uncrossed projections, directly to the lumbar locomotor CPG and indirectly via propriospinal relay neurons Strauss and Lev-Tov, 2003). As stated earlier, these inputs originate from low-and high-threshold somatosensory afferents (Lev-Tov et al., 2010). ...
... The functional purpose of the pathway from the perineal region to the spinal locomotor CPG is not clear. It could play an important survival function, such as facilitating the switch from an exploratory to an escape behavior when a predator contacts this sensitive area (Smith et al., 1988;Whelan et al., 2000;Delvolvé et al., 2001;Bonnot et al., 2002;Strauss and Lev-Tov, 2003;Frigon and Rossignol, 2006;Cherniak et al., 2014;Merlet et al., 2021). Therefore, the spinal locomotor CPG might increase or decrease the gain of cutaneous reflexes from the foot to modulate the effects of somatosensory inputs from the lumbar or perineal region in order to adapt the animal's behavior to task demands. ...
Somatosensory feedback from peripheral receptors dynamically interacts with networks located in the spinal cord and brain to control mammalian locomotion. Although somatosensory feedback from the limbs plays a major role in regulating locomotor output, those from other regions, such as lumbar and perineal areas also shape locomotor activity. In mammals with a complete spinal cord injury, inputs from the lumbar region powerfully inhibit hindlimb locomotion, while those from the perineal region facilitate it. Our recent work in cats with a complete spinal cord injury shows that they also have opposite effects on cutaneous reflexes from the foot. Lumbar inputs increase the gain of reflexes while those from the perineal region decrease it. The purpose of this review is to discuss how somatosensory feedback from the lumbar and perineal regions modulate the spinal locomotor central pattern generator and reflex circuits after spinal cord injury and the possible mechanisms involved. We also discuss how spinal cord injury can lead to a loss of functional specificity through the abnormal activation of functions by somatosensory feedback, such as the concurrent activation of locomotion and micturition. Lastly, we discuss the potential functions of somatosensory feedback from the lumbar and perineal regions and their potential for promoting motor recovery after spinal cord injury.
... body stabilizing pattern generators in the isolated rodent spinal cord (Lev-Tov et al., 2000;Strauss & Lev-Tov, 2003;Blivis et al., 2007;Etlin et al., 2013;Klein & Tresch, 2010;Dose & Taccola, 2012, for the rat; Whelan et al., 2000;Mandadi & Whelan, 2009, for the mouse; see also Marchetti et al., 2001, for lower threshold lumbar afferents). ...
... The search for innovative means to improve the motor function of spinal cord injury patients requires better understanding of the locomotor networks and the neuronal pathways involved in their activation in the absence of supraspinal control. This is feasible using isolated spinal cord preparations of newborn rodents, in which we have shown that graded electrical stimulation of SCA at Aδ strength has a powerful capacity to activate the hindlimb locomotor networks and the body-stabilizing sacral pattern generators (Blivis et al., 2007;Delvolvé et al., 2001;Etlin et al., 2013;Lev-Tov et al., 2000;Strauss & Lev-Tov, 2003). analyses (see Mor & Lev-Tov, 2007), from which the parameters of the rhythm (phase, frequency, and cross power) are extracted ( Figure 1c). ...
... analyses (see Mor & Lev-Tov, 2007), from which the parameters of the rhythm (phase, frequency, and cross power) are extracted ( Figure 1c). Moreover, SCA stimulation is not only an efficient activator of the locomotor CPGs but it also increases the excitability of rostral lumbar motoneurons during the rhythm by engaging ascending oscillatory drive originating from the sacral CPGs (Gabbay & Lev-Tov, 2004;Strauss & Lev-Tov, 2003;Etlin et al., 2013;Cherniak et al., 2017; reviewed by Cherniak et al., 2014;Anglister et al., 2017). ...
Electrical stimulation of the spinal cord is a potent means for activating mammalian stepping in the absence of the descending control from the brain. Previously, we have shown that stimulation of pain delivering (Aδ) sacrocaudal afferents (SCA) has a powerful capacity to activate the sacral and lumbar rhythmogenic networks in the neonatal rodent spinal cord. Relatively little is known about the neural pathways involved in activation of the locomotor networks by Aδ afferents, on their mechanism of action and on the possibility to modulate their activity. We have shown that elevation of the endogenous level of acetylcholine at the sacral cord by blocking cholinesterase could modulate the SCA‐induced locomotor rhythm in a muscarinic receptor‐dependent mechanism. Here, we review these and more recent findings and report that controlled stimulation of SCA in the presence of muscarine is a potent activator of the locomotor network. The possible mechanisms involved in the muscarinic modulation of the locomotor rhythm are discussed in terms of the differential projections of sacral relay neurons, activated by SCA stimulation, to the lumbar locomotor rhythm generators, and to their target motoneurons. Altogether, our studies show that manipulations of cholinergic networks offer a simple and powerful means to control the activity of locomotor networks in the absence of supraspinal control.
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Cover Image for this issue: https://doi.org/10.1111/jnc.15079.
... Tonic electrical stimulations of one of the sacral/coccygeal dorsal roots that notably convey sensory afferent inputs from the tail in rodent, is one relevant method for activating the lumbar locomotor networks in the isolated neonatal rat spinal cord . Activation of these networks is mediated by a sacral relay pathway that projects rostrally through the ventral funiculi (Cherniak et al., 2017;Etlin et al., 2010Etlin et al., , 2014Strauss and Lev-Tov, 2003). This pathway is also probably involved in the pro-locomotor action of perineal stimulations below a spinal cord lesion in cat and rat (Alluin et al., 2015;Barbeau and Rossignol, 1987;Fouad et al., 2000). ...
... Tonic electrical stimulation of sacrococcygeal sensory inputs, which mimic the action of tail pinching Lev-Tov et al., 2010), was previously shown to induce rhythmical activity in the lumbar cord, although the precise organization of the flexor and extensor-like motor outputs has never been fully described (Blivis et al., 2007;Etlin et al., 2013Etlin et al., , 2010Strauss and Lev-Tov, 2003). Fictive locomotion in the isolated spinal cord preparation from newborn rat is characterized by a bilateral alternation of segmental motor bursts, together with an alternation of ipsilateral flexor-like (L2) and extensor-like (L5) motor bursts (Cazalets et al., 1992;Kiehn and Kjaerulff, 1996). ...
... Sur la préparation isolée de moelle épinière de rongeurs néonataux, la stimulation électrique des racines dorsales active les générateurs locomoteurs que ce soit au niveau cervical qu'au niveau lombaire (Marchetti et al., 2001;Juvin et al., 2012). La stimulation électrique des afférences sacro-coccygiennes (SCA pour sacrocaudal afferents), est une méthode extrêmement efficace pour activer les réseaux sensorimoteurs lombaires et sacrés Delvolvé et al., 2001;Strauss et Lev-Tov, 2003;Etlin et al., 2010Etlin et al., , 2013Le Gal et al., 2014). De manière similaire, des épisodes de locomotion fictive ont également pu être obtenus par stimulation des afférences sensorielles sur la préparation isolée de moelle épinière de souris néonatale (Whelan et al., 2000;Gordon et Whelan, 2006 (Connor et al., 2005;Falla et al., 2007;Gibson et al., 2009;Mense, 2009;Walder et al., 2011;Jankowski et al., 2013;Kido et al., 2013;Ross et al., 2014). ...
... Des trains de stimulation électrique (2Hz, 30s, durée des pulses 0.5 ms) appliqués au niveau de racines dorsales sacrée sont également utilisés pour déclencher des activités motrices rythmiques au niveau de la moelle Delvolvé et al., 2001;Gabbay et al., 2002;Strauss et Lev-Tov, 2003). Une paire d'électrodes (stimulation bipolaire) en acier inoxydable est placée au contact d'une racine dorsale sacrée. ...
... La stimulation tonique des afférences sensorielles sacrées, sur des préparations de rat néonatal, engendre une activité rythmique au niveau lombaire dont la nature exacte n'a à ce jour jamais été formellement élucidée (Lev-Tov et Strauss et Lev-Tov, 2003;Etlin et al., 2010Etlin et al., , 2013. Dans ce contexte nous avons montré que l'alternance type flexion/extension est progressivement perdue durant la première semaine postnatale. ...
Lors de la locomotion, la commande rythmique envoyée aux muscles des membres est organisée de manière spatiale et temporelle par les générateurs centraux du patron locomoteur (CPGs) localisés dans la moelle épinière. Ces derniers sont sous le contrôle des centres supraspinaux impliqués dans l'aspect motivationnel du comportement locomoteur dont l’activité est constamment modulée par des afférences sensorielles afin de permettre d'adapter les mouvements aux changements environnementaux. L’objectif majeur de mon travail doctoral était d’explorer les mécanismes des interactions dynamiques entre (1) les centres supraspinaux, (2) les CPGs et (3) les afférences sensorielles dans le contrôle de la locomotion chez le rat nouveau-né intact et spino-lésé. En nous appuyant sur le modèle de préparation de tronc cérébral / moelle épinière isolée in vitro, nous avons montré que la manipulation de l’organisation temporelle de la commande locomotrice en provenance de la formation réticulée (située dans le tronc cérébral) est efficace pour ajuster finement l’activité des CPGs locomoteurs. Nous avons ensuite mis en lumière l’importance des voies descendantes sérotonergiques dans l’intégration de l’information sensorielle par les CPGs locomoteurs durant la première semaine postnatale. Enfin, en combinant des approches comportementales, neurochimiques et électrophysiologiques, nous avons mis en évidence des effets différents mais complémentaires des neuromodulateurs monoaminergiques (sérotonine, dopamine et noradrénaline) dans la réexpression du comportement locomoteur après une lésion spinale. Notre travail ouvre de belles perspectives pour la compréhension du contrôle afférent de la moelle épinière, à la fois dans un contexte non-pathologique et après un traumatisme médullaire.
... Locomotor-like patterns of rhythmicity can be evoked using a number of modalities. These include bath application of excitatory neurochemicals such as NMDA or 5HT (Figure 1.1 A) (Bonnot et al., 2002a), activation of descending pathways through electrical stimulation of the brainstem (Atsuta et al., 1988;Zaporozhets et al., 2004;Liu and Jordan, 2005), activation of sensory afferents by electrically stimulating the dorsal roots ( Figure 1.1 B) , activation of recurrent excitatory collaterals from motoneurons by electrically stimulating the ventral roots (Mentis et al., 2005;Humphreys and Whelan, 2012a;Pujala et al., 2016) or activation of ascending pathways from the cauda equina or sacral spinal cord (Strauss and Lev-Tov, 2003). ...
... On the other hand, activation of sensory afferents or recurrent motoneuron collaterals results in the generation of locomotor-like rhythms that are very similar. Although the rhythms appear the same, they are mediated by different populations of interneurons in the ventral spinal cord (Strauss and Lev-Tov, 2003;Pujala et al., 2016). Thus there are degenerate mechanisms for the generation of locomotorlike rhythms. ...
It has been known for centuries that the brain is not necessary for the generation of movements that allow for animals to walk. For many farmers, the sight of a chicken running around the farm yard following decapitation was fairly common. At the turn of the 20th century Charles Sherrington and Thomas Graham Brown proposed that circuits located within the spinal cord are responsible for the generation of rhythmic movements of the limbs for walking. With over a century of scientific investigation of rhythmically active circuits of vertebrates and invertebrate species, we have learned that rhythmic movements for locomotion, breathing and chewing are controlled by neuronal circuits called central pattern generators. Large emphasis has been directed toward dissecting the central pattern generator circuits for walking. Locomotor movements are remarkably adaptable and respond to not only external demands imposed by the environment but also internal needs of the animal. Thus, the underlying circuits that generate these diverse movements also need to be flexible to readily adjust in response to imposed demands. Nevertheless, the mutability of these rhythm generating circuits is not well understood. Neuromodulation endows spinal circuits with flexible properties that allow motor outputs to be adaptable to modify ongoing movement. I initially started to study how one neuromodulator, dopamine, controls rhythmic network activities of the spinal cord for walking in in the neonatal mouse in vitro (Sharples et al., 2015). My preliminary studies demonstrated that modulation of rhythmic circuits might have state-dependent effects on locomotor rhythms which is consistent with work conducted in invertebrates (Marder et a., 2014). In this thesis, I explored the diverse actions of modulators on spinal networks across varying states of excitability. This is important because changes in behavioural state or pathology result in alterations in network excitability. In general, I demonstrated that neural networks of the spinal cord are degenerate in their ability to generate locomotor rhythms and that neuromodulators can tune this ability through both degenerate and redundant mechanisms.
... This complex and specific connectivity among the different elements of the network has been only partly elucidated. Nevertheless, even if the rhythmogenic source of the pattern is isolated in vitro, and thus deprived of its descending and afferent inputs, the rhythmic pattern can still be triggered by a wide range of electrical stimuli (Atsuta et al., 1990;Magnuson and Trinder, 1997;Strauss and Lev-Tov, 2003;Taccola, 2011;Dose et al., 2013; and pharmacological agents (Cazalets et al., 1992;Houssaini et al., 1993;Kiehn and Kjaerulff, 1996;Taccola and Nistri, 2006) and even by an increase in extracellular K+, which can lead to a broad rise in the overall neuronal network excitability (Bracci et al., 1998). Thus, while a more exact composition and organization of the CPG evolves, it is anticipated that more precise strategies in formulating interventions will facilitate our ability to exploit the automaticity of neural networks and their plasticity. ...
... Afferent inputs, as the ones generated by posterior root stimulation, reach the locomotor networks Rybak et al., 2006;Bui and Brownstone, 2015), as clearly demonstrated by epochs of locomotor patterns elicited in vitro by the selective electrical stimulation of single or multiple DRs, using tight suction electrodes Strauss and Lev-Tov, 2003;Taccola, 2011;. ...
Preclinical and clinical neurophysiological and neurorehabilitation research has generated rather surprising levels of recovery of volitional sensory-motor function in persons with chronic motor paralysis following a spinal cord injury. The key factor in this recovery is largely activity-dependent plasticity of spinal and supraspinal networks. This key factor can be triggered by neuromodulation of these networks with electrical and pharmacological interventions. This review addresses some of the systems-level physiological mechanisms that might explain the effects of electrical modulation and how repetitive training facilitates the recovery of volitional motor control. In particular, we substantiate the hypotheses that: (1) in the majority of spinal lesions, a critical number and type of neurons in the region of the injury survive, but cannot conduct action potentials, and thus are electrically non-responsive; (2) these neuronal networks within the lesioned area can be neuromodulated to a transformed state of electrical competency; (3) these two factors enable the potential for extensive activity-dependent reorganization of neuronal networks in the spinal cord and brain, and (4) propriospinal networks play a critical role in driving this activity-dependent reorganization after injury. Real-time proprioceptive input to spinal networks provides the template for reorganization of spinal networks that play a leading role in the level of coordination of motor pools required to perform a given functional task. Repetitive exposure of multi-segmental sensory-motor networks to the dynamics of task-specific sensory input as occurs with repetitive training can functionally reshape spinal and supraspinal connectivity thus re-enabling one to perform complex motor tasks, even years post injury.
... Previously, we showed that the body-stabilizing sacral networks could activate and modulate the limb-moving lumbar circuitry in the isolated spinal cord of newborn rodents Strauss and Lev-Tov 2003;Blivis et al. 2007). Our studies revealed that activation of the hindlimb CPGs by sacrocaudal afferent (SCA) stimulation involved glutamatergic excitation of heterogeneous groups of sacral relay neurons with crossed and uncrossed ascending projections through the ventral funiculus (VF) and the lateral white matter funiculi Lev-Tov et al. 2010). ...
... Electrical activation of the hindlimb-moving and bodystabilizing CPGs in the isolated rodent spinal cord Mechanical or radiant heat stimulations of sacral dermatomes Blivis et al. 2007;Mandadi and Whelan 2009) and electrical stimulation of sacrocaudal afferents Whelan et al. 2000;Strauss and Lev-Tov 2003;Klein and Tresch 2010;Taccola 2011) potently activate the hindlimb and body-stabilizing CPGs in rodents in the absence of supraspinal control. Our studies of the isolated spinal cord of the newborn rat revealed that the sacrocaudal afferent-induced locomotor rhythm could be blocked by bathing the sacral segments in low-calcium high-magnesium Kreb's saline, to suppress synaptic transmission, or by selective application to these segments of the non-NMDA receptor blocker CNQX (Strauss and Lev-Tov 2003) or the mu-opioid agonist DAMGO (Blivis et al. 2007). ...
... Electrical activation of the hindlimb-moving and bodystabilizing CPGs in the isolated rodent spinal cord Mechanical or radiant heat stimulations of sacral dermatomes Blivis et al. 2007;Mandadi and Whelan 2009) and electrical stimulation of sacrocaudal afferents Whelan et al. 2000;Strauss and Lev-Tov 2003;Klein and Tresch 2010;Taccola 2011) potently activate the hindlimb and body-stabilizing CPGs in rodents in the absence of supraspinal control. Our studies of the isolated spinal cord of the newborn rat revealed that the sacrocaudal afferent-induced locomotor rhythm could be blocked by bathing the sacral segments in low-calcium high-magnesium Kreb's saline, to suppress synaptic transmission, or by selective application to these segments of the non-NMDA receptor blocker CNQX (Strauss and Lev-Tov 2003) or the mu-opioid agonist DAMGO (Blivis et al. 2007). Thus, activation of the hindlimb CPGs by SCA stimulation depends mainly on synaptic excitation of sacral relay neurons with ascending lumbar projections to the locomotor CPGs. ...
Deciphering neuronal pathways that reactivate spinal central pattern generators ( CPG s) and modulate the activity of spinal motoneurons in mammals in the absence of supraspinal control is important for understanding of neural control of movement and for developing novel therapeutic approaches to improve the mobility of spinal cord injury patients. Previously, we showed that the sacral and lumbar cholinergic system could potently modulate the locomotor CPG s in newborn rodents. Here, we review these and our more recent studies of sacral relay neurons with lumbar projections to the locomotor CPG s and to lumbar motoneurons and demonstrate that sacral and lumbar cholinergic components have the capacity to control the frequency of the locomotor CPG s and at the same time the motor output of the activated lumbar motoneurons during motor behavior. A model describing the suggested ascending sacro‐lumbar connectivity involved in modulation of the locomotor rhythm by sacral cholinergic components is proposed and discussed.
This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms .
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... Activation of sacral afferents in vitro can also readily evoke rhythmic locomotor-like activity in neonatal mouse or rat spinal cord preparations [92; 93; 94; 95; 96; 97]. Electrical stimulation of cauda equina afferents is advantageous for producing locomotor activity because the thoracolumbar circuitry necessary for producing this behavior can be accessed via crossed and uncrossed ascending/propriospinal pathways through the sacrococcygeal section of the spinal cord [96]. A recent study showed that bath application of DA caused a depression of the cauda-equina-evoked rhythm [97]. ...
Background:
The basic motor patterns driving rhythmic limb movements during walking are generated by networks of neurons called central pattern generators (CPGs). Within motor control systems, neuromodulators are necessary for proper and efficient CPG function because they induce or regulate essential components of spinal network activity, including firing parameters of CPG neurons and network synaptic strength, allowing the network to change/adapt and sometimes to even become functional.
Methods:
The goal of this work is to focus on classical and recent findings addressing the role of neuromodulators such as glutamate, dopamine, acetylcholine and adenosine in eliciting, changing and sometimes terminating spinal CPG network function in rodents.
Results:
Neuromodulatory inputs onto CPG locomotor networks have been additionally related to inducing state changes such as locomotor timing, phasing and speed, and to the induction/maintenance of actual network function. These inputs originate from supraspinal centers such as the brainstem and from intraspinal neurotransmission. The isolated in vitro rodent spinal cord preparation is a powerful model for studies on locomotor network organization because of its physiological and anatomical accessibility, as well as the incorporation of various transgenic approaches to identify specific neuronal populations. Both roles are accomplished through the action of neuromodulators on ionotropic and metabotropic receptors mediating synaptic neurotransmission, which can be used by neurons that are intrinsic or extrinsic components of a CPG network itself.
Conclusion:
This article has hopefully provided a comprehensive overview of some of the main spinal mechanisms involved in the modulatory control of locomotor motor activity.
