Rhythmic Motor Research Articles

A rare case of sleep - related rhythmic movement disorder in adult with literature review

Sleep - related rhythmic movement disorder (RMD) is characterized by repetitive,stereotyped and rhythmic motor behaviors (not tremors) that occur predominantly during drowsiness or sleep and involve large muscle groups. The onset of RMD is typically in early childhood, rarely continue into adolescence and adulthood. This paper retrospectively analyzed the diagnosis and treatment in a case of adult-onset RMD. A 76 -year-old male mainly presented rhythmic forehead banging during sleep. The number of forehead banging ranged from dozens to tens of seconds, pause seconds after the second attack, lasting 1 to 2 h and can not be recalled after waking up. Polysomnography (PSG) showed sleep efficiency decreased, awakening time prolonged, times of wakefulness increased, sleep structure disordered, non-rapid eye movement (NREM) 1 and 2 sleep increased, rapid eye movement (REM) sleep decreased, sleep latency of REM prolonged. Apnea hypopnea index (AHI) was 8.40. Several abnormal behavior attacks were observed, each attack lasting 3 to 18 s, 0.60 to 1.20 Hz, total time lasting 6 min. The diagnosis was RMD, clonazepam 0.50 mg/night and pramipexole 0.0625 mg/night were given and the result of 33 months follow-up showed effective. By literature review, we know the clinical features, diagnosis and treatment of RMD. We also analyze the reasons of misdiagnosis for reducing diagnostic errors and mistreatments. DOI: 10.3969/j.issn.1672-6731.2017.09.008

Phase changes in neuronal postsynaptic spiking due to short term plasticity.

In the brain, the postsynaptic response of a neuron to time-varying inputs is determined by the interaction of presynaptic spike times with the short-term dynamics of each synapse. For a neuron driven by stochastic synapses, synaptic depression results in a quite different postsynaptic response to a large population input depending on how correlated in time the spikes across individual synapses are. Here we show using both simulations and mathematical analysis that not only the rate but the phase of the postsynaptic response to a rhythmic population input varies as a function of synaptic dynamics and synaptic configuration. Resultant phase leads may compensate for transmission delays and be predictive of rhythmic changes. This could be particularly important for sensory processing and motor rhythm generation in the nervous system.

Roles of dopamine in control of motor rhythm

Roles of dopamine in control of motor rhythm

Synaptic Excitation in Spinal Motoneurons Alternates with Synaptic Inhibition and Is Balanced by Outward Rectification during Rhythmic Motor Network Activity.

Regular firing in spinal motoneurons of red-eared turtles (Trachemys scripta elegans, either sex) evoked by steady depolarization at rest is replaced by irregular firing during functional network activity. The transition caused by increased input conductance and synaptic fluctuations in membrane potential was suggested to originate from intense concurrent inhibition and excitation. We show that the conductance increase in motoneurons during functional network activity is mainly caused by intrinsic outward rectification near threshold for action potentials by activation of voltage and Ca2+ gated K channels. Intrinsic outward rectification facilitates spiking by focusing synaptic depolarization near threshold for action potentials. By direct recording of synaptic currents, we also show that motoneurons are activated by out-of-phase peaks in excitation and inhibition during network activity, whereas continuous low-level concurrent inhibition and excitation may contribute to irregular firing.SIGNIFICANCE STATEMENT Neurons embedded in active neural networks can enter a high-conductance state. High-conductance states were observed in spinal motoneurons during rhythmic motor behavior. Assuming no change in intrinsic conductance, it was suggested that the high-conductance state in motoneurons originated from balanced inhibition and excitation. In this study, we demonstrate that intrinsic outward rectification significantly contributes to the high-conductance state. Outward rectification balances synaptic excitation and maintains membrane potential near spike threshold. In addition, direct synaptic current recordings show out-of-phase excitation and inhibition in motoneurons during rhythmic network activity.

P215 Driving human motor cortical oscillations leads to behaviourally relevant changes in local GABA(A) Inhibition: A tACS-TMS study

Objectives Beta and gamma oscillations are the dominant oscillatory activity in the human motor cortex (M1). However, their physiological basis and precise functional significance remain poorly understood. To this end, we employed Transcranial Magnetic Stimulation (TMS) to examine the physiological basis and behavioural relevance of driving beta and gamma oscillatory activity in the human M1 using transcranial alternating current stimulation (tACS). Methods 20 healthy volunteers participated in four experimental sessions separated by at least 1 week. In Session 1, all subjects had a MEG scan in order to determine individual beta and gamma peak frequency for subsequent tACS sessions. In Sessions 2–4, subjects received tACS at beta frequency (∼20 Hz), gamma frequency (75 Hz) or sham stimulation. tACS was applied for 20 min over the left M1 and the contralateral orbit at individualised intensity. TMS measures (a single MEP, SICI and ICF) were performed at rest and during movement preparation. Results Gamma tACS led to a significant, duration-dependent decrease in local resting-state GABA(A) inhibition (p = 0.002), as quantified by SICI. The magnitude of this effect was positively correlated with the magnitude of GABA(A) decrease during movement preparation (p = 0.003), when gamma activity in motor circuitry is known to increase. In addition, gamma tACS-induced change in GABA(A) inhibition was closely related to performance in a motor learning task, such that subjects who demonstrated a greater increase in GABA(A) inhibition also showed faster short-term learning (p Discussion and conclusions Our findings show that gamma tACS is capable of modulating GABA(A) inhibition in M1 in a behaviourally relevant manner and suggest that tACS may have similar physiological effects to endogenously driven local oscillatory activity. Significance This study contributes to our understanding of the neurophysiological basis of motor rhythms and their behavioural relevance. Moreover, the ability to modulate local interneuronal circuits by tACS in a behaviourally relevant manner provides a basis for tACS as a putative therapeutic intervention.

State-dependent sensorimotor gating in a rhythmic motor system.

Sensory feedback influences motor circuits and/or their projection neuron inputs to adjust ongoing motor activity, but its efficacy varies. Currently, less is known about regulation of sensory feedback onto projection neurons that control downstream motor circuits than about sensory regulation of the motor circuit neurons themselves. In this study, we tested whether sensory feedback onto projection neurons is sensitive only to activation of a motor system, or also to the modulatory state underlying that activation, using the crab Cancer borealis stomatogastric nervous system. We examined how proprioceptor neurons (gastropyloric receptors, GPRs) influence the gastric mill (chewing) circuit neurons and the projection neurons (MCN1, CPN2) that drive the gastric mill rhythm. During gastric mill rhythms triggered by the mechanosensory ventral cardiac neurons (VCNs), GPR was shown previously to influence gastric mill circuit neurons, but its excitation of MCN1/CPN2 was absent. In this study, we tested whether GPR effects on MCN1/CPN2 are also absent during gastric mill rhythms triggered by the peptidergic postoesophageal commissure (POC) neurons. The VCN and POC pathways both trigger lasting MCN1/CPN2 activation, but their distinct influence on circuit feedback to these neurons produces different gastric mill motor patterns. We show that GPR excites MCN1 and CPN2 during the POC-gastric mill rhythm, altering their firing rates and activity patterns. This action changes both phases of the POC-gastric mill rhythm, whereas GPR only alters one phase of the VCN-gastric mill rhythm. Thus sensory feedback to projection neurons can be gated as a function of the modulatory state of an active motor system, not simply switched on/off with the onset of motor activity.NEW & NOTEWORTHY Sensory feedback influences motor systems (i.e., motor circuits and their projection neuron inputs). However, whether regulation of sensory feedback to these projection neurons is consistent across different versions of the same motor pattern driven by the same motor system was not known. We found that gating of sensory feedback to projection neurons is determined by the modulatory state of the motor system, and not simply by whether the system is active or inactive.

Feedback Signal from Motoneurons Influences a Rhythmic Pattern Generator.

Motoneurons are not mere output units of neuronal circuits that control motor behavior but participate in pattern generation. Research on the circuit that controls the crawling motor behavior in leeches indicated that motoneurons participate as modulators of this rhythmic motor pattern. Crawling results from successive bouts of elongation and contraction of the whole leech body. In the isolated segmental ganglia, dopamine can induce a rhythmic antiphasic activity of the motoneurons that control contraction (DE-3 motoneurons) and elongation (CV motoneurons). The study was performed in isolated ganglia where manipulation of the activity of specific motoneurons was performed in the course of fictive crawling (crawling). In this study, the membrane potential of CV was manipulated while crawling was monitored through the rhythmic activity of DE-3. Matching behavioral observations that show that elongation dominates the rhythmic pattern, the electrophysiological activity of CV motoneurons dominates the cycle. Brief excitation of CV motoneurons during crawling episodes resets the rhythmic activity of DE-3, indicating that CV feeds back to the rhythmic pattern generator. CV hyperpolarization accelerated the rhythm to an extent that depended on the magnitude of the cycle period, suggesting that CV exerted a positive feedback on the unit(s) of the pattern generator that controls the elongation phase. A simple computational model was implemented to test the consequences of such feedback. The simulations indicate that the duty cycle of CV depended on the strength of the positive feedback between CV and the pattern generator circuit.SIGNIFICANCE STATEMENT Rhythmic movements of animals are controlled by neuronal networks that have been conceived as hierarchical structures. At the basis of this hierarchy, we find the motoneurons, few neurons at the top control global aspects of the behavior (e.g., onset, duration); and within these two ends, specific neuronal circuits control the actual rhythmic pattern of movements. We have investigated whether motoneurons are limited to function as output units. Analysis of the network that controls crawling behavior in the leech has clearly indicated that motoneurons, in addition to controlling muscle activity, send signals to the pattern generator. Physiological and modeling studies on the role of specific motoneurons suggest that these feedback signals modulate the phase relationship of the rhythmic activity.

Training of motor rhythm in students, practicing football

Цель: проверить влияние методики развития способности к ритму движения студентов на занятиях физической культурой на основе применения средств футбола. Материал: в исследовании принимали участие студенты 1 курса, очной формы обучения, основной медицинской группы (n=40). После короткой разминки (10-15 минут) были даны упражнения на развитие чувства ритма движения в течение 15 минут на каждом занятии. Оценка способности к ритму определялась при помощи теста «подтягивание мяча стопой». Уровень развития общих координационных способностей учитывался в челночном беге 3x10 м. Комплексный тест на уровень технической подготовки футболиста (жонглирование, ведение мяча, обводка стоек и удар по воротам). Результаты: установлена необходимость избирательного развития способности футболиста к ритму движения. Это относится и к развитию координационных способностей у студентов. Представлены новые возможности применения методики развития способности к ритму движения у студентов. Эти возможности реализованы на занятиях физической культурой. Основой таких занятий являются средств футбола. Выводы: При разучивании и выполнении новых и сложных координационных упражнений использовался метод стандартно-повторного упражнения. Метод вариативного упражнения применялся тогда, когда возникала необходимость изменения способа выполнения самих движений. Игровой и соревновательный методы использовали только тогда, когда изучаемое двигательное действие было доведено до автоматизма.

Serotonergic network in the subesophageal zone modulates the motor pattern for food intake in Drosophila

The functional organization of central motor circuits underlying feeding behaviors is not well understood. We have combined electrophysiological and genetic approaches to investigate the regulatory networks upstream of the motor program underlying food intake in the Drosophila larval central nervous system. We discovered that the serotonergic network of the CNS is able to set the motor rhythm frequency of pharyngeal pumping. Pharmacological experiments verified that modulation of the feeding motor pattern is based on the release of serotonin. Classical lesion and laser based cell ablation indicated that the serotonergic neurons in the subesophageal zone represent a redundant network for motor control of larval food intake.

Variations on a theme: species differences in synaptic connectivity do not predict central pattern generator activity.

A fundamental question in comparative neuroethology is the extent to which synaptic wiring determines behavior vs. the extent to which it is constrained by phylogeny. We investigated this by examining the connectivity and activity of homologous neurons in different species. Melibe leonina and Dendronotus iris (Mollusca, Gastropoda, Nudibranchia) have homologous neurons and exhibit homologous swimming behaviors consisting of alternating left-right (LR) whole body flexions. Yet, a homologous interneuron (Si1) differs between the two species in its participation in the swim motor pattern (SMP) and synaptic connectivity. In this study we examined Si1 homologs in two additional nudibranchs: Flabellina iodinea, which evolved LR swimming independently of Melibe and Dendronotus, and Tritonia diomedea, which swims with dorsal-ventral (DV) body flexions. In Flabellina, the contralateral Si1s exhibit alternating rhythmic bursting activity during the SMP and are members of the swim central pattern generator (CPG), as in Melibe The Si1 homologs in Tritonia do not burst rhythmically during the DV SMP but are inhibited and receive bilaterally synchronous synaptic input. In both Flabellina and Tritonia, the Si1 homologs exhibit reciprocal inhibition, as in Melibe However, in Flabellina the inhibition is polysynaptic, whereas in Tritonia it is monosynaptic, as in Melibe In all species, the contralateral Si1s are electrically coupled. These results suggest that Flabellina and Melibe convergently evolved a swim CPG that contains Si1; however, they differ in monosynaptic connections. Connectivity is more similar between Tritonia and Melibe, which exhibit different swimming behaviors. Thus connectivity between homologous neurons varies independently of both behavior and phylogeny.NEW & NOTEWORTHY This research shows that the synaptic connectivity between homologous neurons exhibits species-specific variations on a basic theme. The neurons vary in the extent of electrical coupling and reciprocal inhibition. They also exhibit different patterns of activity during rhythmic motor behaviors that are not predicted by their circuitry. The circuitry does not map onto the phylogeny in a predictable fashion either. Thus neither neuronal homology nor species behavior is predictive of neural circuit connectivity.

Stereotypy of psychogenic nonepileptic seizures.

Psychogenic nonepileptic seizures (PNES) are defined as paroxysmal episodes in which epileptic semiology features are manifested, without the characteristic concomitant electrical discharges seen in epileptic seizures. Although many studies have dealt with semiologic classification of PNES, most of the studies did not raise the question of consistency of PNES in the same patient. The aim of this study was to measure the degree of consistency of PNES among individual patients. We retrospectively reviewed medical records and video- EEG records of all adult patients who underwent monitoring in our center from August 1st 2013 to May 31st 2015. Those who were diagnosed with PNES with or without a background of epilepsy were selected for this study. In order to check consistency between seizures, we analyzed patients who had more than one recorded seizure during monitoring. In case of more than 2 recorded seizures, the first two seizures were analyzed. We found 53 patients who had PNES during this period, 29 of them had more than one seizure. All seizures in the same patient were in the same semiology category. In patients with either motor rhythmic or complex motor seizures, we found a main anatomical region involved. The main anatomical region involved was the same in 13 out of 14 patients. Movement frequency was highly similar between the seizures of the same patient, while duration of seizures was significantly different. Despite significant differences in duration between the first and second seizure in patients with PNES, all other aspects tested were highly similar. This shows that recurrent PNES in the same patient are stereotypic. This supports the hypothesis that PNES is probably a dissociative disorder.

Serotonergic projections to lumbar levels and its plasticity following spinal cord injury

The descending serotonergic pathway, which originates in various populations of brainstem neurons, plays an important role in generating the rhythmic motor pattern associated with locomotor movement. Although the development of its innervation has been studied in rodent spinal cord, it has not been clearly identified how the projection of serotonergic pathway is related to its function. Here, we evaluated the pattern of serotonergic innervation on the lumbar spinal cord from embryonic day 14.5 (E14.5) to adulthood. Before birth, we found that 5-hydroxytryptamine (5-HT) fibers invade the lumbar cord as early as E14.5, penetrate into the gray matter from lateral funiculus by E16.5, and then mainly occupied the ventral horn by E18.5 before localizing in the dorsal horn. After birth, we found that 5-HT invasion of both dorsal horn and ventral horn were present by the 7th postnatal day (P7). Additionally, the 5-HT innervation of these two areas evolved progressively from a diffuse network to a more restricted pattern, particularly at the ventral horn within the motoneuron area from P21 to adulthood. This 5-HT innervation pattern in the lumbar cord provides anatomical evidence that serotonergic fibers establish direct connections with lumbar motoneurons, which offers us a solid foundation that enhancing the plasticity of serotonergic pathway following SCI may facilitate locomotor functional recovery. Therefore, we employed treadmill training to activate serotonergic plasticity after SCI. We found that mice which underwent treadmill training exhibited a better locomotor functional recovery. Meanwhile, the density of 5-HT fibers in the ventral horn was significantly increased and the synaptic formation of 5-HT fibers with lumbar motoneurons was also significantly rescued in the training group mice after SCI. These findings demonstrate that the descending serotonergic projection is a robust and flexible parallel pathway for modulating spinal locomotor function.

Movement Rate Is Encoded and Influenced by Widespread, Coherent Activity of Cerebellar Molecular Layer Interneurons

Inhibition from molecular layer interneurons (MLIs) is thought to play an important role in cerebellar function by sharpening the precision of Purkinje cell spike output. Yet the coding features of MLIs during behavior are poorly understood. To study MLI activity, we used in vivo Ca2+ imaging in head-fixed mice during the performance of a rhythmic motor behavior, licking during water consumption. MLIs were robustly active during lick-related movement across a lobule-specific region of the cerebellum showing high temporal correspondence within their population. Average MLI Ca2+ activity strongly correlated with movement rate but not to the intentional, or unexpected, adjustment of lick position or to sensory feedback that varied with task condition. Chemogenetic suppression of MLI output reduced lick rate and altered tongue movements, indicating that activity of these interneurons not only encodes temporal aspects of movement kinematics but also influences motor outcome pointing to an integral role in online control of rhythmic behavior.SIGNIFICANCE STATEMENT The cerebellum helps fine-tune coordinated motor actions via signaling from projection neurons called Purkinje cells. Molecular layer interneurons (MLIs) provide powerful inhibition onto Purkinje cells, but little is understood about how this inhibitory circuit is engaged during behavior or what type of information is transmitted through these neurons. Our work establishes that MLIs in the lateral cerebellum are broadly activated during movement with calcium activity corresponding to movement rate. We also show that suppression of MLI output slows and disorganizes the precise movement pattern. Therefore, MLIs are an important circuit element in the cerebellum allowing for accurate motor control.

Peptidergic Modulation in the Lobster Cardiac Neuromuscular System: A Transcriptomic Analysis of Peptides and Peptide Receptors in Cardiac Ganglion and Muscle

Central pattern generator (CPG)‐effector systems can produce flexible rhythmic motor output via modulation by both intrinsically‐ and extrinsically‐derived neuropeptides. In the lobster, Homarus americanus, the cardiac neuromuscular system, which consists of the cardiac ganglion (CG) and cardiac muscle (CM), controls the rhythmic motor output of the heart. This is a well‐studied, but simple, CPG‐effector system that has been used extensively for investigating peptidergic control of rhythmic behavior. Here, transcriptomes were generated for the two components that comprise the cardiac neuromuscular system, the cardiac ganglion (CG) and cardiac muscle (CM). Transcripts encoding precursor proteins for approximately ten peptide families, including allatostatin‐C (AST‐C), diuretic hormone 31 (DH31), diuretic hormone 44, myosuppressin, and proctolin, were identified from the CG transcriptome, suggesting that these peptide groups may be produced by neurons in the CG. Transcripts encoding receptors for many of the peptides identified from the CG, including those for all four of the above‐mentioned peptide families, were also identified from the CG and/or CM transcriptomes, suggesting that these peptides serve as intrinsic modulators of the cardiac neuromuscular system. To investigate hormonal modulation in the cardiac neuromuscular system, the transcriptomes were mined for the receptors of peptides known to be present in the sinus gland and/or pericardial organs, two neuroendocrine organs. Receptors for seven peptide families were identified, with some receptors restricted either to the CG (crustacean cardioactive peptide, red pigment concentrating hormone, and tachykinin‐related peptide) or CM (pigment dispersing hormone), and others found in both tissues (AST‐C, myosuppressin, and proctolin). These data suggest that some peptides may have different sites of action within the cardiac neuromuscular system. Immunohistochemistry confirmed that DH31 is produced by the motor neurons of the CG, and suggested that AST‐C is present in the CG. Immunohistochemical confirmation of the other putative intrinsic CG modulators is ongoing.Support or Funding InformationNSF (IOS‐1353023, IOS‐1354567, OCE‐1459235), NIH (8P20GM103423‐12), Cades Fdn., University of Hawaii at Manoa's Undergrad Res. Opp. Prog., APS Undergrad Res. Fellowship, Doherty Fdn./Bowdoin College

Characterization of the Receptors Associated with the Differing Responses to the Neuropeptide, AST‐C, by the Cardiac Ganglion of the American Lobster, Homarus americanus

Central pattern generators (CPGs) are neural networks that produce consistent, rhythmic patterned outputs to reliably activate specific muscles, resulting in repeated and rhythmic movements. The cardiac ganglion (CG) is a CPG in the American lobster, and is responsible for producing a consistent rhythmic heartbeat. Flexibility of rhythmic motor outputs arises from modulation of CPGs, largely by neuropeptides. The lobster heart is modulated by C‐type allatostatins (AST‐C), two of which [pQIRYHQCYFNPISCF, now AST‐C I, and SYWKQCAFNAVSCFamide, now AST‐C II] were previously known; both have been shown to modulate the lobster heart. Using transcriptomes generated from nervous system tissues, we identified a third isoform of AST‐C, GNGDGRLYWRCYFNAVSCF, or AST‐C III, in the lobster. All three AST‐C isoforms consistently lead to decreases in contraction frequency when perfused through an isolated lobster heart; in contrast, all can elicit variable responses in contraction amplitude, with amplitude increasing in some lobsters and decreasing in others. The responses to AST‐C I and AST‐C III are more similar to one another than to AST‐C II in any given lobster.We are currently testing the hypothesis that differences in AST‐C receptor expression among individuals underlie these varying responses. Mining of a Homarus americanus transcriptome has led to the identification of three full‐length and one partial putative AST‐C receptors. We are currently conducting experiments to determine whether and to what extent the four putative AST‐C receptors bind the three AST‐C isoforms. Understanding these receptor‐peptide relationships will allow us to elucidate the role the receptors play in the observed differential response to AST‐C.Support or Funding InformationNSF (IOS‐1353023, IOS‐1354567), NIH (8P20GM103423‐12), Cades Foundation, Doherty Foundation gift to Bowdoin College

Driving Human Motor Cortical Oscillations Leads to Behaviorally Relevant Changes in Local GABAA Inhibition: A tACS-TMS Study.

Beta and gamma oscillations are the dominant oscillatory activity in the human motor cortex (M1). However, their physiological basis and precise functional significance remain poorly understood. Here, we used transcranial magnetic stimulation (TMS) to examine the physiological basis and behavioral relevance of driving beta and gamma oscillatory activity in the human M1 using transcranial alternating current stimulation (tACS). tACS was applied using a sham-controlled crossover design at individualized intensity for 20 min and TMS was performed at rest (before, during, and after tACS) and during movement preparation (before and after tACS). We demonstrated that driving gamma frequency oscillations using tACS led to a significant, duration-dependent decrease in local resting-state GABAA inhibition, as quantified by short interval intracortical inhibition. The magnitude of this effect was positively correlated with the magnitude of GABAA decrease during movement preparation, when gamma activity in motor circuitry is known to increase. In addition, gamma tACS-induced change in GABAA inhibition was closely related to performance in a motor learning task such that subjects who demonstrated a greater increase in GABAA inhibition also showed faster short-term learning. The findings presented here contribute to our understanding of the neurophysiological basis of motor rhythms and suggest that tACS may have similar physiological effects to endogenously driven local oscillatory activity. Moreover, the ability to modulate local interneuronal circuits by tACS in a behaviorally relevant manner provides a basis for tACS as a putative therapeutic intervention.SIGNIFICANCE STATEMENT Gamma oscillations have a vital role in motor control. Using a combined tACS-TMS approach, we demonstrate that driving gamma frequency oscillations modulates GABAA inhibition in the human motor cortex. Moreover, there is a clear relationship between the change in magnitude of GABAA inhibition induced by tACS and the magnitude of GABAA inhibition observed during task-related synchronization of oscillations in inhibitory interneuronal circuits, supporting the hypothesis that tACS engages endogenous oscillatory circuits. We also show that an individual's physiological response to tACS is closely related to their ability to learn a motor task. These findings contribute to our understanding of the neurophysiological basis of motor rhythms and their behavioral relevance and offer the possibility of developing tACS as a therapeutic tool.

Spatial patterning of excitatory and inhibitory neuropil territories during spinal circuit development.

To generate rhythmic motor behaviors, both single neurons and neural circuits require a balance between excitatory inputs that trigger action potentials and inhibitory inputs that promote a stable resting potential (E/I balance). Previous studies have focused on individual neurons and have shown that, over a short spatial scale, excitatory and inhibitory (E/I) synapses tend to form structured territories with inhibitory inputs enriched on cell bodies and proximal dendrites and excitatory inputs on distal dendrites. However, systems-level E/I patterns, at spatial scales larger than single neurons, are largely uncharted. We used immunostaining for PSD-95 and gephyrin postsynaptic scaffolding proteins as proxies for excitatory and inhibitory synapses, respectively, to quantify the numbers and map the distributions of E/I synapses in zebrafish spinal cord at both an embryonic stage and a larval stage. At the embryonic stage, we found that PSD-95 puncta outnumber gephyrin puncta, with the number of gephyrin puncta increasing to match that of PSD-95 puncta at the larval stage. At both stages, PSD-95 puncta are enriched in the most lateral neuropil corresponding to distal dendrites while gephyrin puncta are enriched on neuronal somata and in the medial neuropil. Significantly, similar to synaptic puncta, neuronal processes also exhibit medial-lateral territories at both developmental stages with enrichment of glutamatergic (excitatory) processes laterally and glycinergic (inhibitory) processes medially. This establishment of neuropil excitatory-inhibitory structure largely precedes dendritic arborization of primary motor neurons, suggesting that the structured neuropil could provide a framework for the development of E/I balance at the cellular level. J. Comp. Neurol. 525:1649-1667, 2017. © 2016 Wiley Periodicals, Inc.

Motor Neurons Tune Premotor Activity in a Vertebrate Central Pattern Generator.

Central patterns generators (CPGs) are neural circuits that drive rhythmic motor output without sensory feedback. Vertebrate CPGs are generally believed to operate in a top-down manner in which premotor interneurons activate motor neurons that in turn drive muscles. In contrast, the frog (Xenopus laevis) vocal CPG contains a functionally unexplored neuronal projection from the motor nucleus to the premotor nucleus, indicating a recurrent pathway that may contribute to rhythm generation. In this study, we characterized the function of this bottom-up connection. The X. laevis vocal CPG produces a 50-60 Hz "fast trill" song used by males during courtship. We recorded "fictive vocalizations" in the in vitro CPG from the laryngeal nerve while simultaneously recording premotor activity at the population and single-cell level. We show that transecting the motor-to-premotor projection eliminated the characteristic firing rate of premotor neurons. Silencing motor neurons with the intracellular sodium channel blocker QX-314 also disrupted premotor rhythms, as did blockade of nicotinic synapses in the motor nucleus (the putative location of motor neuron-to-interneuron connections). Electrically stimulating the laryngeal nerve elicited primarily IPSPs in premotor neurons that could be blocked by a nicotinic receptor antagonist. Our results indicate that an inhibitory signal, activated by motor neurons, is required for proper CPG function. To our knowledge, these findings represent the first example of a CPG in which precise premotor rhythms are tuned by motor neuron activity.SIGNIFICANCE STATEMENT Central pattern generators (CPGs) are neural circuits that produce rhythmic behaviors. In vertebrates, motor neurons are not commonly known to contribute to CPG function, with the exception of a few spinal circuits where the functional significance of motor neuron feedback is still poorly understood. The frog hindbrain vocal circuit contains a previously unexplored connection from the motor to premotor region. Our results indicate that motor neurons activate this bottom-up connection, and blocking this signal eliminates normal premotor activity. These findings may promote increased awareness of potential involvement of motor neurons in a wider range of CPGs, perhaps clarifying our understanding of network principles underlying motor behaviors in numerous organisms, including humans.

Asymmetry Factors Shaping Regular and Irregular Bursting Rhythms in Central Pattern Generators.

Central Pattern Generator (CPG) circuits are neural networks that generate rhythmic motor patterns. These circuits are typically built of half-center oscillator subcircuits with reciprocally inhibitory connections. Another common property in many CPGs is the remarkable rich spiking-bursting dynamics of their constituent cells, which balance robustness and flexibility to generate their joint coordinated rhythms. In this paper, we use conductance-based models and realistic connection topologies inspired by the crustacean pyloric CPG to address the study of asymmetry factors shaping CPG bursting rhythms. In particular, we assess the role of asymmetric maximal synaptic conductances, time constants and gap-junction connectivity to establish the regularity of half-center oscillator based CPGs. We map and characterize the synaptic parameter space that lead to regular and irregular bursting activity in these networks. The analysis indicates that asymmetric configurations display robust regular rhythms and that large regions of both regular and irregular but coordinated rhythms exist as a function of the asymmetry in the circuit. Our results show that asymmetry both in the maximal conductances and in the temporal dynamics of mutually inhibitory neurons can synergistically contribute to shape wide regimes of regular spiking-bursting activity in CPGs. Finally, we discuss how a closed-loop protocol driven by a regularity goal can be used to find and characterize regular regimes when there is not time to perform an exhaustive search, as in most experimental studies.

Strength of ~20-Hz Rebound and Motor Recovery After Stroke

Background. Stroke is a major cause of disability worldwide, and effective rehabilitation is crucial to regain skills for independent living. Recently, novel therapeutic approaches manipulating the excitatory-inhibitory balance of the motor cortex have been introduced to boost recovery after stroke. However, stroke-induced neurophysiological changes of the motor cortex may vary despite of similar clinical symptoms. Therefore, better understanding of excitability changes after stroke is essential when developing and targeting novel therapeutic approaches. Objective and Methods. We identified recovery-related alterations in motor cortex excitability after stroke using magnetoencephalography. Dynamics (suppression and rebound) of the ~20-Hz motor cortex rhythm were monitored during passive movement of the index finger in 23 stroke patients with upper limb paresis at acute phase, 1 month, and 1 year after stroke. Results. After stroke, the strength of the ~20-Hz rebound to stimulation of both impaired and healthy hand was decreased with respect to the controls in the affected (AH) and unaffected (UH) hemispheres, and increased during recovery. Importantly, the rebound strength was lower than that of the controls in the AH and UH also to healthy-hand stimulation despite of intact afferent input. In the AH, the rebound strength to impaired-hand stimulation correlated with hand motor recovery. Conclusions. Motor cortex excitability is increased bilaterally after stroke and decreases concomitantly with recovery. Motor cortex excitability changes are related to both alterations in local excitatory-inhibitory circuits and changes in afferent input. Fluent sensorimotor integration, which is closely coupled with excitability changes, seems to be a key factor for motor recovery.