Reciprocal Inhibition Research Articles

Kainate Receptors Play a Role in Modulating Synaptic Transmission in the Olfactory Bulb

Glutamate is the neurotransmitter used at most excitatory synapses in the mammalian brain, including those in the olfactory bulb (OB). There, ionotropic glutamate receptors including N-methyl-d-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) play a role in processes such as reciprocal inhibition and glomerular synchronization. Kainate receptors (KARs) represent another type of ionotropic glutamate receptor, which are composed of five (GluK1–GluK5) subunits. Whereas KARs appear to be heterogeneously expressed in the OB, evidence as to whether these KARs are functional, found at synapses, or modify synaptic transmission is limited. In the present study, coapplication of KAR agonists (kainate, SYM 2081) and AMPAR antagonists (GYKI 52466, SYM 2206) demonstrated that functional KARs are expressed by OB neurons, with a subset of receptors located at synapses. Application of kainate and the GluK1-selective agonist ATPA had modulatory effects on excitatory postsynaptic currents (EPSCs) evoked by stimulation of the olfactory nerve layer. Application of kainate and ATPA also had modulatory effects on reciprocal inhibitory postsynaptic currents (IPSCs) evoked using a protocol that evokes dendrodendritic inhibition. The latter finding suggests that KARs, with relatively slow kinetics, may play a role in circuits in which the relatively brief duration of AMPAR-mediated currents limits the role of AMPARs in synaptic transmission (e.g., reciprocal inhibition at dendrodendritic synapses). Collectively, our findings suggest that KARs, including those containing the GluK1 subunit, modulate excitatory and inhibitory transmission in the OB. These data further suggest that KARs participate in the regulation of synaptic circuits that encode odor information.

Long noncoding RNA MIR31HG inhibits hepatocellular carcinoma proliferation and metastasis by sponging microRNA-575 to modulate ST7L expression

BackgroundEmerging evidences have indicated that long noncoding RNAs (lncRNAs) play essential roles in the development and progression of cancers. Dysregulation of lncRNA MIR31HG has recently been reported in several types of cancers, and researches on the function of MIR31HG in cancers suggested that MIR31HG could act as either oncogene or tumor suppressor. But the functional involvement of MIR31HG has not been studied in hepatocellular carcinoma (HCC).MethodsIn this study, MTS assays, colony formation assay, Wound-healing assay, Transwell assy, and tumor xenografts experiments were used to identify biological effects of MIR31HG on HCC cells HCC proliferation and metastasis in vitro and in vivo. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to show the interactions of MIR31HG and miR-575. The bioinformatics methods were completed to find the target genes of miR-575. And Dual-luciferase reporter assay and Western blot analysis were further used to confirm the target gene of miR-575.ResultsWe found that overexpression of MIR31HG obviously suppressed HCC proliferation and metastasis in vitro and in vivo, whereas knockdown of MIR31HG had the opposite effects. Besides, overexpression of MIR31HG significantly decreased the expression of microRNA-575 (miR-575), which plays an oncogenic role in HCC. Moreover, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay revealed that MIR31HG exerted tumor-suppressive functions by binding directly to miR-575, and there was a reciprocal inhibition between MIR31HG and miR-575 in the same RNA-induced silencing complex (RISC). Furthermore, overexpression of MIR31HG enhanced the expression of suppression of tumorigenicity 7 like (ST7L), which was identified as a downstream target gene of miR-575. Thus, MIR31HG positively regulated ST7L expression through sponging miR-575, and acted as tumor suppressor in HCC.ConclusionsOverall, our study illuminates the role of MIR31HG as a miRNA sponge in HCC, and sheds new light on lncRNA-directed diagnostics and therapeutics in HCC.

LncRNA LOC728196/miR-513c axis facilitates glioma carcinogenesis by targeting TCF7

Numerous long noncoding RNAs (lncRNAs) are reported to be dysregulated in glioma. However, how lncRNA participates in the process of glioma development and progression still remains elusive. Here, we identified a novel lncRNA LOC728196 highly expressed in glioma tissues. LOC728196 high expression predicts low survival rate in patients. Our data proved that LOC728196 knockdown repressed cellular growth, migration and invasion in vitro. Silencing LOC728196 led to impaired growth of glioma in vivo. Mechanistic studies further demonstrated that LOC728196 acts as the sponge for miR-513c to upregulate TCF7 expression. We observed a reciprocal inhibition between LOC728196 and miR-513c. Rescue assay showed that either inhibition of miR-513c or TCF7 overexpression restored the abilities of proliferation, migration and invasion in LOC728196–silenced glioma cells. Taken together, our study provides a comprehensive investigation on the role of LOC728196 in glioma progression and contributes to understanding the vital role of competing endogenous RNA (ceRNA).

MDN brain descending neurons coordinately activate backward and inhibit forward locomotion.

Command-like descending neurons can induce many behaviors, such as backward locomotion, escape, feeding, courtship, egg-laying, or grooming (we define 'command-like neuron' as a neuron whose activation elicits or 'commands' a specific behavior). In most animals, it remains unknown how neural circuits switch between antagonistic behaviors: via top-down activation/inhibition of antagonistic circuits or via reciprocal inhibition between antagonistic circuits. Here, we use genetic screens, intersectional genetics, circuit reconstruction by electron microscopy, and functional optogenetics to identify a bilateral pair of Drosophila larval 'mooncrawler descending neurons' (MDNs) with command-like ability to coordinately induce backward locomotion and block forward locomotion; the former by stimulating a backward-active premotor neuron, and the latter by disynaptic inhibition of a forward-specific premotor neuron. In contrast, direct monosynaptic reciprocal inhibition between forward and backward circuits was not observed. Thus, MDNs coordinate a transition between antagonistic larval locomotor behaviors. Interestingly, larval MDNs persist into adulthood, where they can trigger backward walking. Thus, MDNs induce backward locomotion in both limbless and limbed animals.

Temporomandibular disorder and comorbid neck pain: facts and hypotheses regarding pain-induced and rehabilitation-induced motor activity changes.

According to the "pain adaptation model", temporomandibular disorder (TMD)-related pain induces a paradoxical activity of masticatory muscles: an agonistic hypoactivity during jaw closing and an antagonistic activity during jaw opening (agonist/antagonist co-activation). However, this model suffers several weaknesses; notably, it does not explain all types of neck muscle activities in neck pain (NP), which is a very prevalent TMD comorbid condition. In NP, neck muscle antagonistic activity is increased, and agonistic activity is decreased as postulated by the pain adaptation model. However, synergistic and compensatory activity may occur and agonistic activity may be unchanged or even increased as postulated within the "vicious cycle theory". Thus, both theories would apply partly as outlined currently in musculoskeletal disorders (MSD). Besides pain, psychological stress may also induce motor dysfunction in TMD and NP. In NP, rehabilitation may increase agonistic activity and decrease compensatory activity and antagonistic activity, thus inducing a switch from agonist/antagonist co-activation towards reciprocal inhibition. Thus, rehabilitation-induced motor activity changes constitute a new research field that should improve MSD therapeutics. Additionally, immature tongue function (so-called infantile swallow) might be connected to TMD where low agonistic activity of masticatory muscles would be compensated by facial muscle hyperactivity during oropharyngeal phase of deglutition.

TESTING INFRASPINATUS AND DELTOID MUSCLES WITH NEW TECHNIQUE TO DECREASE DELTOID ACTIVITY DURING TESTING USING EMG ANALYSIS

Muscle strength testing of an injured infraspinatus muscle (IM) is confounded by actions of synergistic muscles such as the posterior deltoid (PD). The purpose of this study was to describe a condition for testing of the IM that results in less EMG activity of the PD musculature. The researchers hypothesized that greater inhibition of the PD could be achieved through active adduction (AA), creating reciprocal inhibition of the PD. Prospective cohort descriptive study. Thirty-four (19 females and 15 males) right-handed subjects between the ages of 22- 31 (mean 24.2 years + /- 6.2) with no previous history of shoulder surgery or pathology participated. Surface electrodes were placed over the muscle bellies of the IM and PD of the right shoulder along with a ground electrode over the C7 spinous process. EMG activity was recorded during resisted external rotation in four different testing conditions (seated active and passive adduction, and side-lying active and passive adduction). The order of test positions was randomly assigned, and each subject completed all four positions with appropriate rest. During AA conditions, subjects were asked to adduct the humerus against a sphygmomanometer (using 80% maximum force output) while maximal effort external rotation was manually resisted. PD activity was significantly less during AA than with no AA (p<0.05) in both test positions. No significant difference occurred between IM EMG activity in the various test conditions. The results of this study suggest that clinicians can reduce activity of the PD without reducing activity of the IM by using AA of the humerus before applying manual resistance to test the IM during manual muscle testing. 1b.

Activation of elbow extensors during passive stretch of flexors in patients with post-stroke spasticity

ObjectivesDeficits in regulation of tonic stretch reflex thresholds (TSRTs) after stroke occur in elbow flexors and extensors leading to spasticity in specific joint ranges. Threshold deregulation may also be responsible for other deficits such as abnormal activation of passively shortening muscles. Goals were to characterize activation of shortening elbow extensors during passive elbow flexor stretch in individuals with stroke, and identify its relationship to upper-limb motor impairment. MethodsThirty-three participants with unilateral stroke participated. TSRTs in elbow flexors were measured by stretching passive elbow flexors at different velocities. EMG responses were recorded from stretched agonist (biceps) and shortened antagonist (triceps) muscles. ResultsTriceps activation during passive biceps stretch occurred in all but 4 participants simultaneously with, before or after biceps activation onset. Biceps and triceps activation onsets and durations decreased with stretch velocity. Biceps TSRT and triceps activation magnitude did not correlate with sensorimotor impairment but greater stroke chronicity tended to be related to higher biceps TSRTs (r = 0.406, p = 0.041). ConclusionsStroke may result in both limitations in reciprocal inhibition and excessive agonist-antagonist co-activation, likely from deficits in TSRT modulation in both muscle groups. SignificanceSince both reciprocal inhibition and co-activation are fundamental to normal motor control, their cooperative action should be considered in designing interventions to increase the ranges of regulation of TSRTs in flexors and extensors to enhance upper limb functional recovery.

Priming With Intermittent Theta Burst Transcranial Magnetic Stimulation Promotes Spinal Plasticity Induced by Peripheral Patterned Electrical Stimulation.

This study explored the effect of corticospinal activity on spinal plasticity by examining the interactions between intermittent theta burst transcranial magnetic stimulation (iTBS) of the motor cortex and peripheral patterned electrical stimulation (PES) of the common peroneal nerve (CPN). Healthy volunteers (n = 10) received iTBS to the tibialis anterior (TA) muscle zone of the motor cortex and PES of the CPN in three separate sessions: (1) iTBS-before-PES, (2) iTBS-after-PES, and (3) sham iTBS-before-PES. The PES protocol used 10 100-Hz pulses every 2 s for 20 min. Reciprocal inhibition (RI) from the TA to soleus muscle and motor cortical excitability of the TA and soleus muscles were assessed at baseline, before PES, and 0, 15, 30, and 45 min after PES. When compared to the other protocols, iTBS-before-PES significantly increased changes in disynaptic RI for 15 min and altered long-loop presynaptic inhibition immediately after PES. Moreover, the iTBS-induced cortical excitability changes in the TA before PES were correlated with the enhancement of disynaptic RI immediately after PES. These results demonstrate that spinal plasticity can be modified by altering cortical excitability. This study provides insight into the interactions between modulation of corticospinal excitability and spinal RI, which may help in developing new rehabilitation strategies.

Effects of the Inerventions method on gross motor function in children with spastic cerebral palsy

Aim of the studyTo investigate the effect of the Inerventions method on gross motor function in children with spastic cerebral palsy (CP). Clinical rationale for the studyThe Inerventions method is the type of transcutaneous electrical nerve stimulation (TENS) delivered through a full-body garment (Mollii suit) that aims to prompt reciprocal inhibition via the antagonist to reduce spasticity in selected muscle groups. Although Mollii is approved by the European Union as a medical device, independent clinical tests have not yet been performed. Materials and methods16 children with spastic CP, aged 4.7 ± 1.3 were recruited and then willingly assigned to the Inerventions method (n = 8) and control groups (n = 8). In the Inerventions method group, TENS was applied 1 h per session, 3 days weekly for 3 weeks. Children of the control group received functional exercises program for the same duration, frequency and length. Outcome measures included the Gross Motor Function Measure, passive range of motion (PROM), the Modified Tardieu Scale, and the Timed Up and Go test. ResultsWhile both groups experienced improvements in gross motor function and mobility, the difference in improvement between children treated with the TENS and physiotherapy did not reach statistical significance. No change occurred in PROM and spasticity in either group following the interventions. ConclusionsThere is no superior efficacy of the Inerventions method compared to conventional physiotherapy.

Synaptic drive in spinal motoneurons during scratch network activity.

Synaptic activity in motoneurons may provide unique insight in the relation between functional network activity and behavior. During scratch network activity in an ex vivo preparation from red-eared turtles ( Trachemys scripta elegans), excitatory and inhibitory synaptic current can be separated and quantified in voltage-clamp recordings. With this technique, we confirm the reciprocal synaptic excitation and inhibition in hip flexor motoneurons during ipsilateral scratching and show that out-of-phase inhibition and excitation also characterize hip extensor motoneurons during ipsi- and contralateral scratching. In contrast, inhibition precedes and partly overlaps excitation in hip flexor-like motoneurons and delays depolarization of membrane potential. We conclude that out-of-phase excitation and inhibition during rhythmic network activity is a common feature in spinal motoneurons. NEW & NOTEWORTHY During network activity, the firing pattern of individual neurons is shaped by their intrinsic conductances and synaptic input. Quantification of synaptic input is, therefore, essential to understand how the properties of individual neurons contribute to function and help to reveal the structure of the network. Here, we show how a combination of recording techniques can be used to quantify and compare the pattern of synaptic activity in different groups of motoneurons during rhythmic network activity.

Effects induced by motor cortex anodal transcranial direct current stimulation on wrist muscles in stroke patients

Transcranial direct current stimulation is used to modify noninvasively cortical brain excitability in humans. It consists in delivering a weak current trough two electrodes: one applied over the motor cortex and a second in supra-orbital position. Recently we showed in healthy subjects that anodal tDCS applied over the motor cortex can be used to modify descending inputs relayed by corticospinal tract on reciprocal inhibition pathways innervating wrist muscles [1] . We found that effects induced by anodal tDCS in wrist extensors and in wrist flexors are opposite: tDCS increases reciprocal inhibition in extensors but decreases reciprocal inhibition in flexors. It appears that modulations induced by anodal tDCS on reciprocal inhibition pathways favor the contraction in wrist extensors. Motor deficit in wrist extensors is usual in hemiplegic patients and the aim of this study is to combine spinal cord MRI and electrophysiological methods to explore effects of tDCS at wrist level in patients with impaired wrist motor control. Anodal tDCS is applied over the non-lesional hemisphere (ipsilateral motor cortex). Its effects at spinal level are explored using electrophysiological techniques based on EMG recordings and percutaneous stimulations of peripheral nerves to elicit reciprocal inhibition at wrist level. MRI study relies on diffusion tensor imaging (DTI) and magnetization transfer (MT) [2] . Preliminary results in hemiplegic patients suggest an increase of reciprocal inhibition contrary to the results found in healthy subjects. They also show a relationship between motor impairment and MRI metrics. It opens new vista for motor rehabilitation of stroke patients.

Inter-hemispheric rivalry versus completion: Lessons from line bisection performance with the right and left hands following callosal section

Unilateral hemispheric stroke disrupts the inter-hemispheric balance which is normally maintained by reciprocal inhibitory influences exerted by each hemisphere on the other. This leads to a state where the damaged hemisphere loses its capacity to support function, beyond the direct outcome of focal tissue loss, due to widespread physiological suppression by the overactive healthy hemisphere. This line of theorizing dominates the practice of tDCS and rTMS application in stroke rehabilitation, where reversal of the pathological balance is aimed using excitatory stimulation of the damaged hemisphere and/or inhibitory stimulation of the healthy hemisphere. We present here an examination of the ‘reciprocal inhibition’ concept in a patient with callosal section. GH (M/35) suffered from idiopathic epilepsy with major convulsions almost every day, despite intensive efforts to control disease activity pharmacologically. He was admitted for rehabilitation after a complete surgical section of the forebrain commissures, leaving him with marked apraxia and tactile anomia in the left hand, and with manifestations resembling left neglect dyslexia. Given the disconnection of each hemisphere from the other, performance of diagnostic tests for spatial neglect, by each hand, is assumed to reflect the net effect of the contralateral hemisphere, in the absence of inhibitory influences exerted by the ipsilateral hemisphere. In representational-drawing and figure-copying tasks executed by the dominant right-hand, GH manifested classical left-side neglect. Each of the two disconnected hemispheres demonstrated ipsilateral inattention in manual cancellation and line bisection tasks. Displacement of the subjective midpoint in line bisection performance was greater in right-hand (left-hemisphere) performance. As the postoperative MRI disclosed no extra-callosal damage, the left neglect pattern shown by the isolated left-hemisphere (right-hand) points to an important role of “completion” rather than “rivalry” in inter-hemispheric relationships, raising questions with regard to current practices of non-invasive brain stimulation in stroke rehabilitation.

Effect of functional electrical stimulation of the peroneal nerve on antagonist resistances measured during swing phase of gait in spastic paresis. A randomized, controlled study

In hemiparesis, functional electrical stimulation (FES) of the peroneal nerve aims to compensate for ankle dorsiflexor paresis in swing phase. The present prospective study compared the effects of gait training with FES vs. conventional therapy on plantar flexor overactivity. Twenty subjects with chronic hemiparesis (6 ± 4years post-lesion; mean ± SD) were randomized into two groups: FES (45 min/day of gait self-training using FES) and Control (CON, 3 × 45 min/week of conventional physiotherapy) for 10 weeks. Outcomes at Day 1 and Week 10 included comfortable speed barefoot gait analysis with gastrocnemius medialis (GM) and soleus (SO) electromyography, yielding:, walking speed; and, at the paretic ankle: maximal passive dorsiflexion during stance, maximal active dorsiflexion during swing, velocity of active dorsiflexion over early swing, coefficient of spastic cocontraction in GM and SO over the three thirds of swing (CSC, calculated by the ratio of the RMS of the electromyogram in the period of interest over the RMS of the electromyogram of the same muscle over 100 ms around its maximal voluntary contraction). Intra- and inter-group comparison used rank-ANOVAs. No difference was observed in walking speed changes (both groups pooled; D1, 0.73 ± 0.25 m/s, W10, 0.80 ± 0.30 m/s, ns) and in passive and active dorsiflexion amplitudes (ns). However, the velocity of active dorsiflexion increased in FES while it decreased in Controls (D1 vs. W10, FES, +5 ± 2°/s, P = 0.02; CON, −4 ± 1°/s, P = 0.04). In parallel, CSC GM in early swing tended to improve in FES only (FES, −41 ± 23%, P = 0.09; CON, −24 ± 89%, ns; between group difference ns). In chronic hemiparesis, FES, which focuses on agonist dorsiflexor stimulation during gait improves active dorsiflexion velocity in swing and may also be associated with reduction of plantar flexor spastic cocontraction. Further studies are required to confirm these findings and evaluate whether reciprocal inhibition toward plantar flexors may be restored by FES.

Nerve conduction study in rehabilitation of patients with residuals and complications of long-standing Bell's palsy

From every 100 cases of Bell’s palsy (idiopathic peripheral facial palsy) from 15 to 30 will not recover completely. Some residuals will remain, and some complications will develop. As residuals, one can name weakness of facial muscles, asymmetry of facial expressions, distortion of taste, hyperacusis, dry eye. Possible complications of long-standing Bell’s palsy (BP) are also numerous: contractures of facial muscles, pathological synkinesis, mass movements, crocodile tears, facial pains, headaches, emotional disbalance etc.&#x0D; Unresolved cases of Bell’s palsy require rehabilitation programs that will address both the issues of general nerve regeneration, complications and irregularities in mimetic movements, and psycho-emotional state of long-standing Bell’s palsy patients. There are several methods and systems to assess the condition of facial nerve and functioning of facial muscles. These scales and systems are either therapist- or patient-graded: House-Brackmann Facial Grading system, Sunnybrook Facial Grading system, Facial Clinimetric Evaluation Scale (FaCE Scale), Synkinesis Assessment Questionnaire (SAQ) and several others.&#x0D; At the same time, to compose a well-balanced and focused rehabilitation program, next to subjective assessments and test-photos of standard facial expressions, it is important to have an objective, instrumentally-measured picture of facial nerve recovery, as well as of the physiological ability of mimetic muscles to perform facial movements, to reflect emotions and to produce articulated speech.&#x0D; In that respect, the surface EMG or Nerve Conduction Study (NCS) is the modality of choice. NCS-examination is non-invasive and is relatively easy to perform. It records Compound Muscle Action Potentials (CMAPs) in response to external stimulation. The analysis of recorded graphs allows to evaluate the level of regeneration and maturity of recovering axons in main branches of the facial nerve.&#x0D; At the same time, the standard protocol of NCS does not offer a detailed assessment of each particular muscle of facial expression. It also requires additional time to swap the active electrode position when changing stimulation side from right to left and vice versa.&#x0D; At Crystal Touch Bell’s palsy clinic, we have developed an amended NCS protocol that addresses all mentioned issues. To allow a more detailed assessment of facial muscles, we have added mm.zygomatici (major et minor) and m.depressor anguli oris to the list of measured facial muscles.&#x0D; In order to perform a more focused stimulation and to receive a more “clean” motor responses from facial muscles, we changed the position of stimulating electrode. In the standard protocol, stimulating electrode is placed either pre- or post-auricularly. In Crystal Touch protocol, we position the stimulating electrode above each particular nerve branch that innervates the measured muscle. Therefore, we use six positions of stimulating electrode that correspond to the six measured facial muscles: m.frontalis, m.orbicularis oculi pars superioris, m.nasalis et m.levator labii superioris, mm.zygomatici (major et minor), m.orbicularis oculi pars superioris, m.depressor anguli oris et m.mentalis.&#x0D; To save time required for the examination, instead of placing reference electrode on the nasal bridge (standard protocol), we use contralateral electrode over the same as measured muscle, as a reference electrode. As there are no anastomoses between left and right facial nerves, stimulation of facial nerve on one side will not evoke CMAPs in contralateral facial muscles. This simple amendment allows to save about 15% of total time required for the examination.&#x0D; In this article we also briefly touch the following issues: distortion in reciprocal inhibition of facial muscles-antagonists, forming of the pathological mimetic patterns in the motor cortex due to lack of proprioceptive feedback during long recovery, and the necessity to further investigate from the electrotechnical, engineering and functional point of view the hypothesis of aberrant regeneration as possible cause of facial synkinesis.

Acute whole-body vibration increases reciprocal inhibition

Based on previous evidence that whole-body vibration (WBV) affects pathways involved in disynaptic reciprocal inhibition (DRI), the present hypothesis-driven experiment aimed to assess the acute effects of WBV on DRI and co-contraction. DRI from ankle dorsiflexors to plantar flexors was investigated during submaximal dorsiflexion before and after 1 min of WBV. With electromyography, musculus soleus (SOL) H-reflex depression following a conditioning stimulation of the peroneal nerve (1.1x motor threshold for the musculus tibialis anterior, TA) was assessed and co-contraction was calculated. After WBV, DRI was significantly increased (+4%, p < 0.05). SOL (−13%, p < 0.05) and TA (−6%, p < 0.05) activities were significantly reduced; co-contraction tended to be diminished (−8%, p = 0.05). Dorsiflexion torque remained unchanged. After WBV, DRI increased during submaximal isometric contraction in healthy subjects. The simultaneous SOL relaxation and TA contraction indicate that a more economic movement execution is of functional significance for WBV application in clinical and athletic treatment.

Central Respiration and Mechanical Ventilation in the Gating of Swallow With Breathing.

Swallow-breathing coordination safeguards the lower airways from tracheal aspiration of bolus material as it moves through the pharynx into the esophagus. Impaired movements of the shared muscles or structures of the aerodigestive tract, or disruptions in the interaction of brainstem swallow and respiratory central pattern generators (CPGs) result in dysphagia. To maximize lower airway protection these CPGs integrate respiratory rhythm generation signals and vagal afferent feedback to synchronize swallow with breathing. Despite extensive study, the roles of central respiratory activity and vagal feedback from the lungs as key elements for effective swallow-breathing coordination remain unclear. The effect of altered timing of bronchopulmonary vagal afferent input on swallows triggered during electrical stimulation of the superior laryngeal nerves or by injection of water into the pharyngeal cavity was studied in decerebrate, paralyzed, and artificially ventilated cats. We observed two types of single swallows that produced distinct effects on central respiratory-rhythm across all conditions: post-inspiratory type swallows disrupted central-inspiratory activity without affecting expiration, whereas expiratory type swallows prolonged expiration without affecting central-inspiratory activity. Repetitive swallows observed during apnea reset the E2 phase of central respiration and produced facilitation of swallow motor output nerve burst durations. Moreover, swallow initiation was negatively modulated by vagal feedback and was reset by lung inflation. Collectively, these findings support a novel model of reciprocal inhibition between the swallow CPG and inspiratory or expiratory cells of the respiratory CPG where lung distension and phases of central respiratory activity represent a dual peripheral and central gating mechanism of swallow-breathing coordination.

Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner

Phosphorylation-dependent YAP translocation is a well-known intracellular mechanism of the Hippo pathway; however, the molecular effectors governing YAP cytoplasmic translocation remains undefined. Recent findings indicate that oncogenic YAP paradoxically suppresses Wnt activity. Here, we show that Wnt scaffolding protein Dishevelled (DVL) is responsible for cytosolic translocation of phosphorylated YAP. Mutational inactivation of the nuclear export signal embedded in DVL leads to nuclear YAP retention, with an increase in TEAD transcriptional activity. DVL is also required for YAP subcellular localization induced by E-cadherin, α-catenin, or AMPK activation. Importantly, the nuclear-cytoplasmic trafficking is dependent on the p53-Lats2 or LKB1-AMPK tumor suppressor axes, which determine YAP phosphorylation status. In vivo and clinical data support that the loss of p53 or LKB1 relieves DVL-linked reciprocal inhibition between the Wnt and nuclear YAP activity. Our observations provide mechanistic insights into controlled proliferation coupled with epithelial polarity during development and human cancer.

Functional emergence of a column-like architecture in layer 5 of mouse somatosensory cortex in vivo.

To investigate how the functional architecture is organized in layer 5 (L5) of the somatosensory cortex of a mouse in vivo, the input-output relationship was investigated using an all-optical approach. The neural activity in L5 was optically recorded using a Ca2+ sensor, R-CaMP2, through a microprism inserted in the cortex under two-photon microscopy, while the L5 was regionally excited using optogenetics. The excitability was spread around the blue-light irradiated region, but the horizontal propagation was limited to within a certain distance (λ < 130μm from the center of the illumination spot). When two regions were photostimulated with a short interval, the excitability of each cluster was reduced. Therefore, a column-like architecture had functionally emerged with reciprocal inhibition through a minimal number of synaptic relays. This could generate a synchronous output from a region of L5 with simultaneous enhancement of the signal-to-noise ratio by silencing of the neighboring regions.

Modulation of plantar pressure and gastrocnemius activity during gait using electrical stimulation of the tibialis anterior in healthy adults.

High plantar flexor moment during the stance phase is known to cause high plantar pressure under the forefoot; however, the effects on plantar pressure due to a change of gastrocnemius medialis (GM) activity during gait, have not been investigated to date. Reciprocal inhibition is one of the effects of electrical stimulation (ES), and is the automatic antagonist alpha motor neuron inhibition which is evoked by excitation of the agonist muscle. The aim of this study was to investigate the influences of ES of the tibialis anterior (TA) on plantar pressure and the GM activity during gait in healthy adults. ES was applied to the TAs of twenty healthy male adults for 30 minutes at the level of intensity that causes a full range of dorsiflexion in the ankle (frequency; 50 Hz, on-time; 10 sec, off-time; 10 sec). Subjects walked 10 meters before and after ES, and we measured the peak plantar pressure (PP), pressure time integral (PTI), and gait parameters by using an F-scan system. The percentage of integrated electromyogram (%IEMG), active time, onset time, peak time, and cessation time of TA and GM were calculated. PP and PTI under the forefoot, rear foot, and total plantar surface significantly decreased after the application of ES. Meanwhile, changes of gait parameters were not observed. %IEMG and the active time of both muscles did not change; however, onset time and peak time of GM became significantly delayed. ES application to the TA delayed the timing of onset and peak in the GM, and caused the decrease of plantar pressure during gait. The present results suggest that ES to the TA could become a new method for the control of plantar pressure via modulation of GM activity during gait.

Unilateral wrist extension training after stroke improves strength and neural plasticity in both arms.

Stroke induces bilateral neurological impairment and muscle weakness yielding neurologically more (MA; paretic) and less affected (LA; non-paretic) sides. "Cross-education" refers to training one side of the body to increase strength in the same muscles on the untrained side. Past work showed dorsiflexion training of the LA side produced bilateral strength increases after stroke. The current study explored the presence and extent of cross-education after arm strength training in chronic stroke. Twenty-four chronic stroke participants completed 5 weeks of maximal wrist extension training using their LA arm. Maximal voluntary contraction force, arm motor impairment and functional performance were measured before and after training. Both spinal cord plasticity (n = 12: reciprocal inhibition and cutaneous reflexes, University of Victoria) and cortical plasticity (n = 12: cortical silent period, short-interval intracortical inhibition, intracortical facilitation and transcallosal inhibition, University of British Columbia) were assessed. Five weeks after training, 20 participants completed a follow-up maximal wrist extension retention test. LA wrist extension force increased 42% and MA by 35%. Strength gains were maintained in the follow-up test. Clinically meaningful increases in Fugl-Meyer scores were noted in four participants. Muscle activation was correlated with cutaneous reflex amplitudes after training in the MA arm. LA cortical silent period and transcallosal inhibition from both hemispheres significantly decreased after training. This study shows that high-intensity training with the neurologically less affected "non-paretic" arm can improve strength bilaterally and alter both spinal and cortical plasticity. The extent to which this plasticity can be enhanced or functionally exploited remains to be examined.