Normal Motor Behavior Research Articles

Fresh Human Umbilical Cord Arteries as a Potential Source for Small-Diameter Vascular Grafts.

The demand for small-diameter vascular grafts has been globally increased but still lacks optimal solutions in this category. This study evaluated the feasibility of utilizing human pretreated fresh and nondecellularized umbilical cord arteries (hUCAs) as vascular grafts without needing any immunosuppression process. A mixed lymphocyte reaction assay revealed that hUCAs did not induce lymphocyte proliferation or cytokine production. To assess the in vivo inflammatory response, hUCAs were buried in fatty tissue under the skin of the abdominal wall in the left and right iliac fossas of rats. The average sizes of the implanted hUCAs remained consistent at 30 days post implantation. To evaluate xenogeneic transplantation, hUCAs were grafted to the abdominal aorta below the kidney of Wister rats. Remarkably, all rats exhibited positive revascularization and perfusion, maintaining blood pressure values of around 110/70 mmHg. Doppler ultrasound consistently indicated good circulation, with the three separate echogenic layers corresponding to the three arterial wall layers throughout the assessment period. Grafted rats exhibited normal motor behavior, accompanied by positive responses to thermal and pain stimulation. Blood biochemical values and whole blood cell counts showed no significant differences between pre and post-transplantation. Histological analysis of the grafts revealed no calcification or thrombosis, and a mild chronic inflammatory response was presented. In conclusion, hUCAs maintained their structural and functional properties after transplantation in rats without immunosuppression. This highlights their potential as a source for allogeneic, readily accessible, small-diameter vascular grafts.

Dopamine-mediated plasticity preserves excitatory connections to direct pathway striatal projection neurons and motor function in a mouse model of Parkinson's disease.

The cardinal symptoms of Parkinson's disease (PD) such as bradykinesia and akinesia are debilitating, and treatment options remain inadequate. The loss of nigrostriatal dopamine neurons in PD produces motor symptoms by shifting the balance of striatal output from the direct (go) to indirect (no-go) pathway in large part through changes in the excitatory connections and intrinsic excitabilities of the striatal projection neurons (SPNs). Here, we report using two different experimental models that a transient increase in striatal dopamine and enhanced D1 receptor activation, during 6-OHDA dopamine depletion, prevent the loss of mature spines and dendritic arbors on direct pathway projection neurons (dSPNs) and normal motor behavior for up to 5 months. The primary motor cortex and midline thalamic nuclei provide the major excitatory connections to SPNs. Using ChR2-assisted circuit mapping to measure inputs from motor cortex M1 to dorsolateral dSPNs, we observed a dramatic reduction in both experimental model mice and controls following dopamine depletion. Changes in the intrinsic excitabilities of SPNs were also similar to controls following dopamine depletion. Future work will examine thalamic connections to dSPNs. The findings reported here reveal previously unappreciated plasticity mechanisms within the basal ganglia that can be leveraged to treat the motor symptoms of PD.

NaV1.1 and NaV1.6 Play Unique and Essential Roles in Muscle Spindle Afferent Function in Adult Mice

Voltage gated sodium channels (NaVs) are crucial for the generation and propagation of action potentials. There are 9 different isoforms found in mammals (NaV1.1-1.9), and NaV1.1, NaV1.6, and NaV1.7 are found in the muscle proprioceptors that sense muscle stretch, the muscle spindle afferents. This sensory information is critical for motor reflexes and the sense of body and limb position in space. We previously found that mice lacking one or both copies of NaV1.1 in peripheral sensory neurons displayed motor deficits, including intention tremors. Muscle spindle afferents in these mice also had unstable static stretch sensitivity but normal dynamic sensitivity, suggesting a specific deficit in the maintenance of proprioceptor excitability when the Piezo2 channel was likely to be closed (Espino, et al., 2022). We hypothesized that NaV1.6 would also be necessary for normal motor behavior and muscle spindle afferent function. We generated sensory neuron specific deletions of NaV1.6 by crossing NaV1.6fl/fl mice with mice expressing PirtCre (NaV1.6cko) and observed severe motor deficits on the open field and rotarod test only in NaV1.6cko (n=15) and not NaV1.6Het (n=12) mice compared to NaV1.6fl/fl controls (n=8). In contrast to mice lacking NaV1.1, we did not observe intention tremors. We used an ex vivo muscle nerve preparation consisting of the extensor digitorum longus muscle and peroneal branch of the sciatic nerve. The muscle was maintained at the length of maximal twitch contraction (Lo) and given a battery of 9 ramp-and-hold stretches (2.5, 5, and 7.5% Lo repeated 3 times each) and 16 sinusoidal vibrations (5-100 μm amplitude; 10-100 Hz frequency). Preliminary results include recordings from 18 adult mice of both sexes (NaV1.6fl/fl n=8; NaV1.6cko n=10). We were only able to find stretch sensitive responses in 3 of 10 NaV1.6cko mice, and those were severely impaired with firing rates less than 5 Hz. In contrast, we found robust slowly adapting responses to stretch in all 8 NaV1.6fl/fl mice. Only 1 of 10 NaV1.6cko mice had any firing in response to vibration, in contrast to the normal dynamic sensitivity observed in NaV1.6fl/fl and NaV1.1cko afferents. This suggests that NaV1.6 plays a critical role in initiating muscle spindle afferent transmission, whereas NaV1.1 is essential for maintaining proprioceptor excitability during static stretch. Future studies will determine whether loss of NaV1.7, which does not result in motor deficits, alters muscle spindle afferent function. This work was supported by NIH Grant 5SC3GM127195 (KAW) a RISE Fellowship 5R25GM71381 (SO), NIH 5T32GM099608-10 and 1T32GM1144303-01A1 (CE). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Transfection of the BDNF Gene in the Surviving Dopamine Neurons in Conjunction with Continuous Administration of Pramipexole Restores Normal Motor Behavior in a Bilateral Rat Model of Parkinson's Disease.

In Parkinson's disease (PD), progressive degeneration of nigrostriatal innervation leads to atrophy and loss of dendritic spines of striatal medium spiny neurons (MSNs). The loss disrupts corticostriatal transmission, impairs motor behavior, and produces nonmotor symptoms. Nigral neurons express brain-derived neurotropic factor (BDNF) and dopamine D3 receptors, both protecting the dopamine neurons and the spines of MSNs. To restore motor and nonmotor symptoms to normality, we assessed a combined therapy in a bilateral rat Parkinson's model, with only 30% of surviving neurons. The preferential D3 agonist pramipexole (PPX) was infused for four ½ months via mini-osmotic pumps and one month after PPX initiation; the BDNF-gene was transfected into the surviving nigral cells using the nonviral transfection NTS-polyplex vector. Overexpression of the BDNF-gene associated with continuous PPX infusion restored motor coordination, balance, normal gait, and working memory. Recovery was also related to the restoration of the average number of dendritic spines of the striatal projection neurons and the number of TH-positive neurons of the substantia nigra and ventral tegmental area. These positive results could pave the way for further clinical research into this promising therapy.

Expression mapping of GREM1 and functional contribution of its secreting cells in the brain using transgenic mouse models

GREMLIN1 (GREM1) is a secreted protein that antagonizes bone morphogenetic proteins (BMPs). While abnormal GREM1 expression has been reported to cause behavioral defects in postpartum mice, the spatial and cellular distribution of GREM1 in the brain and the influence of the GREM1-secreting cells on brain function and behavior remain unclear. To address this, we designed a genetic cassette incorporating a 3×Flag-TeV-HA-T2A-tdTomato sequence, resulting in the creation of a novel Grem1Tag mouse model, expressing an epitope tag (3×Flag-TeV-HA-T2A) followed by a fluorescent reporter (tdTomato) under the control of the endogenous Grem1 promoter. This design facilitated precise tracking of the cell origin and distribution of GREM1 in the brain using tdTomato and Flag (or HA) markers, respectively. We confirmed that the Grem1Tag mouse exhibited normal motor, cognitive, and social behaviors at postnatal 60 days (P60), compared with C57BL/6J controls. Through immunofluorescence staining, we comprehensively mapped the distribution of GREM1-secreting cells across the central nervous system. Pervasive GREM1 expression was observed in the cerebral cortex (Cx), medulla, pons, and cerebellum, with the highest levels in the Cx region. Notably, within the Cx, GREM1 was predominantly secreted by excitatory neurons, particularly those expressing calcium/calmodulin-dependent protein kinase II alpha (Camk2a), while inhibitory neurons (parvalbumin-positive, PV+) and glial cells (oligodendrocytes, astrocytes, and microglia) showed little or no GREM1 expression. To delineate the functional significance of GREM1-secreting cells, a selective ablation at P42 using a diphtheria toxin A (DTA) system resulted in increased anxiety-like behavior and impaired memory in mice. Altogether, our study harnessing the Grem1Tag mouse model reveals the spatial and cellular localization of GREM1 in the mouse brain, shedding light on the involvement of GREM1-secreting cells in modulating brain function and behavior. Our Grem1Tag mouse serves as a valuable tool for further exploring the precise role of GREM1 in brain development and disease.

Neural oscillatory activity and connectivity in children who stutter during a non-speech motor task

BackgroundNeural motor control rests on the dynamic interaction of cortical and subcortical regions, which is reflected in the modulation of oscillatory activity and connectivity in multiple frequency bands. Motor control is thought to be compromised in developmental stuttering, particularly involving circuits in the left hemisphere that support speech, movement initiation, and timing control. However, to date, evidence comes from adult studies, with a limited understanding of motor processes in childhood, closer to the onset of stuttering.MethodsWe investigated the neural control of movement initiation in children who stutter and children who do not stutter by evaluating transient changes in EEG oscillatory activity (power, phase locking to button press) and connectivity (phase synchronization) during a simple button press motor task. We compared temporal changes in these oscillatory dynamics between the left and right hemispheres and between children who stutter and children who do not stutter, using mixed-model analysis of variance.ResultsWe found reduced modulation of left hemisphere oscillatory power, phase locking to button press and phase connectivity in children who stutter compared to children who do not stutter, consistent with previous findings of dysfunction within the left sensorimotor circuits. Interhemispheric connectivity was weaker at lower frequencies (delta, theta) and stronger in the beta band in children who stutter than in children who do not stutter.ConclusionsTaken together, these findings indicate weaker engagement of the contralateral left motor network in children who stutter even during low-demand non-speech tasks, and suggest that the right hemisphere might be recruited to support sensorimotor processing in childhood stuttering. Differences in oscillatory dynamics occurred despite comparable task performance between groups, indicating that an altered balance of cortical activity might be a core aspect of stuttering, observable during normal motor behavior.

Safety Assessments of Electroacupuncture-Mediated Blood–Brain Barrier Opening: An Animal Study

The presence of the Blood–Brain barrier (BBB) makes it difficult for therapeutic agents to reach the brain to treat brain diseases. As an emerging treatment, electroacupuncture (EA)-mediated BBB opening can temporarily increase the permeability of the brain blood vessels to increase the concentration of the therapeutic agent in the brain parenchyma, which offers great clinical benefits. Recent studies have suggested that BBB opening with excessive exposure levels may cause tissue/cell damage and short-term behavioral changes. Here, we investigated whether the EA-mediated BBB opening cause serious adverse events in the normal rat brain tissue and motor behavior, such as brain tissue damage, histopathologic alteration, or aggravated behavioral changes. EA was performed on the accupoint GV26 and GV20. Evans Blue Assay (EBA) and fluorescein isothiocyanate (FITC)–dextran Assay were performed to assess the BBB permeability. Immunofluorescence of GFAP-positive cells was marked and Hematoxylin-eosin (HE) Staining was carried out for assessing brain cortex damage. Tunel Assay was conducted to assess cell apoptosis. ELISA was used to measure the contents of TNF-α and IL-1β in brain tissue to explore the inflammatory response. The open field test, balance beam test and Y-Maze test were carried out to assess and neural behaviour. EA can induce an increase in BBB permeability on rats, allowing the macromolecular tracer Evans blue (EB) and Fluorescein Isothiocyanate (FITC)–Dextran to enter the brain. Histological analysis indicated that there was no obvious red blood cell leakage and a cellular apoptotic response in the brain tissue of rats with EA treatment. In addition, EA stimulation at specific parameters did not impair the rats’ motor ability, balance and coordination, and short-term spatial learning and memory. Our results suggest that EA can safely and effectively open the BBB in rats without causing brain damage and behavioral memory impairment.

Expression Mapping and Functional Analysis of Orphan G-Protein-Coupled Receptor GPR158 in the Adult Mouse Brain Using a GPR158 Transgenic Mouse.

Aberrant expression of G-protein-coupled receptor 158 (GPR158) has been reported to be inextricably linked to a variety of diseases affecting the central nervous system, including Alzheimer's disease (AD), depression, intraocular pressure, and glioma, but the underlying mechanism remains elusive due to a lack of biological and pharmacological tools to elaborate its preferential cellular distribution and molecular interaction network. To assess the cellular localization, expression, and function of GPR158, we generated an epitope-tagged GPR158 mouse model (GPR158Tag) that exhibited normal motor, cognitive, and social behavior, no deficiencies in social memory, and no anxiety-like behavior compared to C57BL/6J control mice at P60. Using immunofluorescence, we found that GPR158+ cells were distributed in several brain regions including the cerebral cortex, hippocampus, cerebellum, and caudate putamen. Next, using the cerebral cortex of the adult GPR158Tag mice as a representative region, we found that GPR158 was only expressed in neurons, and not in microglia, oligodendrocytes, or astrocytes. Remarkably, the majority of GPR158 was enriched in Camk2a+ neurons whilst limited expression was found in PV+ interneurons. Concomitant 3D co-localization analysis revealed that GPR158 was mainly distributed in the postsynaptic membrane, but with a small portion in the presynaptic membrane. Lastly, via mass spectrometry analysis, we identified proteins that may interact with GPR158, and the relevant enrichment pathways were consistent with the immunofluorescence findings. RNA-seq analysis of the cerebral cortex of the GPR158-/- mice showed that GPR158 and its putative interacting proteins are involved in the chloride channel complex and synaptic vesicle membrane composition. Using these GPR158Tag mice, we were able to accurately label GPR158 and uncover its fundamental function in synaptic vesicle function and memory. Thus, this model will be a useful tool for subsequent biological, pharmacological, and electrophysiological studies related to GPR158.

Local synchronicity in dopamine-rich caudate nucleus influences Huntington's disease motor phenotype.

Structural grey and white matter changes precede the manifestation of clinical signs of Huntington's disease by many years. Conversion to clinically manifest disease therefore likely reflects not merely atrophy but a more widespread breakdown of brain function. Here, we investigated the structure-function relationship close to and after clinical onset, in important regional brain hubs, particularly caudate nucleus and putamen, which are central to maintaining normal motor behaviour. In two independent cohorts of patients with premanifest Huntington's disease close to onset and very early manifest Huntington's disease (total n = 84; n = 88 matched controls), we used structural and resting state functional MRI. We show that measures of functional activity and local synchronicity within cortical and subcortical regions remain normal in the premanifest Huntington's disease phase despite clear evidence of brain atrophy. In manifest Huntington's disease, homeostasis of synchronicity was disrupted in subcortical hub regions such as caudate nucleus and putamen, but also in cortical hub regions, for instance the parietal lobe. Cross-modal spatial correlations of functional MRI data with receptor/neurotransmitter distribution maps showed that Huntington's disease-specific alterations co-localize with dopamine receptors D1 and D2, as well as dopamine and serotonin transporters. Caudate nucleus synchronicity significantly improved models predicting the severity of the motor phenotype or predicting the classification into premanifest Huntington's disease or motor manifest Huntington's disease. Our data suggest that the functional integrity of the dopamine receptor-rich caudate nucleus is key to maintaining network function. The loss of caudate nucleus functional integrity affects network function to a degree that causes a clinical phenotype. These insights into what happens in Huntington's disease could serve as a model for what might be a more general relationship between brain structure and function in neurodegenerative diseases in which other brain regions are vulnerable.

Stimulation of extrinsic sympathetic nerves differentially affects neurogenic motor activity in guinea pig distal colon.

The speed of pellet propulsion through the isolated guinea pig distal colon in vitro significantly exceeds in vivo measurements, suggesting a role for inhibitory mechanisms from sources outside the gut. The aim of this study was to investigate the effects of sympathetic nerve stimulation on three different neurogenic motor behaviors of the distal colon: transient neural events (TNEs), colonic motor complexes (CMCs), and pellet propulsion. To do this, segments of guinea pig distal colon with intact connections to the inferior mesenteric ganglion (IMG) were set up in organ baths allowing for simultaneous extracellular suction electrode recordings from smooth muscle, video recordings for diameter mapping, and intraluminal manometry. Electrical stimulation (1-20 Hz) of colonic nerves surrounding the inferior mesenteric artery caused a statistically significant, frequency-dependent inhibition of TNEs, as well as single pellet propulsion, from frequencies of 5Hz and greater. Significant inhibition of CMCs required stimulation frequencies of 10Hz and greater. Phentolamine (3.6μM) abolished effects of colonic nerve stimulation, consistent with a sympathetic noradrenergic mechanism. Sympathetic inhibition was constrained to regions with intact extrinsic nerve pathways, allowing normal motor behaviors to continue without modulation in adjacent extrinsically denervated regions of the same colonic segments. The results demonstrate differential sensitivities to sympathetic input among distinct neurogenic motor behaviors of the colon. Together with findings indicating CMCs activate colo-colonic sympathetic reflexes through the IMG, these results raise the possibility that CMCs may paradoxically facilitate suppression of pellet movement in vivo, through peripheral sympathetic reflex circuits.

Facilitation-inhibition control of motor neuronal persistent inward currents in young and older adults.

A well-coordinated facilitation-inhibition control of motor neuronal persistent inward currents (PICs) via diffuse neuromodulation and local inhibition is essential to ensure motor units discharge at required times and frequencies. Present best estimates indicate that PICs are reduced in older adults; however, it is not yet known whether PIC facilitation-inhibition control is also altered with ageing. We investigated the responses of PICs to (i) a remote handgrip contraction, which is believed to diffusely increase serotonergic input onto motor neurones, and (ii) tendon vibration of the antagonist muscle, which elicits reciprocal inhibition, in young and older adults. High-density surface electromyograms were collected from soleus and tibialis anterior of 18 young and 26 older adults during triangular-shaped plantar and dorsiflexion contractions to 20% (handgrip experiments) and 30% (vibration experiments) of maximum torque (rise-decline rate of 2%/s). A paired-motor-unit analysis was used to calculate ∆F, which is assumed to be proportional to PIC strength. ΔF increased in both soleus (0.55peaks per second (pps), 16.0%) and tibialis anterior (0.42pps, 11.4%) after the handgrip contraction independent of age. Although antagonist tendon vibration reduced ΔF in soleus (0.28pps, 12.6%) independent of age, less reduction was observed in older (0.42pps, 10.7%) than young adults (0.72pps, 17.8%) in tibialis anterior. Our data indicate a preserved ability of older adults to amplify PICs following a remote handgrip contraction, during which increased serotonergic input onto the motor neurones is expected, in both lower leg muscles. However, PIC deactivation in response to reciprocal inhibition was impaired with ageing in tibialis anterior despite being preserved in soleus. KEY POINTS: Motor neuronal persistent inward currents (PICs) are facilitated via diffuse neuromodulation and deactivated by local inhibition to ensure motor units discharge at required times and frequencies, allowing normal motor behaviour. PIC amplitudes appear to be reduced with ageing; however, it is not known whether PIC facilitation-inhibition control is also altered. Remote handgrip contraction, which should diffusely increase serotonergic input onto motor neurones, facilitated PICs similarly in both soleus and tibialis anterior of young and older adults. Antagonist tendon vibration, which induces reciprocal inhibition, reduced PICs in soleus in both young and older adults but had less effect in tibialis anterior in older adults. Data from lower-threshold motor units during low-force contractions suggest that PIC facilitation is preserved with ageing in soleus and tibialis anterior. However, the effect of reciprocal inhibition on the contribution of PICs to motor neurone discharge seems reduced in tibialis anterior but preserved in soleus.

Zinc, brain, behavior

The purpose of the review was to analyze current notions about role of essential trace element zinc in brain activity and therefore in behavior. At the beginning of the review the basic data about zinc metabolism was described. The facts of zinc involvement into neurologic disorders and human cognition were represented. The results of the own investigation, devoted zinc peroral treatment and intrabrain microinjections influence on rats normal and pathological motor behavior were described. In particular, it is shown that zinc, depending on the dose and its mode of entry into the organism, can weaken and prevent the development of picrotoxin-induced neostriatal hyperkinesis (human Huntington horea analog), but it may aggravate hyperkinesis symptoms and even independently cause the motor stereotypy. On the basis of their own data and literary, it was suggested that neurons membranes structures are different sensitive to a certain zinc concentration and what does the specific way of behavior realization is ultimately depend.

A New Definition of Poststroke Spasticity and the Interference of Spasticity With Motor Recovery From Acute to Chronic Stages

The relationship of poststroke spasticity and motor recovery can be confusing. “True” motor recovery refers to return of motor behaviors to prestroke state with the same end-effectors and temporo-spatial pattern. This requires neural recovery and repair, and presumably occurs mainly in the acute and subacute stages. However, according to the International Classification of Functioning, Disability and Health, motor recovery after stroke is also defined as “improvement in performance of functional tasks,” i.e., functional recovery, which is mainly mediated by compensatory mechanisms. Therefore, stroke survivors can execute motor tasks in spite of disordered motor control and the presence of spasticity. Spasticity interferes with execution of normal motor behaviors (“true” motor recovery), throughout the evolution of stroke from acute to chronic stages. Spasticity reduction does not affect functional recovery in the acute and subacute stages; however, appropriate management of spasticity could lead to improvement of motor function, that is, functional recovery, during the chronic stage of stroke. We assert that spasticity results from upregulation of medial cortico-reticulo-spinal pathways that are disinhibited due to damage of the motor cortex or corticobulbar pathways. Spasticity emerges as a manifestation of maladaptive plasticity in the early stages of recovery and can persist into the chronic stage. It coexists and shares similar pathophysiological processes with related motor impairments, such as abnormal force control, muscle coactivation and motor synergies, and diffuse interlimb muscle activation. Accordingly, we propose a new definition of spasticity to better account for its pathophysiology and the complex nuances of different definitions of motor recovery.

Exploring the effects of Ia reciprocal inhibition on neuromodulatory commands in the human lower limb

The control of normal motor behaviors involves sublime interactions between excitatory, inhibitory and neuromodulatory commands to motoneurons. The effects of altered inhibition on neuromodulatory commands has not received much attention in humans. Yet, motoneuron firing patterns can be readily measured from the muscle fibers they innervate, collectively known as motor units (MUs), due to their one‐to‐one spike ratio. Persistent inward currents (PICs) are reduced with activation of Ia fibers from the antagonist muscle in the decerebrate cat. Here, we set out to explore whether estimated PICs are affected by a tonic vibratory input to antagonist tendons in humans. MU firing patterns of the tibialis anterior (TA), soleus (SOL) and medial gastrocnemius (MG) were discriminated using high‐density surface electromyography array electrodes and a convolutive blind source separation algorithm. PICs were estimated using the paired MU analysis technique, which quantifies discharge rate hysteresis (ΔF) by comparing the onset and offset of a high‐threshold MU with respect to a low‐threshold MU, providing an estimate of neuromodulatory drive to the MU. Participants performed isometric plantarflexion and dorsiflexion triangular ramp contractions to 30% of maximal voluntary contraction with 10 s ascending and descending phases. In half of the trials, we applied vibration (128 Hz) to the distal TA tendon (plantarflexion) or Achilles tendon (dorsiflexion) with a constant force of 15 ± 2 N. There were large decreases in ΔF for both the SOL (31.3 ± 7.94%, p = 0.006, d = 0.81) and MG (31.4 ± 10.36%, p = 0.008, d = 0.9) during plantarflexion contractions with vibration applied to the distal TA tendon, and there was a moderate decrease in ΔF for the TA (10.9 ± 8.79%, p = 0.009, d = 0.63) during dorsiflexion with vibration to the Achilles tendon. These findings suggest that Ia reciprocal inhibition from the antagonist muscle can reduce the discharge rate hysteresis, providing insights about the interactions that occur to produce normal human motor behaviors.Support or Funding InformationThis work was supported by National Institute of Health (NIH) grants R01NS098509‐01 and T32HD007418‐23, and a Natural Sciences and Engineering Research Council of Canada (NSERC) Postdoctoral Fellowship.

ВЛИЯНИЕ АЛИМЕНТАРНОЙ НАГРУЗКИ ЦИНКОМ НА НОРМАЛЬНОЕ И ПАТОЛОГИЧЕСКОЕ ДВИГАТЕЛЬНОЕ ПОВЕДЕНИЕ КРЫС

Chronic experiments were performed on rats to study the influence of prolonged acetic zinc alimentary treatment on normal (spontaneous movement in “open field and condition active avoidance reflex in “shuttle box”) and abnormal (choreomyoclonic hyperkinesia, produced by intrastriatal microinjections GABA-A receptors antagonist picrotoxin  2 mcg) motor behavior. 4 mg acetic zinc is used by rats with food ball once a day. 12 mg zinc сonsumption by rats per week did not affected on normal behavior. While 24 mg is produced smaller negative effects on rats reflex performance to 6570% correct responses (of total present during the experiment) but to improved condition avoidance behavior, violated by picrotoxinin rats and reduce the reproducibility of picrotoxin-induced choreo-mioclonic hyperkinesis (human Huntington disease hyperkinesis analog). The influence of zinc on motor behavior depending on its dose and mode of administration is discussed.

The novel pesticide flupyradifurone (Sivanto) affects honeybee motor abilities.

Honeybees and other pollinators are threatened by changing landscapes and pesticides resulting from intensified agriculture. In 2018 the European Union prohibited the outdoor use of three neonicotinoid insecticides due to concerns about pollinators. A new pesticide by the name of "Sivanto" was recently released by Bayer AG. Its active ingredient flupyradifurone binds to the nicotinic acetylcholine receptor (AchR) in the honeybee brain, similar to neonicotinoids. Nevertheless, flupyradifurone is assumed to be harmless for honeybees and can even be applied on flowering crops. So far, only little has been known about sublethal effects of flupyradifurone on honeybees. Intact motor functions are decisive for numerous behaviors including foraging and dancing. We therefore selected a motor assay to investigate in how far sublethal doses of this pesticide affect behavior in young summer and long-lived winter honeybees. Our results demonstrate that flupyradifurone (830 µmol/l) can evoke motor disabilities and disturb normal motor behavior after a single oral administration (1.2 µg/bee). These effects are stronger in long-lived winter bees than in young summer bees. After offering an equal amount of pesticide (1.0-1.75 µg) continuously over 24 h with food the observed effects are slighter. For comparisons we repeated our experiments with the neonicotinoid imidacloprid. Intriguingly, the alterations in behavior induced by this pesticide (4 ng/bee) were different and longer-lasting compared to flupyradifurone, even though both substances bind to nicotinic acetylcholine receptors.

On the Use of t-Distributed Stochastic Neighbor Embedding for Data Visualization and Classification of Individuals with Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder that remains incurable. The available treatments for the disorder include pharmacologic therapies and deep brain stimulation (DBS). These approaches may cause distinct side effects and motor responses. This work presents the application of t-distributed stochastic neighbor embedding (t-SNE), which is a machine learning algorithm for nonlinear dimensionality reduction and data visualization, for the problem of discriminating neurologically healthy individuals from those suffering from PD (treated with levodopa and DBS). Furthermore, the assessment of classification methods is presented. Inertial and electromyographic data were collected while the subjects executed a sequence of four motor tasks. The results were focused on the comparison of the classification performance of a support vector machine (SVM) while discriminating two-dimensional feature sets estimated from Principal Component Analysis (PCA), Sammon's mapping, and t-SNE. The results showed visual and statistical differences for all three investigated groups. Classification accuracy for PCA, Sammon's mapping, and t-SNE was, respectively, 73.5%, 78.6%, and 96.9% for the training set and 67.8%, 74.1%, and 76.6% for the test set. The possibility of discriminating healthy individuals from those with PD treated with levodopa and DBS highlights the fact that each treatment method produces distinct motor behavior. The scatter plots resulting from t-SNE could be used in the clinical practice as an objective tool for measuring the discrepancy between normal and abnormal motor behaviors, being thus useful for the adjustment of treatments and the follow-up of the disorder.

Environmental Factors Influence α‐synuclein Transport In The Gut‐brain Axis In A Rodent Model Of Parkinsonism

In recent years, idiopathic Parkinson's disease (PD) has been hypothesized to be triggered by the gastrointestinal (GI)‐mediated transport of environmental pathogens; these pathogens then travel retrogradely to the central nervous system in a bottom‐up fashion via the vagus nerve, and induce the typical degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc). The presence of misfolded α‐synuclein in SNpc is the characteristic histological hallmark of PD. We have shown previously that oral co‐administration of subthreshold doses of paraquat (1mg/kg) and lectins (0.05%w/v) causes GI dysmotility and may be implicated in PD's etiology.In the present work we aimed to further characterize the effects of this model of Parkinsonism on the gut‐brain axis. Rat groups were gavaged with i) 1% sucrose (control); or ii) 0.5% lectins + paraquat, 1 mg/kg (200μl for 7 days). Motor behavior, and gastric motility/tone were measured 14 and 30 days post‐gavage, via strain gauges sewn to the anterior gastric surface. At the end of the experiment the GI tract and the brainstem were extracted and processed for immunohistochemistry. Organotypic cultures of stomach and small intestine of naïve rats were incubated up to three days in a culture medium containing 0.5% lectins prior to immunohistochemistry. Motor behavioral tests (vibrissae and stepping tests) revealed initial small, albeit significant, motor dysfunctions in the tested rats at 2 weeks post treatment (N=10), the motor dysfunctions were more pronounced at 4 weeks post treatment (N=10). Levodopa (4 mg/kg b.i.d.) re‐established normal motor behavior (N=12).Organotypic cultures revealed that lectins were present in NOS‐ and in NeuN‐ immunoreactive myenteric neurons, as well as in nerve fibers, likely of extrinsic vagal origin. As reported previously (DDW 2017), this experimental model is associated with gastric motor impairment. Tissues from the stomach, small and large intestine of these rats revealed the presence of misfolded α‐synuclein in 40–60 % of myenteric neurons. The presence of α‐synuclein was noted in neurons of the dorsal motor nucleus of the vagus and the SNpc at two weeks post treatment. At four weeks post treatment, the expression of α‐synuclein was more pronounced, and was accompanied by a significant loss of tyrosine‐hydroxylase immunoreactive neurons of the SNpc.The data suggest that prolonged oral exposure to subthreshold doses lectins and paraquat induces a Parkinsonian phenotype that mimics the prodromal GI dysfunctions and α‐synucleopathy progression in the gut‐brain axis observed in patients.Support or Funding InformationNIH DK 55530This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Voluntary inhibitory motor control over involuntary tic movements.

Inhibitory control is crucial for normal adaptive motor behavior. In hyperkinesias, such as tics, disinhibition within the cortico-striato-thalamo-cortical loops is thought to underlie the presence of involuntary movements. Paradoxically, tics are also subject to voluntary inhibitory control. This puzzling clinical observation questions the traditional definition of tics as purely involuntary motor behaviors. Importantly, it suggests novel insights into tic pathophysiology. In this review, we first define voluntary inhibitory tic control and compare it with other notions of tic control from the literature. We then examine the association between voluntary inhibitory tic control with premonitory urges and review evidence linking voluntary tic inhibition to other forms of executive control of action. We discuss the somatotopic selectivity and the neural correlates of voluntary inhibitory tic control. Finally, we provide a scientific framework with regard to the clinical relevance of the study of voluntary inhibitory tic control within the context of the neurodevelopmental disorder of Tourette syndrome. We identify current knowledge gaps that deserve attention in future research. © 2018 International Parkinson and Movement Disorder Society.

Periodic limb movements in complete spinal cord injuries: Important new insights into the pathophysiology of this symptom

Objective Periodic limb movements (PLM) are automatic stereotyped movements of the lower limbs which occurs predominantly at night or when lying down. In a previous study, we identified PLM in numerous patients with spinal cord injuries (SCI), falsely labeled as spasticity and spasms. But unlike spasticity and flexor afferent reflex, the pathophysiology of this movement disorder remains unclear, whether it has a cerebral or spinal origin. Material/Patients and methods Patients with a history of SCI and consecutively addressed for uncontrolled spasticity and spasms despite treatment from March 2014 to July 2016, were systematically assessed by a nocturnal polysomnography (PSG). PLM were defined as a PLM index above 15 events per hour of sleep, according to AASM guidelines. We extracted the data regarding patients presenting with a clinically complete SCI, defined as an ASIA impairment scale scored as A (AIS-A). Results Among the 24 patients initially included, 4 were AIS-A. They all had a thoracic level of injury above Th10. They were all diagnosed with PLM, with a median PLM index of 53.5/h (range [18.2;155]), and PLM arousals of 2.2/h (range [0;15.9]). The initiation of a dopaminergic agonist restored normal sleep motor behaviors in all 4 patients. Discussion/Conclusion The fact that PLM were observed in patients with a clinically complete disruption of the spinal cord, strongly suggested that these movements originates within the spinal cord, possibly below Th10. This hypothesis has been previously raised by the observation of persistent PLM during REM sleep in incomplete SCI patients. We therefore hypothesize the existence of a spinal generator of PLM, at least partly made up by dopaminergic neurons expressing D3 dopa-receptors. This sets the bases for future anatomical and physiological studies for the origination of these movement disorders.