Characterization of Spinal Sensorimotor Network Using Transcutaneous Spinal Stimulation during Voluntary Movement Preparation and Performance

Transcutaneous electrical spinal stimulation (TSS) can be used to selectively activate motor pools based on their anatomical arrangements in the lumbosacral enlargement. These spatial patterns of spinal motor activation may have important clinical implications, especially when there is a need to target specific muscle groups. However, our understanding of the net effects and interplay between the motor pools projecting to agonist and antagonist muscles during the preparation and performance of voluntary movements is still limited. The present study was designed to systematically investigate and differentiate the multi-segmental convergence of supraspinal inputs on the lumbosacral neural network before and during the execution of voluntary leg movements in neurologically intact participants. During the experiments, participants (N = 13) performed isometric (1) knee flexion and (2) extension, as well as (3) plantarflexion and (4) dorsiflexion. TSS consisting of a pair pulse with 50 ms interstimulus interval was delivered over the T12-L1 vertebrae during the muscle contractions, as well as within 50 to 250 ms following the auditory or tactile stimuli, to characterize the temporal profiles of net spinal motor output during movement preparation. Facilitation of evoked motor potentials in the ipsilateral agonists and contralateral antagonists emerged as early as 50 ms following the cue and increased prior to movement onset. These results suggest that the descending drive modulates the activity of the inter-neuronal circuitry within spinal sensorimotor networks in specific, functionally relevant spatiotemporal patterns, which has a direct implication for the characterization of the state of those networks in individuals with neurological conditions.

Short latency stretch reflexes depend on the balance of activity in agonist and antagonist muscles during ballistic elbow movements

The spinal stretch reflex is a fundamental building block of motor function, modulating sensitivity across tasks to augment volitional control. Stretch reflex sensitivity can vary continuously during movement and changes between movement and posture. While there have been many demonstrations of reflex modulation and investigations into the underlying mechanisms, there have been few attempts to provide simple, quantitative descriptions of the relationship between the volitional control and stretch reflex sensitivity throughout tasks that require the coordinated activity of several muscles. Here we develop such a description and use it to test the hypothesis that the modulation of stretch reflex sensitivity during movement can be explained by the balance of activity within the relevant agonist and antagonist muscles better than by the activity only in the muscle homonymous with the elicited reflex. We applied continuous pseudo-random perturbations of elbow angle as subjects completed approximately 500 movements in elbow flexion and extension. Measurements were averaged across the repeated movements to obtain continuous estimates of stretch reflex amplitude and background muscle activity. We also ran a control experiment on a subset of subjects performing postural tasks at muscle activity levels matched to those measured in the movement task. For both experiments, we assessed the relationship between background activity in the agonist and antagonist muscles controlling elbow movement and the stretch reflexes elicited in them. We found that modulation in the stretch reflexes during movement can be described by modulation of the background activity in the agonist and antagonist muscles, and that models incorporating agonists and antagonists are significantly better than those considering only the homonymous muscle. Increases in agonist muscle activity enhanced stretch reflex sensitivity whereas increases in antagonist activity suppressed reflex activity. Surprisingly, the magnitude of these effects was similar, suggesting a balance of control between agonists and antagonist that is very different than the dominance of sensitivity to agonist activity during postural tasks. This greater relative sensitivity to antagonist background activity during movement is due to a large decrease in sensitivity to homonymous muscle activity during movement rather than substantial changes in the influence of antagonist muscle activity.

Role of Receptors in Relation to Plaques and Tangles in Alzheimer’s Disease Pathology

Despite the identification of Aβ plaques and NFTs as biomarkers for Alzheimer’s disease (AD) pathology, therapeutic interventions remain elusive, with neither an absolute prophylactic nor a curative medication available to impede the progression of AD presently available. Current approaches focus on symptomatic treatments to maintain AD patients’ mental stability and behavioral symptoms by decreasing neuronal degeneration; however, the complexity of AD pathology requires a wide range of therapeutic approaches for both preventive and curative treatments. In this regard, this review summarizes the role of receptors as a potential target for treating AD and focuses on the path of major receptors which are responsible for AD progression. This review gives an overall idea centering on major receptors, their agonist and antagonist and future prospects of viral mimicry in AD pathology. This article aims to provide researchers and developers a comprehensive idea about the different receptors involved in AD pathogenesis that may lead to finding a new therapeutic strategy to treat AD.

Effects of GABAA Receptors in Dorsal Hippocampus on Memory Retention of Cholestatic Rats

The molecular mechanisms that result in cognitive deficits following cholestasis are mainly unknown. As there are many GABAA receptors in the hippocampus CA1 region and the crucial role for GABA in modulating memory, we evaluated the effects of GABAA receptor agents in the CA1 of cholestatic rats on memory retention. The interaction between GABAergic and opioidergic systems in the CA1 on memory was also investigated. The effects of administration of GABAA receptor agonist and antagonist, muscimol (60, 120 and 240 ng/ side) and bicuculline (100, 200 and 400 ng/ side), into CA1 on memory retention were studies using passive avoidance learning (PAL) task in bile duct ligated (BDL) rats. Naloxone (250 ng/ side), the mu-opioid receptor antagonist, was also co-administered alone or with bicuculline (400 ng/ side) to indicate the interaction between opioidergic and GABAergic system. Cholestasis inhibited memory retrieval is shown by the decrease in the step-through latency (STLr). Administration of muscimol or bicuculline alone after training potentiated or attenuated respectively amnesia in BDL rats dose-dependently. Naloxone (250 ng /side) alone increased STLr in BDL-treated rats. Bicuculline (100 ng/side) alone antagonized the amnesic effect of muscimol (120 ng/side). Co-administration of bicuculline and naloxone or muscimol and naloxone caused a significant difference in STLr compared to only naloxone treated rats which show the interaction between two systems on memory retention in cholestssis. Bicuculline (100 ng/side) microinjection alone antagonized the amnesic effect of muscimol (120 ng/side). We indicated the contribution of intra-CA1 GABAA receptors on memory retention in cholestatic rats by the PAL test. Blockade of each GABAA or mu-opioid receptors alone could attenuate the amnesia in BDL rats. Furthermore, blockade of both GABAA or mu-opioid receptors reversed the memory deficit in BDL-treated rats, which shows the interaction between GABAergic and opioidergic systems on memory retention in this test.

AgAnt: A computational tool to assess Agonist/Antagonist mode of interaction

Activity modulation of proteins is an essential biochemical process in cell. The interplay of the protein, as receptor, and it's corresponding ligand dictates the functional effect. It is imperative to decipher the receptor-ligand functional effect for understanding native biochemical processes as well as for drug discovery. Experimental activity determination is a time extensive process and computational solution towards prediction of activity specific to the receptor-ligand interaction would be of wide interest. We train machine learning models to differentiate between agonist and antagonist protein-ligand pairs and deploy a pairwise approach to utilize the properties of both the receptor and the ligand.

Prediction Models for Agonists and Antagonists of Molecular Initiation Events for Toxicity Pathways Using an Improved Deep-Learning-Based Quantitative Structure–Activity Relationship System

In silico approaches have been studied intensively to assess the toxicological risk of various chemical compounds as alternatives to traditional in vivo animal tests. Among these approaches, quantitative structure–activity relationship (QSAR) analysis has the advantages that it is able to construct models to predict the biological properties of chemicals based on structural information. Previously, we reported a deep learning (DL) algorithm-based QSAR approach called DeepSnap-DL for high-performance prediction modeling of the agonist and antagonist activity of key molecules in molecular initiating events in toxicological pathways using optimized hyperparameters. In the present study, to achieve high throughput in the DeepSnap-DL system–which consists of the preparation of three-dimensional molecular structures of chemical compounds, the generation of snapshot images from the three-dimensional chemical structures, DL, and statistical calculations—we propose an improved DeepSnap-DL approach. Using this improved system, we constructed 59 prediction models for the agonist and antagonist activity of key molecules in the Tox21 10K library. The results indicate that modeling of the agonist and antagonist activity with high prediction performance and high throughput can be achieved by optimizing suitable parameters in the improved DeepSnap-DL system.