Plasticity In Central Nervous System Research Articles

Plasticity of the Central Nervous System Involving Peripheral Nerve Transfer.

Peripheral nerve injury can lead to partial or complete loss of limb function, and nerve transfer is an effective surgical salvage for patients with these injuries. The inability of deprived cortical regions representing damaged nerves to overcome corresponding maladaptive plasticity after the reinnervation of muscle fibers and sensory receptors is thought to be correlated with lasting and unfavorable functional recovery. However, the concept of central nervous system plasticity is rarely elucidated in classical textbooks involving peripheral nerve injury, let alone peripheral nerve transfer. This article is aimed at providing a comprehensive understanding of central nervous system plasticity involving peripheral nerve injury by reviewing studies mainly in human or nonhuman primate and by highlighting the functional and structural modifications in the central nervous system after peripheral nerve transfer. Hopefully, it will help surgeons perform successful nerve transfer under the guidance of modern concepts in neuroplasticity.

Upper-Extremity Peripheral Nerve Stimulators

Chronic pain conditions are some of the most challenging problems upper-extremity surgeons face and often require a multimodal approach including neuromodulation. Peripheral nerve stimulation (PNS) is one of these modalities, delivering electrical stimulation to peripheral axons to modulate the spinal cord and block out nociceptive signals from the extremity. This blockade leads to long-lasting effects in both the peripheral and central nervous systems. Not only does PNS decrease peripheral pain signals but it also decreases the peripheral inflammatory response and assists with central nervous system plasticity for long-term pain control. Although PNS was initially developed in the 1960s, it has been underrepresented in the literature largely due to the advent of spinal cord stimulation and the lack of Food and Drug Administration-approved hardware for PNS. However, for upper-extremity pain, PNS provides notable benefits over spinal cord stimulation devices, as PNS allows for safer, more specific, and often more effective pain control. As clinicians attempt to limit narcotic use, therapies such as PNS have been revisited and are gaining popularity. We present a narrative review of PNS; discuss its mechanism of action, indications, and surgical technique; and provide a summary of the available literature for the upper-extremity surgeon. Peripheral nerve stimulation offers a solution for chronic, debilitating pain recalcitrant to other treatment modalities.

G-protein coupled receptors and synaptic plasticity in sleep deprivation.

Insufficient sleep has been correlated to many physiological and psychoneurological disorders. Over the years, our understanding of the state of sleep has transcended from an inactive period of rest to a more active state involving important cellular and molecular processes. In addition, during sleep, electrophysiological changes also occur in pathways in specific regions of the mammalian central nervous system (CNS). Activity mediated synaptic plasticity in the CNS can lead to long-term and sometimes permanent strengthening and/or weakening synaptic strength affecting neuronal network behaviour. Memory consolidation and learning that take place during sleep cycles, can be affected by changes in synaptic plasticity during sleep disturbances. G-protein coupled receptors (GPCRs), with their versatile structural and functional attributes, can regulate synaptic plasticity in CNS and hence, may be potentially affected in sleep deprived conditions. In this review, we aim to discuss important functional changes that can take place in the CNS during sleep and sleep deprivation and how changes in GPCRs can lead to potential problems with therapeutics with pharmacological interventions.

Biomaterials patterning regulates neural stem cells fate and behavior: The interface of biology and material science.

The combination of nanotechnology and stem cell biology is one of the most promising advances in the field of regenerative medicine. This novel combination has widely been utilized in vitro settings in an attempt to develop efficient therapeutic strategies to overcome the limited capacity of the central nervous system (CNS) in replacing degenerating neural cells with functionally normal cells after the onset of acute and chronic neurological disorders. Importantly, biomaterials, not only, enhance the endogenous CNS neurogenesis and plasticity, but also, could provide a desirable supportive microenvironment to harness the full potential of the in vitro expanded neural stem cells (NSCs) for regenerative purposes. Here, first, we discuss how the physical and biochemical properties of biomaterials, such as their stiffness and elasticity, could influence the behavior of NSCs. Then, since the NSCs niche or microenvironment is of fundamental importance in controlling the dynamic destiny of NSCs such as their quiescent and proliferative states, topographical effects of surface diversity in biomaterials, that is, the micro-and nano-patterned surfaces will be discussed in detail. Finally, the influence of biomaterials as artificial microenvironments on the behavior of NSCs through the specific mechanotransduction signaling pathway mediated by focal adhesion formation will be reviewed.

The Spatiotemporal Coupling: Regional Energy Failure and Aberrant Proteins in Neurodegenerative Diseases.

The spatial and temporal coordination of each element is a pivotal characteristic of systems, and the central nervous system (CNS) is not an exception. Glial elements and the vascular interface have been considered more recently, together with the extracellular matrix and the immune system. However, the knowledge of the single-element configuration is not sufficient to predict physiological or pathological long-lasting changes. Ionic currents, complex molecular cascades, genomic rearrangement, and the regional energy demand can be different even in neighboring cells of the same phenotype, and their differential expression could explain the region-specific progression of the most studied neurodegenerative diseases. We here reviewed the main nodes and edges of the system, which could be studied to develop a comprehensive knowledge of CNS plasticity from the neurovascular unit to the synaptic cleft. The future goal is to redefine the modeling of synaptic plasticity and achieve a better understanding of neurological diseases, pointing out cellular, subcellular, and molecular components that couple in specific neuroanatomical and functional regions.

Role of Neto1 extracellular domain in modulation of kainate receptors

Kainate receptors play fundamental roles in regulating synaptic transmission and plasticity in central nervous system and are regulated by their cognate auxiliary subunits Neuropilin and tolloid-like proteins 1 and 2 (Neto). While electrophysiology-based insights into functions of Neto proteins are known, biophysical and biochemical studies into Neto proteins have been largely missing till-date. Our biochemical, biophysical, and functional characterization of the purified extracellular domain (ECD) of Neto1 shows that Neto1-ECD exists as monomers in solution and has a micromolar affinity for GluK2 receptors in apo state or closed state. Remarkably, the affinity was ~2.8 fold lower for receptors trapped in the desensitized state, highlighting the conformation-dependent interaction of Neto proteins with kainate receptors. SAXS analysis of Neto1-ECD reveals that their dimensions are long enough to span the entire extracellular domain of kainate receptors. The shape and conformation of Neto1-ECD seems to be altered by calcium ions pointing towards its possible role in modulating Neto1 functions. Functional assays using GluK2 receptors and GluK2/GluA2 chimeric receptors reveal a differential role of Neto1 domains in modulating receptor functions. Although the desensitization rate was not affected by the Neto1-ECD, the recovery rates from the desensitized state are altered.

Central Nervous System Plasticity Influences Language and Cognitive Recovery in Adult Glioma.

Gliomas exist within the framework of complex neuronal circuitry in which network dynamics influence both tumor biology and cognition. The generalized impairment of cognition or loss of language function is a common occurrence for glioma patients. The interface between intrinsic brain tumors such as gliomas and functional cognitive networks are poorly understood. The ability to communicate effectively is critically important for receiving oncological therapies and maintaining a high quality of life. Although the propensity of gliomas to infiltrate cortical and subcortical structures and disrupt key anatomic language pathways is well documented, there is new evidence offering insight into the network and cellular mechanisms underpinning glioma-related aphasia and aphasia recovery. In this review, we will outline the current understanding of the mechanisms of cognitive dysfunction and recovery, using aphasia as an illustrative model.

Lesion-induced changes of brevican expression in the perineuronal net of the superior vestibular nucleus.

Damage to the vestibular sense organs evokes static and dynamic deficits in the eye movements, posture and vegetative functions. After a shorter or longer period of time, the vestibular function is partially or completely restored via a series of processes such as modification in the efficacy of synaptic inputs. As the plasticity of adult central nervous system is associated with the alteration of extracellular matrix, including its condensed form, the perineuronal net, we studied the changes of brevican expression in the perineuronal nets of the superior vestibular nucleus after unilateral labyrinth lesion. Our results demonstrated that the unilateral labyrinth lesion and subsequent compensation are accompanied by the changing of brevican staining pattern in the perineuronal nets of superior vestibular nucleus of the rat. The reduction of brevican in the perineuronal nets of superior vestibular nucleus may contribute to the vestibular plasticity by suspending the non-permissive role of brevican in the restoration of perineuronal net assembly. After a transitory decrease, the brevican expression restored to the control level parallel to the partial restoration of impaired vestibular function. The bilateral changing in the brevican expression supports the involvement of commissural vestibular fibers in the vestibular compensation. All experimental procedures were approved by the 'University of Debrecen - Committee of Animal Welfare' (approval No. 6/2017/DEMAB) and the 'Scientific Ethics Committee of Animal Experimentation' (approval No. HB/06/ÉLB/2270-10/2017; approved on June 6, 2017).

Characterization of Neuronal RNA Modifications during Non-associative Learning in Aplysia Reveals Key Roles for tRNAs in Behavioral Sensitization.

Subtle changes in the landscape of post-transcriptional modifications have emerged as putative regulators of central nervous system plasticity and activity-induced protein synthesis. However, simultaneous characterization of multiple RNA modifications and their covariation during learning and memory paradigms has been impeded by the complexity of animal models and lack of untargeted approaches for identifying pathway-relevant RNA modifications in small-volume samples. Here, we used mass spectrometry to profile spatiotemporal changes in dozens of neuronal RNA modifications in Aplysia californica during behavioral sensitization of a simple defensive reflex. Unique RNA modification patterns were observed in the major ganglia of trained and naı̇ve animals, with two tRNA modifications, namely, 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) and 1-methyladenosine (m1A), at significantly higher levels in trained subjects. We report that tRNAs, and their modifications, correlate with increased polyglutamine synthesis and excitability in neurons, characterizing the first link between noncoding RNA modifications and non-associative learning.

A pilot randomized controlled trial of robotic exoskeleton-assisted exercise rehabilitation in multiple sclerosis

BackgroundCo-occurring mobility and cognitive impairments are common, debilitating, and poorly-managed with pharmacological therapies in persons with multiple sclerosis (MS). Exercise rehabilitation (ER), particularly walking ER, has been suggested as one of the best approaches for managing these manifestations of MS. However, there is a focal lack of efficacy of ER on mobility and cognitive outcomes in persons with MS who present with substantial neurological disability. Such severe neurological disability oftentimes precludes the ability for participation in highly-intensive and repetitive ER that is necessary for eliciting adaptations in mobility and cognition. To address such a concern, robotic exoskeleton-assisted ER (REAER) might represent a promising intervention approach for managing co-occurring mobility and cognitive impairments in those with substantial MS disability who might not benefit from traditional ER. MethodsThe current pilot single-blind, randomized controlled trial (RCT) compared the effects of 4-weeks of REAER with 4-weeks of conventional gait training (CGT) as a standard-of-care control condition on functional mobility (timed up-and-go; TUG), walking endurance (six-minute walk test; 6MWT), cognitive processing speed (CPS; Symbol Digit Modalities Test; SDMT), and brain connectivity (thalamocortical resting-state functional connectivity (RSFC) based on fMRI) outcomes in 10 persons with substantial MS-related neurological disability. ResultsOverall, compared with CGT, 4-weeks of REAER was associated with large improvements in functional mobility (ηp2=.38), CPS (ηp2=.53), and RSFC between the thalamus and ventromedial prefrontal cortex (ηp2=.72), but not walking endurance (ηp2=.01). Further, changes in RSFC were moderately associated with changes in TUG, 6MWT, and SDMT performance, respectively, whereby increased thalamocortical RSFC was associated with improved functional mobility, walking endurance, and CPS (|ρ|>.36). ConclusionThe current pilot RCT provides initial support for REAER as an approach for improving functional mobility and CPS, perhaps based on adaptive and integrative central nervous system plasticity, namely increases in RSFC between the thalamus and ventromedial prefrontal cortex, in a small sample of persons with substantial MS disability. Such a pilot trial provides proof-of-concept data for the design and implementation of an appropriately-powered RCT of REAER in a larger sample of persons with MS who present with co-occurring impairments in both mobility and cognitive functioning.

Involvement of Bcl-xL in Neuronal Function and Development

The B-cell lymphoma (Bcl-2) family of proteins are mainly known for their role in the regulation of apoptosis by preventing pore formation at the mitochondrial outer membrane and subsequent caspase activation. However, Bcl-2 proteins also have non-canonical functions, independent of apoptosis. Indeed, the cell death machinery, including Bcl-2 homologs, was reported to be essential for the central nervous system (CNS), notably with respect to synaptic transmission and axon pruning. Here we focused on Bcl-xL, a close Bcl-2 homolog, which plays a major role in neuronal development, as bclx knock out mice prematurely die at embryonic day 13.5, showing massive apoptosis in the CNS. In addition, we present evidence that Bcl-xL fosters ATP generation by the mitochondria to fuel high energy needs by neurons, and its contribution to synaptic transmission. We discuss how Bcl-xL might control local and transient activation of caspases in neurons without causing cell death. Consistently, Bcl-xL may contribute to morphological changes, such as sprouting and retractation of axon branches, in the context of CNS plasticity. Regarding degenerative diseases and aging, a better understanding of the numerous roles of the cell death machinery in neurons may have future clinical implications.

The Extracellular Domains of GluN Subunits Play an Essential Role in Processing NMDA Receptors in the ER.

N-methyl-D-aspartate receptors (NMDARs) belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian central nervous system (CNS). Functional NMDARs consist of heterotetramers comprised of GluN1, GluN2A-D, and/or GluN3A-B subunits, each of which contains four membrane domains (M1 through M4), an intracellular C-terminal domain, a large extracellular N-terminal domain composed of the amino-terminal domain and the S1 segment of the ligand-binding domain (LBD), and an extracellular loop between M3 and M4, which contains the S2 segment of the LBD. Both the number and type of NMDARs expressed at the cell surface are regulated at several levels, including their translation and posttranslational maturation in the endoplasmic reticulum (ER), intracellular trafficking via the Golgi apparatus, lateral diffusion in the plasma membrane, and internalization and degradation. This review focuses on the roles played by the extracellular regions of GluN subunits in ER processing. Specifically, we discuss the presence of ER retention signals, the integrity of the LBD, and critical N-glycosylated sites and disulfide bridges within the NMDAR subunits, each of these steps must pass quality control in the ER in order to ensure that only correctly assembled NMDARs are released from the ER for subsequent processing and trafficking to the surface. Finally, we discuss the effect of pathogenic missense mutations within the extracellular domains of GluN subunits with respect to ER processing of NMDARs.

Effects of lactate and carbon monoxide interactions on neuroprotection and neuropreservation.

Lactate, historically considered a waste product of anerobic metabolism, is a metabolite in whole-body metabolism needed for normal central nervous system (CNS) functions and a potent signaling molecule and hormone in the CNS. Neuronal activity signals normally induce its formation primarily in astrocytes and production is dependent on anerobic and aerobic metabolisms. Functions are dependent on normal dynamic, expansive, and evolving CNS functions. Levels can change under normal physiologic conditions and with CNS pathology. A readily combusted fuel that is sshuttled throughout the body, lactate is used as an energy source and is needed for CNS hemostasis, plasticity, memory, and excitability. Diffusion beyond the neuron active zone impacts activity of neurons and astrocytes in other areas of the brain. Barriergenesis, function of the blood-brain barrier, and buffering between oxidative metabolism and glycolysis and brain metabolism are affected by lactate. Important to neuroprotection, presence or absence is associated with L-lactate and heme oxygenase/carbon monoxide (a gasotransmitter) neuroprotective systems. Effects of carbon monoxide on L-lactate affect neuroprotection – interactions of the gasotransmitter with L-lactate are important to CNS stability, which will be reviewed in this article.

Can We Capitalize on Central Nervous System Plasticity in Young Athletes to Inoculate Against Injury?

There are numerous physical, social, and psychological benefits of exercise, sport and play for youth athletes. However, dynamic activities come with a risk of injury that has yet to be abated, warranting novel therapeutics to promote injury-resistance and to keep an active lifestyle throughout the lifespan. The purpose of the present manuscript was to summarize the extant literature and potential connecting framework regarding youth brain development and neuroplasticity associated with musculoskeletal injury. This review provides the foundation for our proposed framework that utilizes the OPTIMAL (Optimizing Performance Through Intrinsic Motivation and Attention for Learning) theory of motor learning to elicit desirable biomechanical adaptations to support injury prevention (injury risk reduction), rehabilitation strategies, and exercise performance for youth physical activity and play across all facets of sport (Prevention Rehabilitation Exercise Play; PREP). We conclude that both young male and females are ripe for OPTIMAL PREP strategies that promote desirable movement mechanics by leveraging a unique time window for which their heightened state of central nervous system plasticity is capable of enhanced adaptation through novel therapeutic interventions.

Intrinsic and extrinsic regulators of oligodendrocyte progenitor proliferation and differentiation

Oligodendrocytes are highly specialized glial cells, responsible for producing myelin in the central nervous system (CNS). The multi-stage process of oligodendrocyte development is tightly regulated to ensure proper lineage progression of oligodendrocyte progenitor cells (OPCs) to mature myelin producing oligodendrocytes. This developmental process involves complex interactions between several intrinsic signaling pathways that are modulated by an array of extrinsic factors. Understanding these regulatory processes is of crucial importance, as it may help to identify specific molecular targets both to enhance plasticity in the normal CNS and to promote endogenous recovery following injury or disease. This review describes two major regulators that play important functional roles in distinct phases of oligodendrocyte development: OPC proliferation and differentiation. Specifically, we highlight the roles of the extracellular astrocyte/radial glia-derived protein Endothelin-1 in OPC proliferation and the intracellular Akt/mTOR pathway in OPC differentiation. Lastly, we reflect on how recent advances in neuroscience and scientific technology will enable greater understanding into how intrinsic and extrinsic regulators interact to generate oligodendrocyte diversity.

Therapeutic potential of neuromodulation for demyelinating diseases

Neuromodulation represents a cutting edge class of both invasive and non-invasive therapeutic methods which alter the activity of neurons. Currently, several different techniques have been developed - or are currently being investigated – to treat a wide variety of neurological and neuropsychiatric disorders. Recently, in vivo and in vitro studies have revealed that neuromodulation can also induce myelination, meaning that it could hold potential as a therapy for various demyelinating diseases including multiple sclerosis and progressive multifocal leukencepalopathy. These findings come on the heels of a paradigm shift in the view of myelin’s role within the nervous system from a static structure to an active co-regulator of central nervous system plasticity and participant in neuron-mediated modulation. In the present review, we highlight several of the recent findings regarding the role of neural activity in altering myelination including several soluble and contact-dependent factors that seem to mediate neural activity-dependent myelination. We also highlight several considerations for neuromodulatory techniques, including the need for further research into spatiotemporal precision, dosage, and the safety and efficacy of transcranial focused ultrasound stimulation, an emerging neuromodulation technology. As the field of neuromodulation continues to evolve, it could potentially bring forth methods for the treatment of demyelinating diseases, and as such, further investigation into the mechanisms of neuron-dependent myelination as well as neuro-imaging modalities that can monitor myelination activity is warranted.

Preparation of Peripheral Nerve Stimulation Electrodes for Chronic Implantation in Rats.

Peripheral nerve cuff electrodes have long been used in the neurosciences and related fields for stimulation of, for example, vagus or sciatic nerves. Several recent studies have demonstrated the effectiveness of chronic VNS in enhancing central nervous system plasticity to improve motor rehabilitation, extinction learning, and sensory discrimination. Construction of chronically implantable devices for use in such studies is challenging due to rats' small size, and typical protocols require extensive training of personnel and time-consuming microfabrication methods. Alternatively, commercially available implantable cuff electrodes can be purchased at a significantly higher cost. In this protocol, we present a simple, low-cost method for construction of small, chronically implantable peripheral nerve cuff electrodes for use in rats. We validate the short and long-term reliability of our cuff electrodes by demonstrating that VNS in ketamine/xylazine anesthetized rats produces decreases in breathing rate consistent with activation of the Hering-Breuer reflex, both at the time of implantation and up to 10 weeks after device implantation. We further demonstrate the suitability of the cuff electrodes for use in chronic stimulation studies by pairing VNS with skilled lever press performance to induce motor cortical map plasticity.

Interaction between Polysialic Acid and the MARCKS-ED Peptide at the Molecular Level.

Polysialic acid (polySia) is a highly negatively charged linear homopolymer comprising α-2,8-linked sialic acids. It is abundant in the embryonic brain and modulates various functions such as differentiation and synaptic plasticity in the adult central nervous system by direct binding to its protein partners. One such example is the binding of polySia to myristoylated-alanine rich C-kinase substrate (MARCKS) to modulate neuritogenesis. To understand their interaction mechanism at the molecular level, we performed a binding assay which showed a direct binding of the MARCKS-ED peptide (KKKKKRFSFKKSFKLSGFSFKKNKK) with polySia in a concentration-dependent manner. Molecular dynamics simulations revealed that this binding is not exclusively dominated by electrostatics but can in part be attributed to the presence of near-regularly spaced Phe residues, that confer a compact 3D conformation based on pseudoglycine loop structures supported by Phe-Phe interactions. Our simulations, which are confirmed by circular dichroism measurements, also indicate that the peptide-polySia binding induces large-scale conformational rearrangement of polySia into coils at the binding site, whereas the peptide conformation is relatively unperturbed. As a consequence, we predict that each peptide can bind to a domain extending ∼14 polySia repeat units. Using the fluorescently tagged MARCKS-ED peptide on rat brainstem tissue sections, we demonstrate the ability of the peptide to detect polySia, similarly to polySia-specific antibody mAb735, especially in the spinal trigeminal nucleus and the dorsal vagal complex. This study provides information about the interaction between polySia and its CNS protein binding partner, MARCKS, and provides a fundamental platform for further studies to explore the prospect of the MARCKS-ED as an effective polySia-binding peptide for bioimaging and drug delivery applications.

Role of Brain-Derived Neurotrophic Factor in Cognitive Function and Exercise

Brain-Derived Neurotrophic Factor (BDNF) is a member of neurotrophins and it plays important role in both peripheral nervous system (PNS) and short-term, as well as long-term plasticity in central nervous system. Physical exercise fosters neurocognitive functions and brain plasticity at all ages. However, there was an interesting finding stated that BDNF concentration was found to be lower in the trained athletes compared to that of control. Platelet BDNF is found to be acquired from the blood circulation rather than the megakaryocyte precursor cells. This review directs attention to the role of BDNF on cognitive function intensified by exercise for future perspectives.
 
 
 
 Keywords: BDNF, cognitive function, exercise

Central Nervous System Reorganization and Pain After Spinal Cord Injury: Possible Targets for Physical Therapy-A Systematic Review of Neuroimaging Studies.

Pain is one of the main symptoms associated with spinal cord injury (SCI) and can be associated with changes to the central nervous system (CNS). This article provides an overview of the evidence relating to CNS changes (structural and functional) associated with pain in SCIs. A systematic review was performed, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, on PubMed, Embase, and Web of Science in March 2018. Studies were selected if they concerned changes in the CNS of patients with SCI, regardless of the type of imagery. Data were extracted by 2 blinded reviewers. There is moderate evidence for impaired electroencephalographic function and metabolic abnormalities in the anterior cingulate in patients experiencing pain. There is preliminary evidence that patients with pain have morphological and functional changes to the somatosensory cortex and alterations to thalamic metabolism. There are conflicting data regarding the relationships between lesion characteristics and pain. In contrast, patients without pain can display protective neuroplasticity. Further studies are required to elucidate fully the relationships between pain and neuroplasticity in patients with SCIs. However, current evidence might support the use of physical therapist treatments targeting CNS plasticity in patients with SCI pain.