Neural Plasticity The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Change of Neural Connectivity of the Red Nucleus in Patients with Striatocapsular Hemorrhage: A Diffusion Tensor Tractography Study Thu, 02 Jul 2015 09:15:50 +0000 The red nucleus (RN) is involved in motor control and it is known to have potential to compensate for injury of the corticospinal tract (CST). We investigated the change of connectivity of the RN (RNc) and its relation to motor function in patients with striatocapsular hemorrhage. Thirty-five chronic patients with striatocapsular hemorrhage were recruited. Motricity Index (MI), Modified Brunnstrom Classification (MBC), and Functional Ambulation Category (FAC) were measured for motor function. The probabilistic tractography method was used for evaluation of the RNc. Fractional anisotropy (FA), mean diffusivity (MD), and tract volume (TV) of the RNc were measured. FA and TV ratios of the RNc in patients with discontinuation of the affected CST were significantly higher than those of patients with preserved integrity of the CST in the affected hemisphere (). TV ratio of the RNc showed significant negative correlation with upper MI (weak correlation, ), total MI (weak correlation, ), and MBC (moderate correlation, ), respectively (). We found that the neural structure of the RNc was relatively increased in the unaffected hemisphere compared with the affected hemisphere in patients with more severe injury of the CST. Sung Ho Jang and Hyeok Gyu Kwon Copyright © 2015 Sung Ho Jang and Hyeok Gyu Kwon. All rights reserved. Neural Plasticity in Multiple Sclerosis: The Functional and Molecular Background Thu, 02 Jul 2015 06:08:44 +0000 Multiple sclerosis is an autoimmune neurodegenerative disorder resulting in motor dysfunction and cognitive decline. The inflammatory and neurodegenerative changes seen in the brains of MS patients lead to progressive disability and increasing brain atrophy. The most common type of MS is characterized by episodes of clinical exacerbations and remissions. This suggests the presence of compensating mechanisms for accumulating damage. Apart from the widely known repair mechanisms like remyelination, another important phenomenon is neuronal plasticity. Initially, neuroplasticity was connected with the developmental stages of life; however, there is now growing evidence confirming that structural and functional reorganization occurs throughout our lifetime. Several functional studies, utilizing such techniques as fMRI, TBS, or MRS, have provided valuable data about the presence of neuronal plasticity in MS patients. CNS ability to compensate for neuronal damage is most evident in RR-MS; however it has been shown that brain plasticity is also preserved in patients with substantial brain damage. Regardless of the numerous studies, the molecular background of neuronal plasticity in MS is still not well understood. Several factors, like IL-1β, BDNF, PDGF, or CB1Rs, have been implicated in functional recovery from the acute phase of MS and are thus considered as potential therapeutic targets. Dominika Justyna Ksiazek-Winiarek, Piotr Szpakowski, and Andrzej Glabinski Copyright © 2015 Dominika Justyna Ksiazek-Winiarek et al. All rights reserved. Evolution of Apparent Diffusion Coefficient and Fractional Anisotropy in the Cerebrum of Asphyxiated Newborns Treated with Hypothermia over the First Month of Life Thu, 02 Jul 2015 06:07:24 +0000 The objective of this study was to assess the evolution of diffusion-weighted imaging (DWI) and diffusion-tensor imaging (DTI) over the first month of life in asphyxiated newborns treated with hypothermia and to compare it with that of healthy newborns. Asphyxiated newborns treated with hypothermia were enrolled prospectively; and the presence and extent of brain injury were scored on each MRI. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were measured in the basal ganglia, in the white matter and in the cortical grey matter. Sixty-one asphyxiated newborns treated with hypothermia had a total of 126 ADC and FA maps. Asphyxiated newborns developing brain injury eventually had significantly decreased ADC values on days 2-3 of life and decreased FA values around day 10 and 1 month of life compared with those not developing brain injury. Despite hypothermia treatment, asphyxiated newborns may develop brain injury that still can be detected with advanced neuroimaging techniques such as DWI and DTI as early as days 2-3 of life. A study of ADC and FA values over time may aid in the understanding of how brain injury develops in these newborns despite hypothermia treatment. Saskia Kwan, Elodie Boudes, Anouk Benseler, Guillaume Gilbert, Christine Saint-Martin, Michael Shevell, and Pia Wintermark Copyright © 2015 Saskia Kwan et al. All rights reserved. Deficient Purposeful Use of Forepaws in Female Mice Modelling Rett Syndrome Mon, 22 Jun 2015 12:37:26 +0000 Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases. Motor abnormalities represent a significant part of the spectrum of RTT symptoms. In the present study we investigated motor coordination and fine motor skill domains in MeCP2-308 female mice, a validated RTT model. This was complemented by the in vivo magnetic resonance spectroscopy (MRS) analysis of metabolic profile in behaviourally relevant brain areas. MeCP2-308 heterozygous female mice (Het, 10-12 months of age) were impaired in tasks validated for the assessment of purposeful and coordinated forepaw use (Morag test and Capellini handling task). A fine-grain analysis of spontaneous behaviour in the home-cage also revealed an abnormal handling pattern when interacting with the nesting material, reduced motivation to explore the environment, and increased time devoted to feeding in Het mice. The brain MRS evaluation highlighted decreased levels of bioenergetic metabolites in the striatal area in Het mice compared to controls. Present results confirm behavioural and brain alterations previously reported in MeCP2-308 males and identify novel endpoints on which the efficacy of innovative therapeutic strategies for RTT may be tested. Bianca De Filippis, Mattia Musto, Luisa Altabella, Emilia Romano, Rossella Canese, and Giovanni Laviola Copyright © 2015 Bianca De Filippis et al. All rights reserved. Reversed Effects of Intermittent Theta Burst Stimulation following Motor Training That Vary as a Function of Training-Induced Changes in Corticospinal Excitability Wed, 17 Jun 2015 09:02:34 +0000 Intermittent theta burst stimulation (iTBS) has the potential to enhance corticospinal excitability (CSE) and subsequent motor learning. However, the effects of iTBS following motor learning are unknown. The purpose of the present study was to explore the effect of iTBS on CSE and performance following motor learning. Therefore twenty-four healthy participants practiced a ballistic motor task for a total of 150 movements. iTBS was subsequently applied to the trained motor cortex (STIM group) or the vertex (SHAM group). Performance and CSE were assessed before motor learning and before and after iTBS. Training significantly increased performance and CSE in both groups. In STIM group participants, subsequent iTBS significantly reduced motor performance with smaller reductions in CSE. CSE changes as a result of motor learning were negatively correlated with both the CSE changes and performance changes as a result of iTBS. No significant effects of iTBS were found for SHAM group participants. We conclude that iTBS has the potential to degrade prior motor learning as a function of training-induced CSE changes. That means the expected LTP-like effects of iTBS are reversed following motor learning. Tino Stöckel, Jeffery J. Summers, and Mark R. Hinder Copyright © 2015 Tino Stöckel et al. All rights reserved. Sensory Deprivation during Early Postnatal Period Alters the Density of Interneurons in the Mouse Prefrontal Cortex Tue, 16 Jun 2015 08:42:27 +0000 Early loss of one sensory system can cause improved function of other sensory systems. However, both the time course and neuronal mechanism of cross-modal plasticity remain elusive. Recent study using functional MRI in humans suggests a role of the prefrontal cortex (PFC) in cross-modal plasticity. Since this phenomenon is assumed to be associated with altered GABAergic inhibition in the PFC, we have tested the hypothesis that early postnatal sensory deprivation causes the changes of inhibitory neuronal circuit in different regions of the PFC of the mice. We determined the effects of sensory deprivation from birth to postnatal day 28 (P28) or P58 on the density of parvalbumin (PV), calbindin (CB), and calretinin (CR) neurons in the prelimbic, infralimbic, and dorsal anterior cingulate cortices. The density of PV and CB neurons was significantly increased in layer 5/6 (L5/6). Moreover, the density of CR neurons was higher in L2/3 in sensory deprived mice compared to intact mice. These changes were more prominent at P56 than at P28. These results suggest that long-term sensory deprivation causes the changes of intracortical inhibitory networks in the PFC and the changes of inhibitory networks in the PFC may contribute to cross-modal plasticity. Hiroshi Ueno, Shunsuke Suemitsu, Yosuke Matsumoto, and Motoi Okamoto Copyright © 2015 Hiroshi Ueno et al. All rights reserved. Synaptic Variability Introduces State-Dependent Modulation of Excitatory Spinal Cord Synapses Thu, 11 Jun 2015 16:50:42 +0000 The relevance of neuronal and synaptic variability remains unclear. Cellular and synaptic plasticity and neuromodulation are also variable. This could reflect state-dependent effects caused by the variable initial cellular or synaptic properties or direct variability in plasticity-inducing mechanisms. This study has examined state-dependent influences on synaptic plasticity at connections between excitatory interneurons (EIN) and motor neurons in the lamprey spinal cord. State-dependent effects were examined by correlating initial synaptic properties with the substance P-mediated plasticity of low frequency-evoked EPSPs and the reduction of the EPSP depression over spike trains (metaplasticity). The low frequency EPSP potentiation reflected an interaction between the potentiation of NMDA responses and the release probability. The release probability introduced a variable state-dependent subtractive influence on the postsynaptic NMDA-dependent potentiation. The metaplasticity was also state-dependent: it was greater at connections with smaller available vesicle pools and high initial release probabilities. This was supported by the significant reduction in the number of connections showing metaplasticity when the release probability was reduced by high Mg2+ Ringer. Initial synaptic properties thus introduce state-dependent influences that affect the potential for plasticity. Understanding these conditions will be as important as understanding the subsequent changes. David Parker Copyright © 2015 David Parker. All rights reserved. Localization of Presynaptic Plasticity Mechanisms Enables Functional Independence of Synaptic and Ectopic Transmission in the Cerebellum Wed, 10 Jun 2015 13:40:27 +0000 In the cerebellar molecular layer parallel fibre terminals release glutamate from both the active zone and from extrasynaptic “ectopic” sites. Ectopic release mediates transmission to the Bergmann glia that ensheathe the synapse, activating Ca2+-permeable AMPA receptors and glutamate transporters. Parallel fibre terminals exhibit several forms of presynaptic plasticity, including cAMP-dependent long-term potentiation and endocannabinoid-dependent long-term depression, but it is not known whether these presynaptic forms of long-term plasticity also influence ectopic transmission to Bergmann glia. Stimulation of parallel fibre inputs at 16 Hz evoked LTP of synaptic transmission, but LTD of ectopic transmission. Pharmacological activation of adenylyl cyclase by forskolin caused LTP at Purkinje neurons, but only transient potentiation at Bergmann glia, reinforcing the concept that ectopic sites lack the capacity to express sustained cAMP-dependent potentiation. Activation of mGluR1 caused depression of synaptic transmission via retrograde endocannabinoid signalling but had no significant effect at ectopic sites. In contrast, activation of NMDA receptors suppressed both synaptic and ectopic transmission. The results suggest that the signalling mechanisms for presynaptic LTP and retrograde depression by endocannabinoids are restricted to the active zone at parallel fibre synapses, allowing independent modulation of synaptic transmission to Purkinje neurons and ectopic transmission to Bergmann glia. Katharine L. Dobson and Tomas C. Bellamy Copyright © 2015 Katharine L. Dobson and Tomas C. Bellamy. All rights reserved. Efficacy of Acute Intermittent Hypoxia on Physical Function and Health Status in Humans with Spinal Cord Injury: A Brief Review Mon, 08 Jun 2015 11:46:32 +0000 Spinal cord injury (SCI) results in a loss of motor and sensory function and is consequent with reductions in locomotion, leading to a relatively sedentary lifestyle which predisposes individuals to premature morbidity and mortality. Many exercise modalities have been employed to improve physical function and health status in SCI, yet they are typically expensive, require many trained clinicians to implement, and are thus relegated to specialized rehabilitation centers. These characteristics of traditional exercise-based rehabilitation in SCI make their application relatively impractical considering the time-intensive nature of these regimens and patients’ poor access to exercise. A promising approach to improve physical function in persons with SCI is exposure to acute intermittent hypoxia (IH) in the form of a small amount of sessions of brief, repeated exposures to low oxygen gas mixtures interspersed with normoxic breathing. This review summarizes the clinical application of IH in humans with SCI, describes recommended dosing and potential side effects of IH, and reviews existing data concerning the efficacy of relatively brief exposures of IH to modify health and physical function. Potential mechanisms explaining the effects of IH are also discussed. Collectively, IH appears to be a safe, time-efficient, and robust approach to enhance physical function in chronic, incomplete SCI. Todd A. Astorino, Eric T. Harness, and Ailish C. White Copyright © 2015 Todd A. Astorino et al. All rights reserved. Diverse Short-Term Dynamics of Inhibitory Synapses Converging on Striatal Projection Neurons: Differential Changes in a Rodent Model of Parkinson’s Disease Mon, 08 Jun 2015 06:12:25 +0000 Most neurons in the striatum are projection neurons (SPNs) which make synapses with each other within distances of approximately 100 µm. About 5% of striatal neurons are GABAergic interneurons whose axons expand hundreds of microns. Short-term synaptic plasticity (STSP) between fast-spiking (FS) interneurons and SPNs and between SPNs has been described with electrophysiological and optogenetic techniques. It is difficult to obtain pair recordings from some classes of interneurons and due to limitations of actual techniques, no other types of STSP have been described on SPNs. Diverse STSPs may reflect differences in presynaptic release machineries. Therefore, we focused the present work on answering two questions: Are there different identifiable classes of STSP between GABAergic synapses on SPNs? And, if so, are synapses exhibiting different classes of STSP differentially affected by dopamine depletion? Whole-cell voltage-clamp recordings on SPNs revealed three classes of STSPs: depressing, facilitating, and biphasic (facilitating-depressing), in response to stimulation trains at 20 Hz, in a constant ionic environment. We then used the 6-hydroxydopamine (6-OHDA) rodent model of Parkinson’s disease to show that synapses with different STSPs are differentially affected by dopamine depletion. We propose a general model of STSP that fits all the dynamics found in our recordings. Janet Barroso-Flores, Marco A. Herrera-Valdez, Violeta Gisselle Lopez-Huerta, Elvira Galarraga, and José Bargas Copyright © 2015 Janet Barroso-Flores et al. All rights reserved. Lithium and Valproate Levels Do Not Correlate with Ketamine’s Antidepressant Efficacy in Treatment-Resistant Bipolar Depression Sun, 07 Jun 2015 09:37:43 +0000 Ketamine and lithium both inhibit glycogen synthase kinase 3. In addition, lithium and ketamine have synergistic antidepressant-like effects at individually subeffective doses in rodents. We hypothesized that ketamine’s antidepressant effects would be improved by therapeutic doses of lithium versus valproate and that serum lithium levels would positively correlate with ketamine’s antidepressant efficacy. Thirty-six patients with treatment-resistant bipolar depression maintained on therapeutic-dose lithium (, 0.79 ± 0.15 mEq/L) or valproate (, 79.6 ± 12.4 mg/mL) received 0.5 mg/kg ketamine infusion in a randomized, double-blind, placebo-controlled, crossover trial. The primary depression outcome measure—the Montgomery-Åsberg Depression Rating Scale (MADRS)—was assessed before infusion and at numerous postinfusion time points. Both lithium (F1,118 = 152.08, , and ) and valproate (F1,128 = 20.12, , and ) significantly improved depressive symptoms, but no statistically significant difference was observed between mood stabilizer groups (F1,28 = 2.51, , and ). Serum lithium and valproate levels did not correlate with ketamine’s antidepressant efficacy. Although the study was potentially underpowered, our results suggest that lithium may not potentiate ketamine’s antidepressant efficacy in treatment-resistant bipolar depression. Annie J. Xu, Mark J. Niciu, Nancy B. Lundin, David A. Luckenbaugh, Dawn F. Ionescu, Erica M. Richards, Jennifer L. Vande Voort, Elizabeth D. Ballard, Nancy E. Brutsche, Rodrigo Machado-Vieira, and Carlos A. Zarate Jr. Copyright © 2015 Annie J. Xu et al. All rights reserved. α7 Nicotinic Receptor Promotes the Neuroprotective Functions of Astrocytes against Oxaliplatin Neurotoxicity Wed, 03 Jun 2015 09:00:17 +0000 Neuropathies are characterized by a complex response of the central nervous system to injuries. Glial cells are recruited to maintain neuronal homeostasis but dysregulated activation leads to pain signaling amplification and reduces the glial neuroprotective power. Recently, we highlighted the property of α7 nicotinic-acetylcholine-receptor (nAChR) agonists to relieve pain and induce neuroprotection simultaneously with a strong increase in astrocyte density. Aimed to study the role of α7 nAChR in the neuron-glia cross-talk, we treated primary rat neurons and astrocytes with the neurotoxic anticancer drug oxaliplatin evaluating the effect of the α7 nAChR agonist PNU-282987 (PNU). Oxaliplatin (1 μM, 48 h) reduced cell viability and increased caspase-3 activity of neuron monocultures without damaging astrocytes. In cocultures, astrocytes were not able to protect neurons by oxaliplatin even if glial cell metabolism was stimulated (pyruvate increase). On the contrary, the coculture incubation with 10 μM PNU improved neuron viability and inhibited apoptosis. In the absence of astrocytes, the protection disappeared. Furthermore, PNU promoted the release of the anti-inflammatory cytokine TGF-β1 and the expression of the glutamate-detoxifying enzyme glutamine synthetase. The α7 nAChR stimulation protects neurons from oxaliplatin toxicity through an astrocyte-mediated mechanism. α7 nAChR is suggested for recovering the homeostatic role of astrocytes. Lorenzo Di Cesare Mannelli, Barbara Tenci, Matteo Zanardelli, Paola Failli, and Carla Ghelardini Copyright © 2015 Lorenzo Di Cesare Mannelli et al. All rights reserved. The Effect of Development in Respiratory Sensory Gating Measured by Electrocortical Activations Tue, 02 Jun 2015 06:34:09 +0000 The perception of respiratory sensations can be of significant importance to individuals for survival and greatly impact quality of life. Respiratory sensory gating, similar to somatosensory gating with exteroceptive stimuli, is indicative of brain cortices filtering out repetitive respiratory stimuli and has been investigated in adults with and without diseases. Respiratory gating can be tested with the respiratory-related evoked potential (RREP) method in the electroencephalogram with a paired inspiratory occlusion paradigm. Here, the RREP N1 component elicited by the second stimulus (S2) shows reduced amplitudes compared to the RREP N1 component elicited by the first stimulus (S1). However, little is known regarding the effect of development on respiratory sensory gating. The present study examined respiratory sensory gating in 22 typically developed school-aged children and 22 healthy adults. Paired inspiratory occlusions of 150-ms each with an inter-stimulus-interval of 500-ms were delivered randomly every 2–4 breaths during recording. The main results showed a significantly larger RREP N1 S2/S1 ratio in the children group than in the adult group. In addition, children compared to adults demonstrated significantly smaller N1 peak amplitudes in response to S1. Our results suggest that school-aged children, compared to adults, display reduced respiratory sensory gating. Pei-Ying S. Chan, Chia-Hsiung Cheng, and Andreas von Leupoldt Copyright © 2015 Pei-Ying S. Chan et al. All rights reserved. 7 Channels Regulate Firing during Synaptic Integration in GABAergic Striatal Neurons Sun, 31 May 2015 14:06:32 +0000 Striatal projection neurons (SPNs) process motor and cognitive information. Their activity is affected by Parkinson’s disease, in which dopamine concentration is decreased and acetylcholine concentration is increased. Acetylcholine activates muscarinic receptors in SPNs. Its main source is the cholinergic interneuron that responds with a briefer latency than SPNs during a cortical command. Therefore, an important question is whether muscarinic G-protein coupled receptors and their signaling cascades are fast enough to intervene during synaptic responses to regulate synaptic integration and firing. One of the most known voltage dependent channels regulated by muscarinic receptors is the 7/KCNQ channel. It is not known whether these channels regulate the integration of suprathreshold corticostriatal responses. Here, we study the impact of cholinergic muscarinic modulation on the synaptic response of SPNs by regulating 7 channels. We found that 7 channels regulate corticostriatal synaptic integration and that this modulation occurs in the dendritic/spines compartment. In contrast, it is negligible in the somatic compartment. This modulation occurs on sub- and suprathreshold responses and lasts during the whole duration of the responses, hundreds of milliseconds, greatly altering SPNs firing properties. This modulation affected the behavior of the striatal microcircuit. M. Belén Pérez-Ramírez, Antonio Laville, Dagoberto Tapia, Mariana Duhne, Esther Lara-González, José Bargas, and Elvira Galarraga Copyright © 2015 M. Belén Pérez-Ramírez et al. All rights reserved. Relationship between Zinc (Zn2+) and Glutamate Receptors in the Processes Underlying Neurodegeneration Wed, 27 May 2015 06:34:46 +0000 The results from numerous studies have shown that an imbalance between particular neurotransmitters may lead to brain circuit dysfunction and development of many pathological states. The significance of glutamate pathways for the functioning of the nervous system is equivocal. On the one hand, glutamate transmission is necessary for neuroplasticity, synaptogenesis, or cell survival, but on the other hand an excessive and long-lasting increased level of glutamate in the synapse may lead to cell death. Under clinical conditions, hyperactivity of the glutamate system is associated with ischemia, epilepsy, and neurodegenerative diseases such as Alzheimer’s, Huntington’s, and many others. The achievement of glutamate activity in the physiological range requires efficient control by endogenous regulatory factors. Due to the fact that the free pool of ion Zn2+ is a cotransmitter in some glutamate neurons; the role of this element in the pathophysiology of a neurodegenerative diseases has been intensively studied. There is a lot of evidence for Zn2+ dyshomeostasis and glutamate system abnormalities in ischemic and neurodegenerative disorders. However, the precise interaction between Zn2+ regulative function and the glutamate system is still not fully understood. This review describes the relationship between Zn2+ and glutamate dependent signaling pathways under selected pathological central nervous system (CNS) conditions. Bartłomiej Pochwat, Gabriel Nowak, and Bernadeta Szewczyk Copyright © 2015 Bartłomiej Pochwat et al. All rights reserved. Inhibition of Hyperpolarization-Activated Cation Current in Medium-Sized DRG Neurons Contributed to the Antiallodynic Effect of Methylcobalamin in the Rat of a Chronic Compression of the DRG Tue, 26 May 2015 09:04:34 +0000 Recently several lines of evidence demonstrated that methylcobalamin (MeCbl) might have potential analgesic effect in experimental and clinical studies. However, it was reported that MeCbl had no effect on treating lumbar spinal stenosis induced pain. Thus, the effects of short-term and long-term administration of MeCbl were examined in the chronic compression of dorsal root ganglion (CCD) model. We found that mechanical allodynia was significantly inhibited by a continuous application of high dose and a single treatment of a super high dose of MeCbl. Little is known about mechanisms underlying the analgesia of MeCbl. We examined the effect of MeCbl on the spontaneous activity (SA), the excitability, and hyperpolarization-activated nonselective cation ion current in compressed medium-sized dorsal root ganglion (DRG) neurons using extracellular single fiber recording in vivo and whole-cell patch clamp in vitro. We found that MeCbl significantly inhibited the SA of A-type sensory neurons in a dose-dependent manner and inhibited the excitability of medium-sized DRG neurons. In addition, MeCbl also decreased current density in injured medium-sized DRG neurons. Our results proved that MeCbl might exert an analgesic effect through the inhibition current and then might inhibit the hyperexcitability of primary sensory neurons under neuropathic pain state. Ming Zhang, Wenjuan Han, Jianyong Zheng, Fancheng Meng, Xiying Jiao, Sanjue Hu, and Hui Xu Copyright © 2015 Ming Zhang et al. All rights reserved. The Role of the Right Dorsolateral Prefrontal Cortex in Phasic Alertness: Evidence from a Contingent Negative Variation and Repetitive Transcranial Magnetic Stimulation Study Sun, 24 May 2015 11:26:13 +0000 Phasic alertness represents the ability to increase response readiness to a target following an external warning stimulus. Specific networks in the frontal and parietal regions appear to be involved in the alert state. In this study, we examined the role of the right dorsolateral prefrontal cortex (DLPFC) during the attentional processing of a stimulus using a cued double-choice reaction time task. The evaluation of these processes was conducted by means of Event-Related Potentials (ERPs), in particular by using the Contingent Negative Variation (CNV), and repetitive 1-Hz Transcranial Magnetic Stimulation (rTMS). Transient virtual inhibition of the right DLPFC induced by real 1-Hz rTMS stimulation led to a significant decrease in total CNV and W1-CNV areas if compared with the basal and post-sham rTMS conditions. Reaction times (RTs) did not decrease after inhibitory rTMS, but they did improve after sham stimulation. These results suggest that the right DLPFC plays a crucial role in the genesis and maintenance of the alerting state and learning processes. Daniela Mannarelli, Caterina Pauletti, Antonello Grippo, Aldo Amantini, Vito Augugliaro, Antonio Currà, Paolo Missori, Nicoletta Locuratolo, Maria C. De Lucia, Steno Rinalduzzi, and Francesco Fattapposta Copyright © 2015 Daniela Mannarelli et al. All rights reserved. Neurexin-Neuroligin Synaptic Complex Regulates Schizophrenia-Related DISC1/Kal-7/Rac1 “Signalosome” Wed, 20 May 2015 16:34:20 +0000 Neurexins (NXs) and neuroligins (NLs) are cell adhesion molecules that are localized at opposite sites of synaptic membranes. They interact with each other to promote the assembly, maintenance, and function of synapses in the central nervous system. Both NX and NL are cleaved from a membrane-attached intracellular domain in an activity-dependent manner, generating the soluble ectodomain of NX or NL. Expression of the NX1 and NX3 genes in the brain appears to be regulated by a schizophrenia-related protein, DISC1. Here, we show that soluble ecto-NX1β can regulate the expression of DISC1 and induce signaling downstream of DISC1. We also show that NL1 binds to a well-characterized DISC1 interaction partner, Kal-7, and this interaction can be compromised by DISC1. Our results indicate that the NX/NL synaptic complex is intrinsically involved in the regulation of DISC1 function, thus contributing to a better understanding of the pathology of schizophrenia. Sylwia Owczarek, Marie Louise Bang, and Vladimir Berezin Copyright © 2015 Sylwia Owczarek et al. All rights reserved. Cordycepin Decreases Compound Action Potential Conduction of Frog Sciatic Nerve In Vitro Involving Ca2+-Dependent Mechanisms Tue, 19 May 2015 14:43:16 +0000 Cordycepin has been widely used in oriental countries to maintain health and improve physical performance. Compound nerve action potential (CNAP), which is critical in signal conduction in the peripheral nervous system, is necessary to regulate physical performance, including motor system physiological and pathological processes. Therefore, regulatory effects of cordycepin on CNAP conduction should be elucidated. In this study, the conduction ability of CNAP in isolated frog sciatic nerves was investigated. Results revealed that cordycepin significantly decreased CNAP amplitude and conductive velocity in a reversible and concentration-dependent manner. At 50 mg/L cordycepin, CNAP amplitude and conductive velocity decreased by 62.18 ± 8.06% and 57.34% ± 6.14% compared with the control amplitude and conductive velocity, respectively. However, the depressive action of cordycepin on amplitude and conductive velocity was not observed in Ca2+-free medium or in the presence of Ca2+ channel blockers (CdCl2/LaCl3). Pretreatment with L-type Ca2+ channel antagonist (nifedipine/deltiazem) also blocked cordycepin-induced responses; by contrast, T-type and P-type Ca2+ channel antagonists (Ni2+) failed to block such responses. Therefore, cordycepin decreased the conduction ability of CNAP in isolated frog sciatic nerves via L-type Ca2+ channel-dependent mechanism. Li-Hua Yao, Hui-Min Yu, Qiu-Ping Xiong, Wei Sun, Yan-Liang Xu, Wei Meng, Yu-Ping Li, Xin-Ping Liu, and Chun-Hua Yuan Copyright © 2015 Li-Hua Yao et al. All rights reserved. Social Experience-Dependent Myelination: An Implication for Psychiatric Disorders Tue, 19 May 2015 09:08:25 +0000 Myelination is one of the strategies to promote the conduction velocity of axons in order to adjust to evolving environment in vertebrates. It has been shown that myelin formation depends on genetic programing and experience, including multiple factors, intracellular and extracellular molecules, and neuronal activities. Recently, accumulating studies have shown that myelination in the central nervous system changes more dynamically in response to neuronal activities and experience than expected. Among experiences, social experience-dependent myelination draws attention as one of the critical pathobiologies of psychiatric disorders. In this review, we summarize the mechanisms of neuronal activity-dependent and social experience-dependent myelination and discuss the contribution of social experience-dependent myelination to the pathology of psychiatric disorders. Michihiro Toritsuka, Manabu Makinodan, and Toshifumi Kishimoto Copyright © 2015 Michihiro Toritsuka et al. All rights reserved. Parthenolide Relieves Pain and Promotes M2 Microglia/Macrophage Polarization in Rat Model of Neuropathy Mon, 18 May 2015 12:01:26 +0000 Neuropathic pain treatment remains a challenge because pathomechanism is not fully understood. It is believed that glial activation and increased spinal nociceptive factors are crucial for neuropathy. We investigated the effect of parthenolide (PTL) on the chronic constriction injury to the sciatic nerve (CCI)-induced neuropathy in rat. We analyzed spinal changes in glial markers and M1 and M2 polarization factors, as well as intracellular signaling pathways. PTL (5 µg; i.t.) was preemptively and then daily administered for 7 days after CCI. PTL attenuated the allodynia and hyperalgesia and increased the protein level of IBA1 (a microglial/macrophage marker) but did not change GFAP (an astrocyte marker) on day 7 after CCI. PTL reduced the protein level of M1 (IL-1β, IL-18, and iNOS) and enhanced M2 (IL-10, TIMP1) factors. In addition, it downregulated the phosphorylated form of NF-κB, p38MAPK, and ERK1/2 protein level and upregulated STAT3. In primary microglial cell culture we have shown that IL-1β, IL-18, iNOS, IL-6, IL-10, and TIMP1 are of microglial origin. Summing up, PTL directly or indirectly attenuates neuropathy symptoms and promotes M2 microglia/macrophages polarization. We suggest that neuropathic pain therapies should be shifted from blanketed microglia/macrophage suppression toward maintenance of the balance between neuroprotective and neurotoxic microglia/macrophage phenotypes. Katarzyna Popiolek-Barczyk, Natalia Kolosowska, Anna Piotrowska, Wioletta Makuch, Ewelina Rojewska, Agnieszka M. Jurga, Dominika Pilat, and Joanna Mika Copyright © 2015 Katarzyna Popiolek-Barczyk et al. All rights reserved. Dehydration-Induced Anorexia Reduces Astrocyte Density in the Rat Corpus Callosum Mon, 18 May 2015 08:37:18 +0000 Anorexia nervosa is an eating disorder associated with severe weight loss as a consequence of voluntary food intake avoidance. Animal models such as dehydration-induced anorexia (DIA) mimic core features of the disorder, including voluntary reduction in food intake, which compromises the supply of energy to the brain. Glial cells, the major population of nerve cells in the central nervous system, play a crucial role in supplying energy to the neurons. The corpus callosum (CC) is the largest white matter tract in mammals, and more than 99% of the cell somata correspond to glial cells in rodents. Whether glial cell density is altered in anorexia is unknown. Thus, the aim of this study was to estimate glial cell density in the three main regions of the CC (genu, body, and splenium) in a murine model of DIA. The astrocyte density was significantly reduced (~34%) for the DIA group in the body of the CC, whereas in the genu and the splenium no significant changes were observed. DIA and forced food restriction (FFR) also reduced the ratio of astrocytes to glial cells by 57.5% and 22%, respectively, in the body of CC. Thus, we conclude that DIA reduces astrocyte density only in the body of the rat CC. Daniel Reyes-Haro, Francisco Emmanuel Labrada-Moncada, Ricardo Miledi, and Ataúlfo Martínez-Torres Copyright © 2015 Daniel Reyes-Haro et al. All rights reserved. Anandamide, Acting via CB2 Receptors, Alleviates LPS-Induced Neuroinflammation in Rat Primary Microglial Cultures Mon, 18 May 2015 08:34:41 +0000 Microglial activation is a polarized process divided into potentially neuroprotective phenotype M2 and neurotoxic phenotype M1, predominant during chronic neuroinflammation. Endocannabinoid system provides an attractive target to control the balance between microglial phenotypes. Anandamide as an immune modulator in the central nervous system acts via not only cannabinoid receptors (CB1 and CB2) but also other targets (e.g., GPR18/GPR55). We studied the effect of anandamide on lipopolysaccharide-induced changes in rat primary microglial cultures. Microglial activation was assessed based on nitric oxide (NO) production. Analysis of mRNA was conducted for M1 and M2 phenotype markers possibly affected by the treatment. Our results showed that lipopolysaccharide-induced NO release in microglia was significantly attenuated, with concomitant downregulation of M1 phenotypic markers, after pretreatment with anandamide. This effect was not sensitive to CB1 or GPR18/GPR55 antagonism. Administration of CB2 antagonist partially abolished the effects of anandamide on microglia. Interestingly, administration of a GPR18/GPR55 antagonist by itself suppressed NO release. In summary, we showed that the endocannabinoid system plays a crucial role in the management of neuroinflammation by dampening the activation of an M1 phenotype. This effect was primarily controlled by the CB2 receptor, although functional cross talk with GPR18/GPR55 may occur. Natalia Malek, Katarzyna Popiolek-Barczyk, Joanna Mika, Barbara Przewlocka, and Katarzyna Starowicz Copyright © 2015 Natalia Malek et al. All rights reserved. Striatal Injury with 6-OHDA Transiently Increases Cerebrospinal GFAP and S100B Mon, 18 May 2015 08:34:40 +0000 Both glial fibrillary acidic protein (GFAP) and S100B have been used as markers of astroglial plasticity, particularly in brain injury; however, they do not necessarily change in the same time frame or direction. Herein, we induced a Parkinson’s disease (PD) model via a 6-OHDA intrastriatal injection in rats and investigated the changes in GFAP and S100B using ELISA in the substantia nigra (SN), striatum, and cerebrospinal fluid on the 1st, 7th, and 21st days following the injection. The model was validated using measurements of rotational behaviour induced by methylphenidate and tyrosine hydroxylase in the dopaminergic pathway. To our knowledge, this is the first measurement of cerebrospinal fluid S100B and GFAP in the 6-OHDA model of PD. Gliosis (based on a GFAP increase) was identified in the striatum, but not in the SN. We identified a transitory increment of cerebrospinal fluid S100B and GFAP on the 1st and 7th days, respectively. This initial change in cerebrospinal fluid S100B was apparently related to the mechanical lesion. However, the 6-OHDA-induced S100B secretion was confirmed in astrocyte cultures. Current data reinforce the idea that glial changes precede neuronal damage in PD; however, these findings also indicate that caution is necessary regarding the interpretation of data in this PD model. Cristiane Batassini, Núbia Broetto, Lucas Silva Tortorelli, Milene Borsoi, Caroline Zanotto, Fabiana Galland, Tadeu Mello Souza, Marina Concli Leite, and Carlos-Alberto Gonçalves Copyright © 2015 Cristiane Batassini et al. All rights reserved. Translational Research in Bipolar Disorders Sun, 17 May 2015 08:13:27 +0000 Rodrigo Machado-Vieira, Benicio N. Frey, Ana C. Andreazza, and João Quevedo Copyright © 2015 Rodrigo Machado-Vieira et al. All rights reserved. Neural Stimulation Has a Long-Term Effect on Foreign Vocabulary Acquisition Thu, 14 May 2015 12:52:02 +0000 Acquisition of a foreign language is a challenging task that is becoming increasingly more important in the world nowadays. There is evidence suggesting that the frontal and temporal cortices are involved in language processing and comprehension, but it is still unknown whether foreign language acquisition recruits additional cortical areas in a causal manner. For the first time, we used transcranial random noise stimulation on the frontal and parietal brain areas, in order to compare its effect on the acquisition of unknown foreign words and a sham, or placebo, condition was also included. This type of noninvasive neural stimulation enhances cortical activity by boosting the spontaneous activity of neurons. Foreign vocabulary acquisition was tested both immediately and seven days after the stimulation. We found that stimulation on the posterior parietal, but not the dorsolateral prefrontal cortex or sham stimulation, significantly improved the memory performance in the long term. These results suggest that the posterior parietal cortex is directly involved in acquisition of foreign vocabulary, thus extending the “linguistic network” to this area. Achille Pasqualotto, Begüm Kobanbay, and Michael J. Proulx Copyright © 2015 Achille Pasqualotto et al. All rights reserved. Preclinical Evidences for an Antimanic Effect of Carvedilol Thu, 14 May 2015 07:21:37 +0000 Oxidative imbalance, alterations in brain-derived neurotrophic factor (BDNF), and mitochondrial dysfunction are implicated in bipolar disorder (BD) pathophysiology and comorbidities, for example, cardiovascular conditions. Carvedilol (CVD), a nonselective beta-blocker widely used for the treatment of hypertension, presents antioxidant and mitochondrial stabilizing properties. Thus, we hypothesized that CVD would prevent and/or reverse mania-like behavioral and neurochemical alterations induced by lisdexamfetamine dimesylate (LDX). To do this, male Wistar rats were submitted to two different protocols, namely, prevention and reversal. In the prevention treatment the rats received daily oral administration (mg/kg) of CVD (2.5, 5 or 7.5), saline, valproate (VAL200), or the combination of CVD5 + VAL100 for 7 days. From the 8th to 14th day LDX was added. In the reversal protocol LDX was administered for 7 days with the drugs being added from the 8th to 14th day of treatment. Two hours after the last administration the behavioral (open field and social interaction) and neurochemical (reduced glutathione, lipid peroxidation, and BDNF) determinations were performed. The results showed that CVD prevented and reversed the behavioral and neurochemical alterations induced by LDX. The administration of CVD5 + VAL100 potentiated the effect of VAL200 alone. Taken together these results demonstrate a possible antimanic effect of CVD in this preclinical model. Greicy Coelho de Souza, Julia Ariana de S. Gomes, Ana Isabelle de Góis Queiroz, Maíra Morais de Araújo, Lígia Menezes Cavalcante, Michel de Jesus Souza Machado, Aline Santos Monte, David Freitas de Lucena, João Quevedo, André Ferrer Carvalho, and Danielle Macêdo Copyright © 2015 Greicy Coelho de Souza et al. All rights reserved. Chondroitin Sulfate Induces Depression of Synaptic Transmission and Modulation of Neuronal Plasticity in Rat Hippocampal Slices Wed, 13 May 2015 11:24:48 +0000 It is currently known that in CNS the extracellular matrix is involved in synaptic stabilization and limitation of synaptic plasticity. However, it has been reported that the treatment with chondroitinase following injury allows the formation of new synapses and increased plasticity and functional recovery. So, we hypothesize that some components of extracellular matrix may modulate synaptic transmission. To test this hypothesis we evaluated the effects of chondroitin sulphate (CS) on excitatory synaptic transmission, cellular excitability, and neuronal plasticity using extracellular recordings in the CA1 area of rat hippocampal slices. CS caused a reversible depression of evoked field excitatory postsynaptic potentials in a concentration-dependent manner. CS also reduced the population spike amplitude evoked after orthodromic stimulation but not when the population spikes were antidromically evoked; in this last case a potentiation was observed. CS also enhanced paired-pulse facilitation and long-term potentiation. Our study provides evidence that CS, a major component of the brain perineuronal net and extracellular matrix, has a function beyond the structural one, namely, the modulation of synaptic transmission and neuronal plasticity in the hippocampus. Elisa Albiñana, Javier Gutierrez-Luengo, Natalia Hernández-Juarez, Andrés M. Baraibar, Eulalia Montell, Josep Vergés, Antonio G. García, and Jesus M. Hernández-Guijo Copyright © 2015 Elisa Albiñana et al. All rights reserved. Magnetic Seizure Therapy for Unipolar and Bipolar Depression: A Systematic Review Wed, 13 May 2015 09:52:03 +0000 Objective. Magnetic seizure therapy (MST) is a novel, experimental therapeutic intervention, which combines therapeutic aspects of electroconvulsive therapy (ECT) and transcranial magnetic stimulation, in order to achieve the efficacy of the former with the safety of the latter. MST might prove to be a valuable tool in the treatment of mood disorders, such as major depressive disorder (MDD) and bipolar disorder. Our aim is to review current literature on MST. Methods. OVID and MEDLINE databases were used to systematically search for clinical studies on MST. The terms “magnetic seizure therapy,” “depression,” and “bipolar” were employed. Results. Out of 74 studies, 8 met eligibility criteria. There was considerable variability in the methods employed and samples sizes were small, limiting the generalization of the results. All studies focused on depressive episodes, but few included patients with bipolar disorder. The studies found reported significant antidepressant effects, with remission rates ranging from 30% to 40%. No significant cognitive side effects related to MST were found, with a better cognitive profile when compared to ECT. Conclusion. MST was effective in reducing depressive symptoms in mood disorders, with generally less side effects than ECT. No study focused on comparing MST to ECT on bipolar depression specifically. Eric Cretaz, André R. Brunoni, and Beny Lafer Copyright © 2015 Eric Cretaz et al. All rights reserved. The Potential Role of the NLRP3 Inflammasome as a Link between Mitochondrial Complex I Dysfunction and Inflammation in Bipolar Disorder Wed, 13 May 2015 09:50:38 +0000 Mitochondrial dysfunction and activation of the inflammatory system are two of the most consistently reported findings in bipolar disorder (BD). More specifically, altered levels of inflammatory cytokines and decreased levels of mitochondrial complex I subunits have been found in the brain and periphery of patients with BD, which could lead to increased production of mitochondrial reactive oxygen species (ROS). Recent studies have shown that mitochondrial production of ROS and inflammation may be closely linked through a redox sensor known as nod-like receptor pyrin domain-containing 3 (NLRP3). Upon sensing mitochondrial release of ROS, NLRP3 assembles the NLRP3 inflammasome, which releases caspase 1 to begin the inflammatory cascade. In this review, we discuss the potential role of the NLRP3 inflammasome as a link between complex I dysfunction and inflammation in BD and its therapeutic implications. Helena Kyunghee Kim, Wenjun Chen, and Ana Cristina Andreazza Copyright © 2015 Helena Kyunghee Kim et al. All rights reserved.