Neural Plasticity The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . 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. Cytomegalovirus Antibody Elevation in Bipolar Disorder: Relation to Elevated Mood States Wed, 13 May 2015 09:24:54 +0000 The neurobiology of mood states is complicated by exposure to everyday stressors (e.g., psychosocial, ubiquitous environmental infections like CMV), each fluctuating between latency and reactivation. CMV reactivation induces proinflammatory cytokines (e.g., TNF-α) associated with induction of neurotoxic metabolites and the presence of mood states in bipolar disorder (BD). Whether CMV reactivation is associated with bipolar diagnoses (trait) or specific mood states is unclear. We investigated 139 BD type I and 99 healthy controls to determine if concentrations of IgG antibodies to Herpesviridae (e.g., CMV, HSV-1, and HSV-2) were associated with BD-I diagnosis and specific mood states. We found higher CMV antibody concentration in BD-I than in healthy controls (, ; ) but no difference in HSV-1 () or HSV-2 (). Compared to euthymic BD-I volunteers, CMV IgG was higher in BD-I volunteers with elevated moods () but not different in depressed moods (). While relationships presented between BD-I diagnosis, mood states, and CMV antibodies are encouraging, they are limited by the study’s cross sectional nature. Nevertheless, further testing is warranted to replicate findings and determine whether reactivation of CMV infection exacerbates elevated mood states in BD-I. A. R. Prossin, R. H. Yolken, M. Kamali, M. M. Heitzeg, J. B. Kaplow, W. H. Coryell, and M. G. McInnis Copyright © 2015 A. R. Prossin et al. All rights reserved. The Use of Cannabis as a Predictor of Early Onset of Bipolar Disorder and Suicide Attempts Wed, 13 May 2015 09:03:13 +0000 Introduction. Bipolar disorder (BD) implies risk of suicide. The age at onset (AAO) of BD carries prognostic significance. Substance abuse may precede the onset of BD and cannabis is the most common illicit drug used. The main goal of this study is to review the association of cannabis use as a risk factor for early onset of BD and for suicide attempts. Materials and Methods. PubMed database was searched for articles using key words “bipolar disorder,” “suicide attempts,” “cannabis,” “marijuana,” “early age at onset,” and “early onset.” Results. The following percentages in bipolar patients were found: suicide attempts 3.6–42%; suicide attempts and substance use 5–60%; suicide attempts and cannabis use 15–42%. An early AAO was associated with cannabis misuse. The mean age of the first manic episode in individuals with and without BD and cannabis use disorder (CUD) was 19.5 and 25.1 years, respectively. The first depressive episode was at 18.5 and 24.4 years, respectively. Individuals misusing cannabis showed increased risk of suicide. Discussion. Cannabis use is associated with increased risk of suicide attempts and with early AAO. However, the effect of cannabis at the AAO and suicide attempts is not clear. Rafaela Torres Portugal Leite, Sarah de Oliveira Nogueira, João Paulo Rodrigues do Nascimento, Laisa Soares de Lima, Taís Bastos da Nóbrega, Mariana da Silva Virgínio, Lucas Monte da Costa Moreno, Bruno Henrique Barbosa Sampaio, and Fábio Gomes de Matos e Souza Copyright © 2015 Rafaela Torres Portugal Leite et al. All rights reserved. Normal Metabolic Levels in Prefrontal Cortex in Euthymic Bipolar I Patients with and without Suicide Attempts Wed, 13 May 2015 07:58:24 +0000 Introduction/Objective. Evidence suggests that the prefrontal cortex has been implicated in the pathophysiology of bipolar disorder (BD), but few neurochemical studies have evaluated this region in bipolar patients and there is no information from BD suicide attempters using Proton Magnetic Resonance Spectroscopy (H+MRS). The objective was to evaluate the metabolic function of the medial orbital frontal cortex in euthymic BD type I suicide and nonsuicide attempters compared to healthy subjects by H+MRS. Methods. 40 euthymic bipolar I outpatients, 19 without and 21 with history of suicide attempt, and 22 healthy subjects were interviewed using the Structured Clinical Interview with the DSM-IV axis I, the Hamilton Depression Rating Scale, the Young Mania Rating Scale, and the Barratt Impulsiveness Scale-11 and underwent H+MRS. Results. We did not find any metabolic abnormality in medial orbital frontal regions of suicide and nonsuicide BD patients and BD patients as a group compared to healthy subjects. Conclusions. The combined chronic use of psychotropic drugs with neuroprotective or neurotrophic effects leading to a euthymic state for longer periods of time may improve neurometabolic function, at least measured by H+MRS, even in suicide attempters. Besides, these results may implicate mood dependent alterations in brain metabolic activity. However, more studies with larger sample sizes of this heterogeneous disorder are warranted to clarify these data. Marlos Vasconcelos Rocha, Fabiana Nery-Fernandes, José Luiz Guimarães, Lucas de Castro Quarantini, Irismar Reis de Oliveira, Giovanna G. Ladeia-Rocha, Andrea Parolin Jackowski, César de Araujo Neto, and Ângela Miranda-Scippa Copyright © 2015 Marlos Vasconcelos Rocha et al. All rights reserved. Disruption in the Blood-Brain Barrier: The Missing Link between Brain and Body Inflammation in Bipolar Disorder? Wed, 13 May 2015 07:56:35 +0000 The blood-brain barrier (BBB) regulates the transport of micro- and macromolecules between the peripheral blood and the central nervous system (CNS) in order to maintain optimal levels of essential nutrients and neurotransmitters in the brain. In addition, the BBB plays a critical role protecting the CNS against neurotoxins. There has been growing evidence that BBB disruption is associated with brain inflammatory conditions such as Alzheimer’s disease and multiple sclerosis. Considering the increasing role of inflammation and oxidative stress in the pathophysiology of bipolar disorder (BD), here we propose a novel model wherein transient or persistent disruption of BBB integrity is associated with decreased CNS protection and increased permeability of proinflammatory (e.g., cytokines, reactive oxygen species) substances from the peripheral blood into the brain. These events would trigger the activation of microglial cells and promote localized damage to oligodendrocytes and the myelin sheath, ultimately compromising myelination and the integrity of neural circuits. The potential implications for research in this area and directions for future studies are discussed. Jay P. Patel and Benicio N. Frey Copyright © 2015 Jay P. Patel and Benicio N. Frey. All rights reserved. Correlation between Peripheral Levels of Brain-Derived Neurotrophic Factor and Hippocampal Volume in Children and Adolescents with Bipolar Disorder Wed, 13 May 2015 07:48:47 +0000 Pediatric bipolar disorder (PBD) is a serious mental disorder that affects the development and emotional growth of affected patients. The brain derived neurotrophic factor (BDNF) is recognized as one of the possible markers of the framework and its evolution. Abnormalities in BDNF signaling in the hippocampus could explain the cognitive decline seen in patients with TB. Our aim with this study was to evaluate possible changes in hippocampal volume in children and adolescents with BD and associate them to serum BDNF. Subjects included 30 patients aged seven to seventeen years from the ProCAB (Program for Children and Adolescents with Bipolar Disorder). We observed mean right and left hippocampal volumes of 41910.55 and 41747.96 mm3, respectively. No statistically significant correlations between peripheral BDNF levels and hippocampal volumes were found. We believe that the lack of correlation observed in this study is due to the short time of evolution of BD in children and adolescents. Besides studies with larger sample sizes to confirm the present findings and longitudinal assessments, addressing brain development versus a control group and including drug-naive patients in different mood states may help clarify the role of BDNF in the brain changes consequent upon BD. Tatiana Lauxen Peruzzolo, Mauricio Anes, Andre de Moura Kohmann, Ana Claudia Mércio Loredo Souza, Ramiro Borges Rodrigues, Juliana Basso Brun, Roberta Peters, Bianca Wollenhaupt de Aguiar, Flavio Kapczinski, Silzá Tramontina, Luis Augusto Paim Rohde, and Cristian Patrick Zeni Copyright © 2015 Tatiana Lauxen Peruzzolo et al. All rights reserved. CRMP4 and CRMP2 Interact to Coordinate Cytoskeleton Dynamics, Regulating Growth Cone Development and Axon Elongation Sun, 10 May 2015 06:39:28 +0000 Cytoskeleton dynamics are critical phenomena that underpin many fundamental cellular processes. Collapsin response mediator proteins (CRMPs) are highly expressed in the developing nervous system, mediating growth cone guidance, neuronal polarity, and axonal elongation. However, whether and how CRMPs associate with microtubules and actin coordinated cytoskeletal dynamics remain unknown. In this study, we demonstrated that CRMP2 and CRMP4 interacted with tubulin and actin in vitro and colocalized with the cytoskeleton in the transition-zone in developing growth cones. CRMP2 and CRMP4 also interacted with one another coordinately to promote growth cone development and axonal elongation. Genetic silencing of CRMP2 enhanced, whereas overexpression of CRMP2 suppressed, the inhibitory effects of CRMP4 knockdown on axonal development. In addition, knockdown of CRMP2 or overexpression of truncated CRMP2 reversed the promoting effect of CRMP4. With the overexpression of truncated CRMP2 or CRMP4 lacking the cytoskeleton interaction domain, the promoting effect of CRMP was suppressed. These data suggest a model in which CRMP2 and CRMP4 form complexes to bridge microtubules and actin and thus work cooperatively to regulate growth cone development and axonal elongation. Minghui Tan, Caihui Cha, Yongheng Ye, Jifeng Zhang, Sumei Li, Fengming Wu, Sitang Gong, and Guoqing Guo Copyright © 2015 Minghui Tan et al. All rights reserved. Plasticity Induced by Intermittent Theta Burst Stimulation in Bilateral Motor Cortices Is Not Altered in Older Adults Wed, 06 May 2015 15:24:51 +0000 Numerous studies have reported that plasticity induced in the motor cortex by transcranial magnetic stimulation (TMS) is attenuated in older adults. Those investigations, however, have focused solely on the stimulated hemisphere. Compared to young adults, older adults exhibit more widespread activity across bilateral motor cortices during the performance of unilateral motor tasks, suggesting that the manifestation of plasticity might also be altered. To address this question, twenty young (<35 years old) and older adults (>65 years) underwent intermittent theta burst stimulation (iTBS) whilst attending to the hand targeted by the plasticity-inducing procedure. The amplitude of motor evoked potentials (MEPs) elicited by single pulse TMS was used to quantify cortical excitability before and after iTBS. Individual responses to iTBS were highly variable, with half the participants showing an unexpected decrease in cortical excitability. Contrary to predictions, however, there were no age-related differences in the magnitude or manifestation of plasticity across bilateral motor cortices. The findings suggest that advancing age does not influence the capacity for, or manifestation of, plasticity induced by iTBS. Daina S. E. Dickins, Martin V. Sale, and Marc R. Kamke Copyright © 2015 Daina S. E. Dickins et al. All rights reserved. Functional and Structural Brain Plasticity Enhanced by Motor and Cognitive Rehabilitation in Multiple Sclerosis Wed, 06 May 2015 11:44:45 +0000 Rehabilitation is recognized to be important in ameliorating motor and cognitive functions, reducing disease burden, and improving quality of life in patients with multiple sclerosis (MS). In this systematic review, we summarize the existing evidences that motor and cognitive rehabilitation may enhance functional and structural brain plasticity in patients with MS, as assessed by means of the most advanced neuroimaging techniques, including diffusion tensor imaging and task-related and resting-state functional magnetic resonance imaging (MRI). In most cases, the rehabilitation program was based on computer-assisted/video game exercises performed in either an outpatient or home setting. Despite their heterogeneity, all the included studies describe changes in white matter microarchitecture, in task-related activation, and/or in functional connectivity following both task-oriented and selective training. When explored, relevant correlation between improved function and MRI-detected brain changes was often found, supporting the hypothesis that training-induced brain plasticity is specifically linked to the trained domain. Small sample sizes, lack of randomization and/or an active control group, as well as missed relationship between MRI-detected changes and clinical performance, are the major drawbacks of the selected studies. Knowledge gaps in this field of research are also discussed to provide a framework for future investigations. Luca Prosperini, Maria Cristina Piattella, Costanza Giannì, and Patrizia Pantano Copyright © 2015 Luca Prosperini et al. All rights reserved. CREB Regulates Experience-Dependent Spine Formation and Enlargement in Mouse Barrel Cortex Tue, 05 May 2015 09:59:33 +0000 Experience modifies synaptic connectivity through processes that involve dendritic spine rearrangements in neuronal circuits. Although cAMP response element binding protein (CREB) has a key function in spines changes, its role in activity-dependent rearrangements in brain regions of rodents interacting with the surrounding environment has received little attention so far. Here we studied the effects of vibrissae trimming, a widely used model of sensory deprivation-induced cortical plasticity, on processes associated with dendritic spine rearrangements in the barrel cortex of a transgenic mouse model of CREB downregulation (mCREB mice). We found that sensory deprivation through prolonged whisker trimming leads to an increased number of thin spines in the layer V of related barrel cortex (Contra) in wild type but not mCREB mice. In the barrel field controlling spared whiskers (Ipsi), the same trimming protocol results in a CREB-dependent enlargement of dendritic spines. Last, we demonstrated that CREB regulates structural rearrangements of synapses that associate with dynamic changes of dendritic spines. Our findings suggest that CREB plays a key role in dendritic spine dynamics and synaptic circuits rearrangements that account for new brain connectivity in response to changes in the environment. Annabella Pignataro, Antonella Borreca, Martine Ammassari-Teule, and Silvia Middei Copyright © 2015 Annabella Pignataro et al. All rights reserved. Neurodevelopmental Plasticity in Pre- and Postnatal Environmental Interactions: Implications for Psychiatric Disorders from an Evolutionary Perspective Tue, 28 Apr 2015 11:30:06 +0000 Psychiatric disorders are disadvantageous behavioral phenotypes in humans. Accordingly, a recent epidemiological study has reported decreased fecundity in patients with psychiatric disorders, such as schizophrenia and autism spectrum disorders. Moreover, the fecundity of the relatives of these patients is not exceedingly higher compared to the fecundity of the relatives of normal subjects. Collectively, the prevalence of psychiatric disorders among humans is expected to decrease over generations. Nevertheless, in reality, the prevalence rates of psychiatric disorders in humans either have been constant over a long period of time or have even increased more recently. Several attempts to explain this fact have been made using biological mechanisms, such as de novo gene mutations or variants, although none of these explanations is fully comprehensive. Here, we propose a hypothesis towards understanding the biological mechanisms of psychiatric disorders from evolutionary perspectives. This hypothesis considers that behavioral phenotypes associated with psychiatric disorders might have emerged in the evolution of organisms as a neurodevelopmental adaptation against adverse environmental conditions associated with stress. Young-A Lee, Yoshie Yamaguchi, and Yukiori Goto Copyright © 2015 Young-A Lee et al. All rights reserved. Increase in Short-Interval Intracortical Facilitation of the Motor Cortex after Low-Frequency Repetitive Magnetic Stimulation of the Unaffected Hemisphere in the Subacute Phase after Stroke Tue, 28 Apr 2015 09:04:44 +0000 Low-frequency repetitive transcranial magnetic stimulation of the unaffected hemisphere (UH-LF-rTMS) in patients with stroke can decrease interhemispheric inhibition from the unaffected to the affected hemisphere and improve hand dexterity and strength of the paretic hand. The objective of this proof-of-principle study was to explore, for the first time, effects of UH-LF-rTMS as add-on therapy to motor rehabilitation on short-term intracortical inhibition (SICI) and intracortical facilitation (ICF) of the motor cortex of the unaffected hemisphere () in patients with ischemic stroke. Eighteen patients were randomized to receive, immediately before rehabilitation treatment, either active or sham UH-LF-rTMS, during two weeks. Resting motor threshold (rMT), SICI, and ICF were measured in before the first session and after the last session of treatment. There was a significant increase in ICF in the active group compared to the sham group after treatment, and there was no significant differences in changes in rMT or SICI. ICF is a measure of intracortical synaptic excitability, with a relative contribution of spinal mechanisms. ICF is typically upregulated by glutamatergic agonists and downregulated by gabaergic antagonists. The observed increase in ICF in the active group, in this hypothesis-generating study, may be related to reorganization induced by UH-LF-rTMS. Eduardo Arruda Mello, Leonardo G. Cohen, Sarah Monteiro dos Anjos, Juliana Conti, Karina Nocelo F. Andrade, Fernanda Tovar Moll, Theo Marins, Corina A. Fernandes, Waldyr Rodrigues Jr., and Adriana Bastos Conforto Copyright © 2015 Eduardo Arruda Mello et al. All rights reserved. Modulation of Hippocampal Neural Plasticity by Glucose-Related Signaling Tue, 21 Apr 2015 08:54:35 +0000 Hormones and peptides involved in glucose homeostasis are emerging as important modulators of neural plasticity. In this regard, increasing evidence shows that molecules such as insulin, insulin-like growth factor-I, glucagon-like peptide-1, and ghrelin impact on the function of the hippocampus, which is a key area for learning and memory. Indeed, all these factors affect fundamental hippocampal properties including synaptic plasticity (i.e., synapse potentiation and depression), structural plasticity (i.e., dynamics of dendritic spines), and adult neurogenesis, thus leading to modifications in cognitive performance. Here, we review the main mechanisms underlying the effects of glucose metabolism on hippocampal physiology. In particular, we discuss the role of these signals in the modulation of cognitive functions and their potential implications in dysmetabolism-related cognitive decline. Marco Mainardi, Salvatore Fusco, and Claudio Grassi Copyright © 2015 Marco Mainardi et al. All rights reserved. Anxious and Nonanxious Mice Show Similar Hippocampal Sensory Evoked Oscillations under Urethane Anesthesia: Difference in the Effect of Buspirone Thu, 09 Apr 2015 13:47:24 +0000 Hippocampal oscillations recorded under urethane anesthesia are proposed to be modulated by anxiolytics. All classes of clinically effective anxiolytics were reported to decrease the frequency of urethane theta; however, recent findings raise concerns about the direct correlation of anxiolysis and the frequency of hippocampal theta. Here, we took advantage of our two inbred mouse strains displaying extremes of anxiety (anxious (AX) and nonanxious (nAX)) to compare the properties of hippocampal activity and to test the effect of an anxiolytic drugs. No difference was observed in the peak frequency or in the peak power between AX and nAX strains. Buspirone (Bus) applied in 2.5 mg/kg decreased anxiety of AX but did not have any effect on nAX as was tested by elevated plus maze and open field. Interestingly, Bus treatment increased hippocampal oscillatory frequency in the AX but left it unaltered in nAX mice. Saline injection did not have any effect on the oscillation. Paired-pulse facilitation was enhanced by Bus in the nAX, but not in the AX strain. Collectively, these results do not support the hypothesis that hippocampal activity under urethane may serve as a marker for potential anxiolytic drugs. Moreover, we could not confirm the decrease of frequency after anxiolytic treatment. János Horváth, Balázs Barkóczi, Géza Müller, and Viktor Szegedi Copyright © 2015 János Horváth et al. All rights reserved. Neuroplastic Effects of Combined Computerized Physical and Cognitive Training in Elderly Individuals at Risk for Dementia: An eLORETA Controlled Study on Resting States Tue, 07 Apr 2015 09:04:02 +0000 The present study investigates whether a combined cognitive and physical training may induce changes in the cortical activity as measured via electroencephalogram (EEG) and whether this change may index a deceleration of pathological processes of brain aging. Seventy seniors meeting the clinical criteria of mild cognitive impairment (MCI) were equally divided into 5 groups: 3 experimental groups engaged in eight-week cognitive and/or physical training and 2 control groups: active and passive. A 5-minute long resting state EEG was measured before and after the intervention. Cortical EEG sources were modelled by exact low resolution brain electromagnetic tomography (eLORETA). Cognitive function was assessed before and after intervention using a battery of neuropsychological tests including the minimental state examination (MMSE). A significant training effect was identified only after the combined training scheme: a decrease in the post- compared to pre-training activity of precuneus/posterior cingulate cortex in delta, theta, and beta bands. This effect was correlated to improvements in cognitive capacity as evaluated by MMSE scores. Our results indicate that combined physical and cognitive training shows indices of a positive neuroplastic effect in MCI patients and that EEG may serve as a potential index of gains versus cognitive declines and neurodegeneration. This trial is registered with Identifier NCT02313935. Charis Styliadis, Panagiotis Kartsidis, Evangelos Paraskevopoulos, Andreas A. Ioannides, and Panagiotis D. Bamidis Copyright © 2015 Charis Styliadis et al. All rights reserved. Are Visual Peripheries Forever Young? Mon, 06 Apr 2015 09:33:55 +0000 The paper presents a concept of lifelong plasticity of peripheral vision. Central vision processing is accepted as critical and irreplaceable for normal perception in humans. While peripheral processing chiefly carries information about motion stimuli features and redirects foveal attention to new objects, it can also take over functions typical for central vision. Here I review the data showing the plasticity of peripheral vision found in functional, developmental, and comparative studies. Even though it is well established that afferent projections from central and peripheral retinal regions are not established simultaneously during early postnatal life, central vision is commonly used as a general model of development of the visual system. Based on clinical studies and visually deprived animal models, I describe how central and peripheral visual field representations separately rely on early visual experience. Peripheral visual processing (motion) is more affected by binocular visual deprivation than central visual processing (spatial resolution). In addition, our own experimental findings show the possible recruitment of coarse peripheral vision for fine spatial analysis. Accordingly, I hypothesize that the balance between central and peripheral visual processing, established in the course of development, is susceptible to plastic adaptations during the entire life span, with peripheral vision capable of taking over central processing. Kalina Burnat Copyright © 2015 Kalina Burnat. All rights reserved. Modeling Maintenance of Long-Term Potentiation in Clustered Synapses: Long-Term Memory without Bistability Sun, 05 Apr 2015 13:42:39 +0000 Memories are stored, at least partly, as patterns of strong synapses. Given molecular turnover, how can synapses maintain strong for the years that memories can persist? Some models postulate that biochemical bistability maintains strong synapses. However, bistability should give a bimodal distribution of synaptic strength or weight, whereas current data show unimodal distributions for weights and for a correlated variable, dendritic spine volume. Thus it is important for models to simulate both unimodal distributions and long-term memory persistence. Here a model is developed that connects ongoing, competing processes of synaptic growth and weakening to stochastic processes of receptor insertion and removal in dendritic spines. The model simulates long-term (>1 yr) persistence of groups of strong synapses. A unimodal weight distribution results. For stability of this distribution it proved essential to incorporate resource competition between synapses organized into small clusters. With competition, these clusters are stable for years. These simulations concur with recent data to support the “clustered plasticity hypothesis” which suggests clusters, rather than single synaptic contacts, may be a fundamental unit for storage of long-term memory. The model makes empirical predictions and may provide a framework to investigate mechanisms maintaining the balance between synaptic plasticity and stability of memory. Paul Smolen Copyright © 2015 Paul Smolen. All rights reserved. Altered Theta Oscillations and Aberrant Cortical Excitatory Activity in the 5XFAD Model of Alzheimer’s Disease Thu, 02 Apr 2015 09:54:09 +0000 Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by impairment of memory function. The 5XFAD mouse model was analyzed and compared with wild-type (WT) controls for aberrant cortical excitability and hippocampal theta oscillations by using simultaneous video-electroencephalogram (EEG) monitoring. Seizure staging revealed that 5XFAD mice exhibited cortical hyperexcitability whereas controls did not. In addition, 5XFAD mice displayed a significant increase in hippocampal theta activity from the light to dark phase during nonmotor activity. We also observed a reduction in mean theta frequency in 5XFAD mice compared to controls that was again most prominent during nonmotor activity. Transcriptome analysis of hippocampal probes and subsequent qPCR validation revealed an upregulation of Plcd4 that might be indicative of enhanced muscarinic signalling. Our results suggest that 5XFAD mice exhibit altered cortical excitability, hippocampal dysrhythmicity, and potential changes in muscarinic signaling. Magdalena Elisabeth Siwek, Ralf Müller, Christina Henseler, Astrid Trog, Andreas Lundt, Carola Wormuth, Karl Broich, Dan Ehninger, Marco Weiergräber, and Anna Papazoglou Copyright © 2015 Magdalena Elisabeth Siwek et al. All rights reserved.