The malleable brain: plasticity of neural circuits and behavior: A review from students to students

One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long-lasting increases or decreases in the strength of synaptic connections, referred to as long-term potentiation (LTP) and long-term depression (LTD) respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity-related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by LTP and LTD, we discuss system-wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity.Fil: Schaefer, Natascha. University of Wuerzburg; AlemaniaFil: Rotermund, Carola. University of Tuebingen; AlemaniaFil: Blumrich, Eva Maria. Universitat Bremen; AlemaniaFil: Lourenco, Mychael V.. Universidade Federal do Rio de Janeiro; BrasilFil: Joshi, Pooja. Robert Debre Hospital; FranciaFil: Hegemann, Regina U.. University of Otago; Nueva ZelandaFil: Jamwal, Sumit. ISF College of Pharmacy; IndiaFil: Ali, Nilufar. Augusta University; Estados UnidosFil: García Romero, Ezra Michelet. Universidad Veracruzana; MéxicoFil: Sharma, Sorabh. Birla Institute of Technology and Science; IndiaFil: Ghosh, Shampa. Indian Council of Medical Research; IndiaFil: Sinha, Jitendra K.. Indian Council of Medical Research; IndiaFil: Loke, Hannah. Hudson Institute of Medical Research; AustraliaFil: Jain, Vishal. Defence Institute of Physiology and Allied Sciences; IndiaFil: Lepeta, Katarzyna. Polish Academy of Sciences; ArgentinaFil: Salamian, Ahmad. Polish Academy of Sciences; ArgentinaFil: Sharma, Mahima. Polish Academy of Sciences; ArgentinaFil: Golpich, Mojtaba. University Kebangsaan Malaysia Medical Centre; MalasiaFil: Nawrotek, Katarzyna. University Of Lodz; ArgentinaFil: Paid, Ramesh K.. Indian Institute of Chemical Biology; IndiaFil: Shahidzadeh, Sheila M.. Syracuse University; Estados UnidosFil: Piermartiri, Tetsade. Universidade Federal de Santa Catarina; BrasilFil: Amini, Elham. University Kebangsaan Malaysia Medical Centre; MalasiaFil: Pastor, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Wilson, Yvette. University of Melbourne; AustraliaFil: Adeniyi, Philip A.. Afe Babalola University; NigeriaFil: Datusalia, Ashok K.. National Brain Research Centre; IndiaFil: Vafadari, Benham. Polish Academy of Sciences; ArgentinaFil: Saini, Vedangana. University of Nebraska; Estados UnidosFil: Suárez Pozos, Edna. Instituto Politécnico Nacional; MéxicoFil: Kushwah, Neetu. Defence Institute of Physiology and Allied Sciences; IndiaFil: Fontanet, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Turner, Anthony J.. University of Leeds; Reino Unid

Genes Linking Mitochondrial Function, Cognitive Impairment and Depression are Associated with Endophenotypes Serving Precision Medicine

Mitochondria densely populate cells in central nervous system providing essential energy for neurons and influencing synaptic plasticity. Harm to these organelles can impair cognitive performance through damaged neurotransmission and altered Ca2+ homeostasis. Impaired cognition could be one underlying factor which can characterize major depressive disorder, a huge burden for society marked by depressed mood and anhedonia. A growing body of evidence binds mitochondrial dysfunctions with the disease. Cognitive disturbances with different severity are also observable in several patients, suggesting that damage or inherited alterations of mitochondria may have an important role in depression. Since several different biological and environmental factors can lead to depression, mitochondrial changes may represent a significant subgroup of depressive patients although cognitive correlates can remain undiscovered without a specific focus. Hypothesis driven studies instead of GWAS can pinpoint targets relevant only in a subset of depressed population. This review highlights results mainly from candidate gene studies on nuclear DNA of mitochondrion-related proteins, including TOMM40, MTHFD1L, ATP6V1B2 and MAO genes, also implicated in Alzheimer's disease, and alterations in the mitochondrial genome to argue for endophenotypes where impaired mitochondrial function may be the leading cause for depressive symptomatology and parallel cognitive dysfunction

Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF)

This work has been supported by Bristol Research into Alzheimer’s and Care of the Elderly (BRACE), the Sigmund Gestetner Trust Fund (University of Bristol), the Alzheimer’s Society and the Alumni of the University of Bristol. K.C. and D.J.W. were supported by UK Wellcome Trust-MRC Neurodegenerative Disease Initiative Programme. J.H.Y. was supported by the Korea-UK Alzheimer’s Research Consortium Programme under the Korean Ministry of Health and Welfare. T.M.P. and S.C. were supported by Bristol-Chonnam Frontier Programme under the Chonnam National University Hospital. K.C. was supported by the Wolfson Research Merit Award and Royal Society, London.This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer’s disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging.Publisher PDFPeer reviewe

Amyotrophic lateral sclerosis alters the metabolic aging profile in patient derived fibroblasts

Aging is a major risk factor for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). As metabolic alterations are a hallmark of aging and have previously been observed in ALS, it is important to examine the effect of aging in the context of ALS metabolic function. Here, using a newly established phenotypic metabolic approach, we examined the effect of aging on the metabolic profile of fibroblasts derived from ALS cases compared to controls. We found that ALS fibroblasts have an altered metabolic profile, which is influenced by age. In control cases, we found significant increases with age in NADH metabolism in the presence of several metabolites including lactic acid, trehalose, uridine and fructose, which was not recapitulated in ALS cases. Conversely, we found a reduction of NADH metabolism with age of biopsy, age of onset and age of death in the presence of glycogen in the ALS cohort. Furthermore, we found that NADH production correlated with disease progression rates in relation to a number of metabolites including inosine and α-ketoglutaric acid. Inosine or α-ketoglutaric acid supplementation in ALS fibroblasts was bioenergetically favourable. Overall, we found aging related defects in energy substrates that feed carbon into glycolysis at various points as well as the tricarboxylic acid (TCA) cycle in ALS fibroblasts, which was validated in induced neuronal progenitor cell derived iAstrocytes. Our results suggest that supplementing those pathways may protect against age related metabolic dysfunction in ALS

Association between TNF-a-308 G/A polymorphism and oral cancer risk among Malaysian Indian and indigenous / Mojtaba Golpich

The primary role of tumor necrosis factor alpha (TNF-α) gene is to regulate immune cells. Dysregulation and, in particular, overproduction of this gene has been found to increase susceptibility to a variety of human diseases such as cancer. The aim of this study is to investigate the association of single nucleotide polymorphism (SNP) in TNF-α −308 promoter and the risk of oral cancer among the Malaysian Indian and Indigenous population.The study included 143 confirmed oral squamous cell carcinoma (OSCC) (mean age = 63.69 ± 12.84) and 79 healthy controls (mean age = 50.43 ± 16.35). The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was employed to analyze TNF-α −308 promoter polymorphism, which were confirmed by direct sequencing. Chi-square, simple logistic regression and stratified analysis were performed using the SPSS (ver 15.0) to study the role of TNF-α polymorphism in modulating the risk of oral cancer. The wild-type genotype (GG) was seen in 88.8% (127) of OSCC patients in comparison to 87.3% (69) controls; while variant genotypes (GA & AA) were seen in 9.8% (14) and 1.4% (2) of cases and 11.4% (9) and 1.3% (1) of controls respectively. Also no significant association was observed between variant genotypes (GA & AA) and oral cancer risk. Polymorphism of TNF-α at position −308 G/A may not be a risk factor for oral cancer because we did not find a statistically significant association between the TNF-α −308 G/A polymorphism and oral cancer risk (p = .710 and p = .946 for GA and AA respectively). In conclusion, no association was seen between TNF-α −308 G/A polymorphism and oral cancer risk among the Malaysian Indian and Indigenous population

A Study of the Relationships between Family Functioning and Psychological Hardiness among Parents with Exceptional Children and Normal Children

Objectives: The objective behind this study was investigating the relationships between family functioning and psychological hardiness in parents of exceptional children versus parents of normal children. Methods: The study was causal-comparative. Population included all parents of normal and exceptional students in Bojnurd City studying in ordinary and exceptional schools in the academic year 2010-2011. Participants were 190 parents: 50 parents with exceptional children and 140 with normal children. Multistage cluster sampling was used too select the sample. Family functioning questionnaire and psychological hardiness questionnaire were used for data collection. Data were analyzed using Kolmogrov-Smirnov test, independent t-test, Mann-Whitney U test, and Spearman correlation. Results: Findings suggested there was significant statistical relationship between family functioning and psychological hardiness in parents of exceptional and normal children (P<0.0001), and family functioning was significantly higher in parents of exceptional children compared to parents of normal children (P<0.0001). In addition, psychological hardiness was significantly higher in normal children parents compared to exceptional children parents (P<0.001). Discussion: Results indicate significant relationship between family functioning and psychological hardiness in parents of normal and exceptional children

The Investigation of Difference Career Maturity Based on Identity Status among Adolescence with Visual Disorder

Objectives: The current study aimed at investigating the relationship between identity status and career maturity among adolescents with visual disorders, as compared to normal adolescents. Methods: The study had two populations: all normal high school students in Tehran city (including boys and girls) and all visually-disabled high school students in Tehran (including boys and girls). The sample consisted of 275 students, of whom 65 were students with visual disabilities and 210 were normal students. For the students with visual disabilities the sample included all the population and normal students were selected using a multi-stage sampling. To collect data, participants completed Dellas Identity Status Inventory (DISI-O) and Career Development Inventory -Australian- Short Form (CDI-A-SF). Data were analyzed using kolmogrov-Smirnov test, one way analysis of variance, T-test for independent groups and covariance. Results: Results indicated career maturity differed significantly by different identity status of the participants (P<0.0001). The statistical differences obtained indicated there were relationships between identity status and career maturity. It was also found career maturity differed significantly among normal and visually-disabled students (P=0.04). However, no significant difference was found among male and female students in terms of career maturity (P=0.14). Discussion: The results of the current study suggested career maturity differed by the four identity statuses. And there is differences between career maturity in normal and visual disabilities group&rsquo;s results indicated mean score of normal student in career maturity was significantly higher than the other group

Brain Lipopolysaccharide Preconditioning-Induced Gene Reprogramming Mediates a Tolerance State in Electroconvulsive Shock Model of Epilepsy

There is increasing evidence pointing toward the role of inflammatory processes in epileptic seizures, and reciprocally, prolonged seizures induce more inflammation in the brain. In this regard, effective strategies to control epilepsy resulting from neuroinflammation could be targeted. Based on the available data, preconditioning (PC) with low dose lipopolysaccharide (LPS) through the regulation of the TLR4 signaling pathway provides neuroprotection against subsequent challenge with injury in the brain. To test this, we examined the effects of a single and chronic brain LPS PC, which is expected to lead to reduction of inflammation against epileptic seizures induced by electroconvulsive shock (ECS). A total of 60 male Sprague Dawley rats were randomly assigned to five groups: control, vehicle (single and chronic), and LPS PC (single and chronic). We first recorded the data regarding the behavioral and histological changes. We further investigated the alterations of gene and protein expression of important mediators in relation to TLR4 and inflammatory signaling pathways. Interestingly, significant increased presence of NFκB inhibitors [Src homology 2-containing inositol phosphatase-1 (SHIP1) and Toll interacting protein (TOLLIP)] was observed in LPS-preconditioned animals. This result was also associated with over-expression of IRF3 activity and anti-inflammatory markers, along with down-regulation of pro-inflammatory mediators. Summarizing, the analysis revealed that PC with LPS prior to seizure induction may have a neuroprotective effect possibly by reprogramming the signaling response to injury

Aptamer Technologies in Neuroscience, Neuro-Diagnostics and Neuro-Medicine Development

Aptamers developed using in vitro Systematic Evolution of Ligands by Exponential Enrichment (SELEX) technology are single-stranded nucleic acids 10–100 nucleotides in length. Their targets, often with specificity and high affinity, range from ions and small molecules to proteins and other biological molecules as well as larger systems, including cells, tissues, and animals. Aptamers often rival conventional antibodies with improved performance, due to aptamers’ unique biophysical and biochemical properties, including small size, synthetic accessibility, facile modification, low production cost, and low immunogenicity. Therefore, there is sustained interest in engineering and adapting aptamers for many applications, including diagnostics and therapeutics. Recently, aptamers have shown promise as early diagnostic biomarkers and in precision medicine for neurodegenerative and neurological diseases. Here, we critically review neuro-targeting aptamers and their potential applications in neuroscience research, neuro-diagnostics, and neuro-medicine. We also discuss challenges that must be overcome, including delivery across the blood–brain barrier, increased affinity, and improved in vivo stability and in vivo pharmacokinetic properties