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

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

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

Image_1_Brain Lipopolysaccharide Preconditioning-Induced Gene Reprogramming Mediates a Tolerance State in Electroconvulsive Shock Model of Epilepsy.PDF

<p>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.</p

Design and production of the recombinant peptide-fusion protein.

<p><b>A)</b> The short peptides TACH and LATA were fused to MAP30 as a central protein using a six amino-acid linker. The TACH-MAP30-LATA expression cassette including 6XHis tag at the N-terminal of fusion protein was cloned into the appropriate <i>E</i>. <i>coli</i> expression vector and transformed into <i>E</i>. <i>coli</i> BL21. <b>B)</b> SDS-PAGE was done to determine the molecular weight of the purified peptide-fusion protein (~37 kDa). <b>C)</b> Immunoblotting using anti-6XHis tag antibody.</p

The anti-proliferative activity of the peptides.

<p>The individual components of the fusion protein (TACH, LATA and MAP30) showed higher inhibition against cancer cells compared with normal cells in an overall dose range of 0–200 μM based on the maximal toxic concentration of each peptide. The 50% cytotoxic concentration (CC₅₀) of the peptide-fusion protein (TACH- MAP30-LATA) towards HepG2 (0.35±0.1 μM) and MCF-7 (0.58±0.1 μM) was significantly lower than WRL68 (1.83±0.2 μM) and ARPE19 (2.5±0.1 μM). Two Way-ANOVA, P<0.001.</p

Production of the recombinant peptide-fusion protein (TACH- MAP30-LATA) and MAP30 by a recombinant <i>E</i>. <i>coli</i>.

<p><b>A)</b> Total dried biomass of <i>E</i>. <i>coli</i> after the chemical induction at all of the time points of the fermentation process. <b>B)</b> Relative total recombinant protein to the biomass of TACH-MAP30-LATA and MAP30. <b>C)</b> Recombinant protein yield from inclusion bodies. <b>D)</b> Western blot analysis of the purified recombinant peptide-fusion protein at each time point of the fermentation process (Two Way-ANOVA, p>0.05).</p

Cellular uptake of the peptide-fusion protein (TACH-MAP30-LATA) and MAP30 by cancer and normal cells.

<p><b>A)</b> Fluorescence ELISA-like cell-based assay at 0 to 2.5 μM showed the peptide-fusion protein was internalized more efficiently than MAP30 into cancer cells (HepG2 and MCF-7) compared with normal cells (WRL68 and ARPE19) in a dose-dependent manner<b>. B)</b> Confocal laser microscopy analysis showed TACH-MAP30-LATA was preferentially uptaken by HepG2 and MCF-7, compared with normal cells (WRL68 and ARPE19), whereas the cellular uptake of MAP30 was less in all cell lines.</p

Purification of inclusion bodies by solubilization and refolding in alkaline-based buffer containing redox agents.

<p><b>A)</b> Semi-solubilization of inclusion bodies in dH₂O (pH 12) after 10 min of incubation. L1, the isolated inclusion bodies; L2, purified protein (final product); L3, removing of host cell proteins; L4, remaining insoluble aggregates after final solubilization (each line duplicated). <b>B)</b> Refolding of soluble protein in buffer containing oxidized and reduced glutathione to reform the disulphide bridges of TACH. The refolded protein showed different levels under reducing and non-reducing conditions of the SDS-PAGE, indicating the formation of disulphide bridges. <b>C)</b> SDS-PAGE analysis of the fusion protein. L1, a single band at the expected size for the monomer. L2, double bands of the fusion protein. The upper faint band at the dimer size and the lower thick band at the monomer size (arrows).</p

Treatment of liver normal cells (WRL68) and liver cancer cells (HepG2) with combinations of doxorubicin and increasing concentrations of the peptide-fusion protein.

<p>The dose of doxorubicin (2.5 μM) that showed 100% of normal cell viability and approximately 80% of cancer cells viability was used with increasing concentrations (0–1.4 μM) of TACH-MAP30-LATA. The results showed significant reduction in cancer cell viability compared with normal cells (Two Way ANOVA, P<0.001).</p