Enriched Environment Attenuates Enhanced Trait Anxiety in Association with Normalization of Aberrant Neuro-Inflammatory Events.

Neuroinflammation is discussed to play a role in specific subgroups of different psychiatric disorders, including anxiety disorders. We have previously shown that a mouse model of trait anxiety (HAB) displays enhanced microglial density and phagocytic activity in key regions of anxiety circuits compared to normal-anxiety controls (NAB). Using minocycline, we provided causal evidence that reducing microglial activation within the dentate gyrus (DG) attenuated enhanced anxiety in HABs. Besides pharmacological intervention, "positive environmental stimuli", which have the advantage of exerting no side-effects, have been shown to modulate inflammation-related markers in human beings. Therefore, we now investigated whether environmental enrichment (EE) would be sufficient to modulate upregulated neuroinflammation in high-anxiety HABs. We show for the first time that EE can indeed attenuate enhanced trait anxiety, even when presented as late as adulthood. We further found that EE-induced anxiolysis was associated with the attenuation of enhanced microglial density (using Iba-1 as the marker) in the DG and medial prefrontal cortex. Additionally, EE reduced Iba1 + CD68+ microglia density within the anterior DG. Hence, the successful attenuation of trait anxiety by EE was associated in part with the normalization of neuro-inflammatory imbalances. These results suggest that pharmacological and/or positive behavioral therapies triggering microglia-targeted anti-inflammatory effects could be promising as novel alternatives or complimentary anxiolytic therapeutic approaches in specific subgroups of individuals predisposed to trait anxiety.

Novel fleximer pyrazole-containing adenosine analogues: chemical, enzymatic and highly efficient biotechnological synthesis.

Nucleoside analogues have long served as key chemotherapeutic drugs for the treatment of viral infections and cancers. Problems associated with the development of drug resistance have led to a search for the design of nucleosides capable of bypassing point mutations in the target enzyme's binding site. As a possible answer to this, the Seley-Radtke group developed a flexible nucleoside scaffold (fleximers), where the heterocyclic purine base is split into its two components, i.e. pyrimidine and imidazole. Herein, we present a series of new pyrazole-containing flex-bases and the corresponding fleximer analogues of 8-aza-7-deaza nucleosides. Subsequent studies found that pyrazole-containing flex-bases are substrates of purine nucleoside phosphorylase (PNP). We have compared the chemical synthesis of fleximers and enzymatic approaches with both isolated enzymes and the use of E. coli cells overproducing PNP. The latter provided stereochemically pure pyrazole-containing ß-d-ribo- and ß-d-2'-deoxyribo-fleximers and are beneficial in terms of environmental issues, are more economical, and streamline the steps required from a chemical approach. The reaction is carried out in water, avoiding hazardous chemicals, and the products are isolated by ion-exchange chromatography using water/ethanol mixtures for elution. Moreover, the target nucleosides were obtained on a multi-milligram scale with >97-99% purity, and the reactions can be easily scaled up.

Prefrontal and Hippocampal Structure Predict Statistical Learning Ability in Early Childhood.

Statistical learning can be used to gain sensitivity to many important regularities in our environment, including structure that is foundational to language and visual perception. As yet, little is known about how statistical learning takes place in the human brain, especially in children's developing brains and with regard to the broader neurobiology of learning and memory. We therefore explored the relationship between statistical learning and the thickness and volume of structures that are traditionally implicated in declarative and procedural memory, focusing specifically on the left inferior PFC, the hippocampus, and the caudate during early childhood (ages 5-8.5 years). We found that the thickness of the left inferior frontal cortex and volume of the right hippocampus predicted statistical learning ability in young children. Importantly, these regions did not change in thickness or volume with age, but the relationship between learning and the right hippocampus interacted with age such that older children's hippocampal structure more strongly predicted performance. Overall, the data show that children's statistical learning is supported by multiple neural structures that are more broadly implicated in learning and memory, especially declarative memory (hippocampus) and attention/top-down control (the PFC).

Epigenetic Mechanisms Within the Cingulate Cortex Regulate Innate Anxiety-Like Behavior.

BACKGROUND: Pathological anxiety originates from a complex interplay of genetic predisposition and environmental factors, acting via epigenetic mechanisms. Epigenetic processes that can counteract detrimental genetic risk towards innate high anxiety are not well characterized. METHODS: We used female mouse lines of selectively bred high (HAB)- vs low (LAB)-innate anxiety-related behavior and performed select environmental and pharmacological manipulations to alter anxiety levels as well as brain-specific manipulations and immunohistochemistry to investigate neuronal mechanisms associated with alterations in anxiety-related behavior. RESULTS: Inborn hyperanxiety of high anxiety-like phenotypes was effectively reduced by environmental enrichment exposure. c-Fos mapping revealed that hyperanxiety in high anxiety-like phenotypes was associated with blunted challenge-induced neuronal activation in the cingulate-cortex, which was normalized by environmental enrichment. Relating this finding with epigenetic modifications, we found that high anxiety-like phenotypes (compared with low-innate anxiety phenotypes) showed reduced acetylation in the hypoactivated cingulate-cortex neurons following a mild emotional challenge, which again was normalized by environmental enrichment. Paralleling the findings using environmental enrichment, systemic administration of histone-deacetylase-inhibitor MS-275 elicited an anxiolytic-like effect, which was correlated with increased acetylated-histone-3 levels within cingulate-cortex. Finally, as a proof-of-principle, local MS-275 injection into cingulate-cortex rescued enhanced innate anxiety and increased acetylated-histone-3 within the cingulate-cortex, suggesting this epigenetic mark as a biomarker for treatment success. CONCLUSIONS: Taken together, the present findings provide the first causal evidence that the attenuation of high innate anxiety-like behavior via environmental/pharmacological manipulations is epigenetically mediated via acetylation changes within the cingulate-cortex. Finally, histone-3 specific histone-deacetylase-inhibitor could be of therapeutic importance in anxiety disorders.

Lower Affinity of Isradipine for L-Type Ca2+ Channels during Substantia Nigra Dopamine Neuron-Like Activity: Implications for Neuroprotection in Parkinson's Disease.

Ca2+-influx through L-type Ca2+-channels (LTCCs) is associated with activity-related stressful oscillations of Ca2+ levels within dopaminergic (DA) neurons in the substantia nigra (SN), which may contribute to their selective degeneration in Parkinson's disease (PD). LTCC blockers were neuroprotective in mouse neurotoxin models of PD, and isradipine is currently undergoing testing in a phase III clinical trial in early PD. We report no evidence for neuroprotection by in vivo pretreatment with therapeutically relevant isradipine plasma levels, or Cav1.3 LTCC deficiency in 6-OHDA-treated male mice. To explain this finding, we investigated the pharmacological properties of human LTCCs during SN DA-like and arterial smooth muscle (aSM)-like activity patterns using whole-cell patch-clamp recordings in HEK293 cells (Cav1.2 α1-subunit, long and short Cav1.3 α1-subunit splice variants; ß3/α2δ1). During SN DA-like pacemaking, only Cav1.3 variants conducted Ca2+ current (ICa) at subthreshold potentials between action potentials. SN DA-like burst activity increased integrated ICa during (Cav1.2 plus Cav1.3) and after (Cav1.3) the burst. Isradipine inhibition was splice variant and isoform dependent, with a 5- to 11-fold lower sensitivity to Cav1.3 variants during SN DA-like pacemaking compared with Cav1.2 during aSM-like activity. Supratherapeutic isradipine concentrations reduced the pacemaker precision of adult mouse SN DA neurons but did not affect their somatic Ca2+ oscillations. Our data predict that Cav1.2 and Cav1.3 splice variants contribute differentially to Ca2+ load in SN DA neurons, with prominent Cav1.3-mediated ICa between action potentials and after bursts. The failure of therapeutically relevant isradipine levels to protect SN DA neurons can be explained by weaker state-dependent inhibition of SN DA LTCCs compared with aSM Cav1.2.SIGNIFICANCE STATEMENT The high vulnerability of dopamine (DA) neurons in the substantia nigra (SN) to neurodegenerative stressors causes Parkinson's disease (PD). Ca2+ influx through voltage-gated L-type Ca2+ channels (LTCCs), in particular Cav1.3, appears to contribute to this vulnerability, and the LTCC inhibitor isradipine is currently being tested as a neuroprotective agent for PD in a phase III clinical trial. However, in our study isradipine plasma concentrations approved for therapy were not neuroprotective in a PD mouse model. We provide an explanation for this observation by demonstrating that during SN DA-like neuronal activity LTCCs are less sensitive to isradipine than Cav1.2 LTCCs in resistance blood vessels (mediating dose-limiting vasodilating effects) and even at supratherapeutic concentrations isradipine fails to reduce somatic Ca2+ oscillations of SN DA neurons.

New modified 2-aminobenzimidazole nucleosides: Synthesis and evaluation of their activity against herpes simplex virus type 1.

Using the enzymatic transglycosylation reaction ß-d-ribo- and 2'-deoxyribofuranosides of 2-amino-5,6-difluorobenzimidazole nucleosides have been synthesized. 2-Amino-5,6-difluoro-benzimidazole riboside proved to exhibit a selective antiviral activity (selectivity index >32) against a wild strain of the herpes simplex virus type 1, as well as towards virus strains that are resistant to acyclovir, cidofovir, and foscarnet. We believe that this compound might be used for treatment of herpes infections in those cases, when acyclovir is not efficient.

As Working Memory Grows: A Developmental Account of Neural Bases of Working Memory Capacity in 5- to 8-Year Old Children and Adults.

Working memory develops slowly: Even by age 8, children are able to maintain only half the number of items that adults can remember. Neural substrates that support performance on working memory tasks also have a slow developmental trajectory and typically activate to a lesser extent in children, relative to adults. Little is known about why younger participants elicit less neural activation. This may be due to maturational differences, differences in behavioral performance, or both. Here we investigate the neural correlates of working memory capacity in children (ages 5-8) and adults using a visual working memory task with parametrically increasing loads (from one to four items) using fMRI. This task allowed us to estimate working memory capacity limit for each group. We found that both age groups increased the activation of frontoparietal networks with increasing working memory loads, until working memory capacity was reached. Because children's working memory capacity limit was half of that for adults, the plateau occurred at lower loads for children. Had a parametric increase in load not been used, this would have given an impression of less activation overall and less load-dependent activation for children relative to adults. Our findings suggest that young children and adults recruit similar frontoparietal networks at working memory loads that do not exceed capacity and highlight the need to consider behavioral performance differences when interpreting developmental differences in neural activation.

Recognition of Artificial Nucleobases by E. coli Purine Nucleoside Phosphorylase versus its Ser90Ala Mutant in the Synthesis of Base-Modified Nucleosides.

A wide range of natural purine analogues was used as probe to assess the mechanism of recognition by the wild-type (WT) E. coli purine nucleoside phosphorylase (PNP) versus its Ser90Ala mutant. The results were analyzed from viewpoint of the role of the Ser90 residue and the structural features of the bases. It was found that the Ser90 residue of the PNP 1) plays an important role in the binding and activation of 8-aza-7-deazapurines in the synthesis of their nucleosides, 2) participates in the binding of α-D-pentofuranose-1-phosphates at the catalytic site of the PNP, and 3) catalyzes the dephosphorylation of intermediary formed 2-deoxy-α-D-ribofuranose-1-phosphate in the trans-2-deoxyribosylation reaction. 5-Aza-7-deazaguanine manifested excellent substrate activity for both enzymes, 8-amino-7-thiaguanine and 2-aminobenzothiazole showed no substrate activity for both enzymes. On the contrary, the 2-amino derivatives of benzimidazole and benzoxazole are substrates and are converted into the N1- and unusual N2-glycosides, respectively. 9-Deaza-5-iodoxanthine showed moderate inhibitory activity of the WT E. coli PNP, whereas 9-deazaxanthine and its 2'-deoxyriboside are weak inhibitors.

Neural substrates of the development of cognitive control in children ages 5-10 years.

Cognitive conflict detection and resolution develops with age across childhood and likely supports age-related increases in other aspects of cognitive and emotional development. Little is known about the neural correlates of conflict detection and resolution in early childhood. In the current study, we investigated age-related change in neural recruitment during a blocked spatial-incompatibility task (Simon task) in children ages 5-10 years using fMRI. Cortical thickness was measured using structural MRI. Across all children, there was greater activation in right prefrontal and bilateral parietal cortices for incompatible than compatible conditions. In older children, compared with younger children, there was decreased activation and decreased gray matter thickness in the medial PFC. Thickness and activation changes across age were associated within participants, such that thinner cortex was associated with less activation in the rostral ACC. These findings suggest that developmental change in medial PFC activation supports performance on cognitive control tasks in early childhood.

Development and Validation of a Shortened Form of SELweb EE, a Web-Based Assessment of Children's Social and Emotional Competence.

This article describes the development and validation of a shortened form of SELweb EE, a web-based assessment for social-emotional skills in the early elementary grades. Using a Rasch approach, in the first study, we used data from two archival data sets to reduce the number of items in three subtests to create short forms that maintained item fit, item difficulty, item discrimination, and test information function range. In the second study, we created and administered a short form of SELweb EE to a demographically diverse cross-validation sample of 22,683 students. We evaluated the shortened assessment subtests' score reliability, fit to a hypothesized factor structure, and association with age and other variables to evaluate criterion-related validity. Findings from this study suggest that score reliabilities, factor structure, and criterion-related validity for the short form are similar to corresponding properties of the long form. In addition, using a confirmatory factor analysis framework, the short form of SELweb EE demonstrated evidence of configural, metric, and scalar invariance across sex, ethnicity, and language. Shortening SELweb EE reduced the mean administration duration from 36 to 24 minutes. This reduction substantially increases its usability and feasibility while maintaining its psychometric merit.

Effect of magnesium chloride on psychomotor activity, emotional status, and acute behavioural responses to clonidine, d-amphetamine, arecoline, nicotine, apomorphine, and L-5-hydroxytryptophan.

BACKGROUND: The beneficial effects of magnesium (Mg) salts on central manifestations of Mg deficiency are well known. Mg replacement therapy can be effective to prevent some of the serious depression-like and anxiety-related behaviour sequelae of Mg deficiency. However, few experimental studies have been undertaken on Mg-deficiency-induced behavioural changes. Even fewer studies have been carried out on acute behavioural responses to clonidine, D-amphetamine, arecoline, nicotine, apomorphine, and L-5-hydroxytryptophan (HTP), which might characterize possible neuromediator changes in Mg deficiency. The effects of correcting Mg deficiency by magnesium chloride (MgCl2 · 6H2O) and the combination of this salt with vitamin B6, on the behavioural manifestations of Mg deficiency have never been described as well. OBJECTIVE: The aims of this study were: to estimate effect of MgCl2 · 6H2O alone and in combination with vitamin B6 on acute behavioural responses to agonists or blockers of the main neurotransmitter systems in CNS, psychomotor activity and emotional status of rats fed with Mg-deficient diet for 49 days. In our study open field test has shown that in Mg-deficient rats locomotor activity and vertical activity, number of visiting and residence time in central squares were decreased significantly. In the elevated plus maze test, the number of visiting open arms and residence time of rats were significantly less as compared with the control group. In the forced swimming test, time immobile was significantly increased by 44.29% and time of swimming was decreased by 52.79% compared to control. RESULTS: In our study Mg-deficient rats were more sensitive to d-amphetamine-induced motor stereotypes. Mg deficiency antagonized 5-hydroxytryptophan-induced head-twitch response and arecoline-induced tremor. Supplement of MgCl2 · 6H2O with vitamin B6 administered to a Mg-deficient rat increased the Mg level in plasma and erythrocytes. Furthermore, this increase was in relation to vitamin B6 given to the animal. Mg supplementation alone and in combination with pyridoxine normalized acute behavioural responses to d-amphetamine, 5-hydroxytryptophan, and arecoline in Mg deficient rats with a return to pre-deficient levels observed in the Mg sufficient group. DISCUSSION: Combination of Mg salts and pyridoxine hydrochloride can be effective at treating some behavior form of primary Mg deficiency.

Neuronal correlates underlying the role of the zinc sensing receptor (GPR39) in passive-coping behaviour.

The Zn2+ receptor GPR39 is proposed to be involved in the pathophysiology of depression. GPR39 knockout (KO) animals show depressive- and anxiety-like behaviour, and resistance to conventional monoamine-based antidepressants. However, it is unclear as to which brain regions are involved in the pro-depressive phenotype of GPR39KO mice and the resistance to monoamine-targeting antidepressant treatment. Our current study confirmed previous results, showing that mice lacking GPR39 display enhanced passive coping-like behaviour compared with their wild-type controls. Furthermore, this study shows for the first time that GPR39KO displayed aberrant challenge-induced neuronal activity in key brain regions associated with passive coping behaviour. Imipramine induced only a marginal reduction in the enhanced passive coping behaviour in GPR39KO mice, which was associated with attenuation of the hyperactive prefrontal cortex. Similarly, the aberrant activity within the amygdalar subregions was normalized following imipramine treatment in the GPR39KO mice, indicating that imipramine mediates these effects independently of GPR39 in the prefrontal cortex and amygdala. However, imipramine failed to modulate the aberrant brain activity in other brain regions, such as the anterior CA3 and the dentate gyrus, in GPR39KO mice. Normalization of aberrant activity in these areas has been shown previously to accompany successful behavioural effects of antidepressants. Taken together, our data suggest that monoamine-based antidepressants such as imipramine exert their action via GPR39-dependent and -independent pathways. Failure to modulate passive-coping related aberrant activity in important brain areas of the depression circuitry is proposed to mediate/contribute to the greatly reduced antidepressant action of monoamine-based antidepressants in GPR39KO mice.

Measurement of Cognition for the National Children's Study.

The National Children's Study Cognitive Health Domain Team developed detailed plans for assessing cognition longitudinally from infancy to early adulthood. These plans identify high-priority aspects of cognition that can be measured efficiently and effectively, and we believe they can serve as a model for future large-scale longitudinal research. For infancy and toddlerhood, we proposed several paradigms that collectively allowed us to assess six broad cognitive constructs: (1) executive function skills, (2) episodic memory, (3) language, (4) processing speed, (5) spatial and numerical processing, and (6) social cognition. In some cases, different trial sequences within a paradigm allow for the simultaneous assessment of multiple cognitive skills (e.g., executive function skills and processing speed). We define each construct, summarize its significance for understanding developmental outcomes, discuss the feasibility of its assessment throughout development, and present our plan for measuring specific skills at different ages. Given the need for well-validated, direct behavioral measures of cognition that can be used in large-scale longitudinal studies, especially from birth to age 3 years, we also initiated three projects focused on the development of new measures.

Neuroinflammatory alterations in trait anxiety: modulatory effects of minocycline.

High trait anxiety is a substantial risk factor for developing anxiety disorders and depression. While neuroinflammation has been identified to contribute to stress-induced anxiety, little is known about potential dysregulation in the neuroinflammatory system of genetically determined pathological anxiety or high trait anxiety individuals. We report microglial alterations in various brain regions in a mouse model of high trait anxiety (HAB). In particular, the dentate gyrus (DG) of the hippocampus of HABs exhibited enhanced density and average cell area of Iba1+, and density of phagocytic (CD68+/Iba1+) microglia compared to normal anxiety (NAB) controls. Minocycline was used to assess the capacity of a putative microglia 'inhibitor' in modulating hyperanxiety behavior of HABs. Chronic oral minocycline indeed reduced HAB hyperanxiety, which was associated with significant decreases in Iba1+ and CD68+Iba1+ cell densities in the DG. Addressing causality, it was demonstrated that longer (10 days), but not shorter (5 days), periods of minocycline microinfusions locally into the DG of HAB reduced Iba-1+ cell density and attenuated hyperanxiety-related behavior, indicating that neuroinflammation in the DG is at least partially involved in the maintenance of pathological anxiety. The present data reveal evidence of disturbances in the microglial system of individuals with high trait anxiety. Minocycline attenuated HAB hyperanxiety, likely by modulation of microglial activity within the DG. Thus, the present data suggest that drugs with microglia-targeted anti-inflammatory properties could be promising as novel alternative or complimentary anxiolytic therapeutic approaches in specific subgroups of individuals genetically predisposed to hyperanxiety.

More than a matter of getting 'unstuck': flexible thinkers use more abstract representations than perseverators.

Why do people perseverate, repeating prior behaviours that are no longer appropriate? Many accounts point to isolated deficits in processes such as inhibition or attention. We instead posit a fundamental difference in rule representations: flexible switchers use active representations that rely on later-developing prefrontal cortical areas and are more abstract, whereas perseverators use latent representations that rely on earlier-developing posterior cortical and subcortical areas and are more stimulus-specific. Thus, although switchers and perseverators should apply the rules they use to familiar stimuli equally reliably, perseverators should show unique limitations in generalizing their rules to novel stimuli, a process that requires abstract representations. Two behavioural experiments confirmed this counterintuitive prediction early in development. Three-year-old children sorted cards by one rule, were asked to switch to another rule, and then were asked simply to continue their behaviour, with novel cards. Perseverators applied the rule they were using (the first rule) just as reliably as switchers applied the rule they were using (the second rule) with familiar cards; however, only switchers generalized their rule to novel cards. This finding supports an early link between active representations that support switching and abstract representations that support generalization. We interpret this synergy in terms of prefrontal cortical development.

Role for Chromatin Remodeling Factor Chd1 in Learning and Memory.

Precise temporal and spatial regulation of gene expression in the brain is a prerequisite for cognitive processes such as learning and memory. Epigenetic mechanisms that modulate the chromatin structure have emerged as important regulators in this context. While posttranslational modification of histones or the modification of DNA bases have been examined in detail in many studies, the role of ATP-dependent chromatin remodeling factors (ChRFs) in learning- and memory-associated gene regulation has largely remained obscure. Here we present data that implicate the highly conserved chromatin assembly and remodeling factor Chd1 in memory formation and the control of immediate early gene (IEG) response in the hippocampus. We used various paradigms to assess short-and long-term memory in mice bearing a mutated Chd1 gene that gives rise to an N-terminally truncated protein. Our data demonstrate that the Chd1 mutation negatively affects long-term object recognition and short- and long-term spatial memory. We found that Chd1 regulates hippocampal expression of the IEG early growth response 1 (Egr1) and activity-regulated cytoskeleton-associated (Arc) but not cFos and brain derived neurotrophic factor (Bdnf), because the Chd1-mutation led to dysregulation of Egr1 and Arc expression in naive mice and in mice analyzed at different stages of object location memory (OLM) testing. Of note, Chd1 likely regulates Egr1 in a direct manner, because chromatin immunoprecipitation (ChIP) assays revealed enrichment of Chd1 upon stimulation at the Egr1 genomic locus in the hippocampus and in cultured cells. Together these data support a role for Chd1 as a critical regulator of molecular mechanisms governing memory-related processes, and they show that this function involves the N-terminal serine-rich region of the protein.

Low magnesium diet alters distribution of macroelements and trace elements in tissues and organs of female rats.

The aim of the present study was to assess whether dietary magnesium deficiency can alter distribution of macroelements and trace elements in different organs and tissues. Experiments were carried out on 12 adult female Wistar rats, which were fed either a diet with low Mg content (≤20mgkg-1 of diet) (LMgD) or a diet with daily recommended Mg content (≈500mgkg-1) as control group (CG) for 70 days. On the 70th day of the experiment heart, aorta, femoral skeletal muscle, forebrain, cerebellum, pituitary gland, thyroid gland, ovaries, uterus, liver, kidneys, and spleen were taken for analysis of mineral content. Concentrations of Fe and Ca were measured by inductively coupled plasma-atomic emission spectrometry, and levels of Na, K, Mg, Co, Cu, Zn, Ni, Se, I were determined by inductively coupled plasma mass spectrometry. On the 70th day, LMgD led to significant reduction of Mg level in red blood cells, plasma, aorta, uterus and thyroid gland compared to CG as well as resulted in significant decrease of Mg/Ca ratio in kidneys, spleen and ovaries. Contrary to this, an increase of Mg/Ca ratio was found in cerebellum of LMgD group. Significant decrease of K concentration was shown in aorta of LMgD animals compared to CG whereas myocardial K concentration was increased in LMgD group. Na level was two-fold higher in skeletal muscles of rats that received LMgD in comparison to CG (p=0.006). Increased concentrations of Fe in ovaries and uterus were found in LMgD. Mg restriction did not affect Zn concentration in any of tasted tissues. Se level was higher in spleen and lower in uterus of LMgD animals compared to CG. MgD was accompanied by increased level of Co in skeletal muscles and decreased its level in kidneys and uterus. LMgD feeding was associated with decreased concentrations of Ni in heart, thyroid gland, spleen, uterus and Co in heart, aorta, liver, kidneys, spleen and ovaries. The changes of Mg, K, Co content were accompanied by dramatic (10-fold) decrease of I concentration in aorta of LMgD animals. LMgD causes decrease of I content in ovaries and increase of I level in uterus vs CG. Thus, distribution of macroelements (Ca, Na, K) was weakly affected by Mg restriction that led to the most evident alterations of Co and Ni tissue levels. Moreover, mineral balance of uterus seems to be the most susceptible to low Mg intake. Hypomagnesaemia resulted in significant changes of 5 studied trace elements (Fe, Se, Cu, Ni and Co).

Protective effect of magnesium acetyltaurate against NMDA-induced retinal damage involves restoration of minerals and trace elements homeostasis.

Glutamate-mediated excitotoxicity involving N-methyl-d-aspartate (NMDA) receptors has been recognized as a final common outcome in pathological conditions involving death of retinal ganglion cells (RGCs). Overstimulation of NMDA receptors results in influx of calcium (Ca) and sodium (Na) ions and efflux of potassium (K). NMDA receptors are blocked by magnesium (Mg). Such changes due to NMDA overstimulation are also associated with not only the altered levels of minerals but also that of trace elements and redox status. Both the decreased and elevated levels of trace elements such as iron (Fe), zinc (Zn), copper (Cu) affect NMDA receptor excitability and redox status. Manganese (Mn), and selenium (Se) are also part of antioxidant defense mechanisms in retina. Additionally endogenous substances such as taurine also affect NMDA receptor activity and retinal redox status. Therefore, the aim of this study was to evaluate the effect of Mg acetyltaurate (MgAT) on the retinal mineral and trace element concentration, oxidative stress, retinal morphology and retinal cell apoptosis in rats after-NMDA exposure. One group of Sprague Dawley rats received intravitreal injection of vehicle while 4 other groups similarly received NMDA (160nmolL-1). Among the NMDA injected groups, 3 groups also received MgAT (320nmolL-1) as pre-treatment, co-treatment or post-treatment. Seven days after intravitreal injection, rats were sacrificed, eyes were enucleated and retinae were isolated for estimation of mineral (Ca, Na, K, Mg) and trace element (Mn, Cu, Fe, Se, Zn) concentration using Inductively Coupled Plasma (DRC ICP-MS) techniques (NexION 300D), retinal oxidative stress using Elisa, retinal morphology using H&E staining and retinal cell apoptosis using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Intravitreal NMDA injection resulted in increased concentration of Ca (4.6 times, p<0.0001), Mg (1.5 times, p<0.01), Na (3 times, p<0.0001) and K (2.3 times, p<0.0001) compared to vehicle injected group. This was accompanied with significant increase of Ca/Mg and Na/K ratios, 3 and 1.27 times respectively, compared to control group. The trace elements such as Cu, Fe and Zn also showed a significant increase amounting to 3.3 (p<0.001), 2.3 (p<0.0001) and 3 (p<0.0001) times respectively compared to control group. Se was increased by 60% (p<0.005). Pre-treatment with MgAT abolished effect of NMDA on minerals and trace elements more effectively than co- and post-treatment. Similar observations were made for retinal oxidative stress, retinal morphology and retinal cell apoptosis. In conclusion, current study demonstrated the protective effect of MgAT against NMDA-induced oxidative stress and retinal cell apoptosis. This effect of MgAT was associated with restoration of retinal concentrations of minerals and trace elements. Further studies are warranted to explore the precise molecular targets of MgAT. Nevertheless, MgAT seems a potential candidate in the management of diseases involving NMDA-induced excitotoxicity.

Magnesium deficiency and oxidative stress: an update.

Magnesium deficiency (MgD) has been shown to impact numerous biological processes at the cellular and molecular levels. In the present review, we discuss the relationship between MgD and oxidative stress (OS). MgD is accompanied by increased levels of OS markers such as lipid, protein and DNA oxidative modification products. Additionally, a relationship was detected between MgD and a weakened antioxidant defence. Different mechanisms associated with MgD are involved in the development and maintenance of OS. These mechanisms include systemic reactions such as inflammation and endothelial dysfunction, as well as changes at the cellular level, such as mitochondrial dysfunction and excessive fatty acid production.

Adolescent development of context-dependent stimulus-reward association memory and its neural correlates.

Expression of learned stimulus-reward associations based on context is essential for regulation of behavior to meet situational demands. Contextual regulation improves during development, although the developmental progression of relevant neural and cognitive processes is not fully specified. We therefore measured neural correlates of flexible, contextual expression of stimulus-reward associations in pre/early-adolescent children (ages 9-13 years) and young adults (ages 19-22 years). After reinforcement learning using standard parameters, a contextual reversal manipulation was used whereby contextual cues indicated that stimulus-reward associations were the same as previously reinforced for some trials (consistent trials) or were reversed on other trials (inconsistent trials). Subjects were thus required to respond according to original stimulus-reward associations vs. reversed associations based on trial-specific contextual cues. Children and young adults did not differ in reinforcement learning or in relevant functional magnetic resonance imaging (fMRI) correlates. In contrast, adults outperformed children during contextual reversal, with better performance specifically for inconsistent trials. fMRI signals corresponding to this selective advantage included greater activity in lateral prefrontal cortex (LPFC), hippocampus, and dorsal striatum for young adults relative to children. Flexible expression of stimulus-reward associations based on context thus improves via adolescent development, as does recruitment of brain regions involved in reward learning and contextual expression of memory. HighlightsEarly-adolescent children and young adults were equivalent in reinforcement learning.Adults outperformed children in contextual expression of stimulus-reward associations.Adult advantages correlated with increased activity of relevant brain regions.Specific neurocognitive developmental changes support better contextual regulation.