Blood-brain barrier biomarkers.

The blood-brain barrier (BBB) is a dynamic interface that regulates the exchange of molecules and cells between the brain parenchyma and the peripheral blood. The BBB is mainly composed of endothelial cells, astrocytes and pericytes. The integrity of this structure is essential for maintaining brain and spinal cord homeostasis and protection from injury or disease. However, in various neurological disorders, such as traumatic brain injury, Alzheimer's disease, and multiple sclerosis, the BBB can become compromised thus allowing passage of molecules and cells in and out of the central nervous system parenchyma. These agents, however, can serve as biomarkers of BBB permeability and neuronal damage, and provide valuable information for diagnosis, prognosis and treatment. Herein, we provide an overview of the BBB and changes due to aging, and summarize current knowledge on biomarkers of BBB disruption and neurodegeneration, including permeability, cellular, molecular and imaging biomarkers. We also discuss the challenges and opportunities for developing a biomarker toolkit that can reliably assess the BBB in physiologic and pathophysiologic states.

Specific nanoprobe design for MRI: Targeting laminin in the blood-brain barrier to follow alteration due to neuroinflammation.

Chronic neuroinflammation is characterized by increased blood-brain barrier (BBB) permeability, leading to molecular changes in the central nervous system that can be explored with biomarkers of active neuroinflammatory processes. Magnetic resonance imaging (MRI) has contributed to detecting lesions and permeability of the BBB. Ultra-small superparamagnetic particles of iron oxide (USPIO) are used as contrast agents to improve MRI observations. Therefore, we validate the interaction of peptide-88 with laminin, vectorized on USPIO, to explore BBB molecular alterations occurring during neuroinflammation as a potential tool for use in MRI. The specific labeling of NPS-P88 was verified in endothelial cells (hCMEC/D3) and astrocytes (T98G) under inflammation induced by interleukin 1ß (IL-1ß) for 3 and 24 hours. IL-1ß for 3 hours in hCMEC/D3 cells increased their co-localization with NPS-P88, compared with controls. At 24 hours, no significant differences were observed between groups. In T98G cells, NPS-P88 showed similar nonspecific labeling among treatments. These results indicate that NPS-P88 has a higher affinity towards brain endothelial cells than astrocytes under inflammation. This affinity decreases over time with reduced laminin expression. In vivo results suggest that following a 30-minute post-injection, there is an increased presence of NPS-P88 in the blood and brain, diminishing over time. Lastly, EAE animals displayed a significant accumulation of NPS-P88 in MRI, primarily in the cortex, attributed to inflammation and disruption of the BBB. Altogether, these results revealed NPS-P88 as a biomarker to evaluate changes in the BBB due to neuroinflammation by MRI in biological models targeting laminin.

Analysis of the psychometric properties of the Buss-Perry Aggression Questionnaire (AQ) in Colombian adolescents / Análisis de las propiedades psicométricas del cuestionario de agresividad (AQ) de Buss y Perry en adolescentes colombianos

The psychometric properties of the Buss and Perry AQ questionnaire of aggression, one of the most used questionnaires worldwide to measure aggressive behavior, were examined in a sample of adolescents (n=779 participants) from the cities of Barranquilla (n= 410) and Pereira (n= 369), in Colombia. In total, 752 participants (Mean age of 15.3 years, SD = 1.9; 57,4%. women and 42,6 men) completed the Buss and Perry AQ questionnaire. Subsequently, the univariate and multivariate normality of the items was evaluated, and a confirmatory factor analysis (CFA) was performed on the data set. Likewise, the fit of two models was evaluated, a multidimensional a priori model, and a model with a second-order factor (aggressive behavior), which could explain the variance of the items. Finally, the reliability indices of the questionnaire were identified. The results showed acceptable goodness-of-fit indices (X2/df = 2.29, CFI = .977, IFI = .977, GFI = .984, AGFI = .979, RNI = .984, NFI = .972, RMSEA of .047 [90% CI = .016 - .036] and SRMR = .059) for the second-order one-factor model, as well as acceptable reliability indices (α= .55 - .88). In conclusion, these results show that the scale can be applicable to Colombian preadolescents and adolescents, but warn of the limitations of its use for the non-aggression subscale. Nevertheless, the application of the scale in its original version is suggested to determine its psychometric behavior. (AU)

Las propiedades psicométricas del cuestionario de agresión Buss y Perry AQ, uno de los cuestionarios más utilizados mundialmente para medir la conducta agresiva, fue examinado en una muestra de adolescentes (n=779 participantes) de las ciudades de Barranquilla (n= 410) y Pereira (n= 369), en Colombia. En total, 752 participantes (edad media de 15,3 años, DE = 1,9; 57,4%. mujeres y 42,6 hombres) completaron el cuestionario AQ de Buss y Perry. Posteriormente, se evaluó la normalidad univariante y multivariante de los ítems, y se realizó un análisis factorial confirmatorio (AFC) sobre el conjunto de datos. Asimismo, se evaluó el ajuste de dos modelos, un modelo multidimensional a priori, y un modelo con un factor de segundo orden (conducta agresiva), que podría explicar la varianza de los ítems. Por último, se identificaron los índices de fiabilidad del cuestionario. Los resultados mostraron índices de bondad de ajuste aceptables (X2/df = 2,29, CFI = .977, IFI = .977, GFI = .984, AGFI = .979, RNI = .984, NFI = .972, RMSEA de .047 [90% CI = .016 - .036] y SRMR = .059) para el modelo de un factor de segundo orden, así como índices de fiabilidad aceptables (α= .55 - .88). En conclusión, estos resultados muestran que la escala puede ser aplicable a preadolescentes y adolescentes colombianos, pero advierten de las limitaciones de su uso para la subescala de no agresión. No obstante, se sugiere la aplicación de la escala en su versión original para determinar su comportamiento psicométrico. (AU)

Role of Calcium Modulation in the Pathophysiology and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most frequent cause of progressive dementia in senior adults. It is characterized by memory loss and cognitive impairment secondary to cholinergic dysfunction and N-methyl-D-aspartate (NMDA)-mediated neurotoxicity. Intracellular neurofibrillary tangles, extracellular plaques composed of amyloid-ß (Aß), and selective neurodegeneration are the anatomopathological hallmarks of this disease. The dysregulation of calcium may be present in all the stages of AD, and it is associated with other pathophysiological mechanisms, such as mitochondrial failure, oxidative stress, and chronic neuroinflammation. Although the cytosolic calcium alterations in AD are not completely elucidated, some calcium-permeable channels, transporters, pumps, and receptors have been shown to be involved at the neuronal and glial levels. In particular, the relationship between glutamatergic NMDA receptor (NMDAR) activity and amyloidosis has been widely documented. Other pathophysiological mechanisms involved in calcium dyshomeostasis include the activation of L-type voltage-dependent calcium channels, transient receptor potential channels, and ryanodine receptors, among many others. This review aims to update the calcium-dysregulation mechanisms in AD and discuss targets and molecules with therapeutic potential based on their modulation.

Astrocytes as a Therapeutic Target in Alzheimer's Disease-Comprehensive Review and Recent Developments.

Alzheimer's disease (AD) is a frequent and disabling neurodegenerative disorder, in which astrocytes participate in several pathophysiological processes including neuroinflammation, excitotoxicity, oxidative stress and lipid metabolism (along with a critical role in apolipoprotein E function). Current evidence shows that astrocytes have both neuroprotective and neurotoxic effects depending on the disease stage and microenvironmental factors. Furthermore, astrocytes appear to be affected by the presence of amyloid-beta (Aß), with alterations in calcium levels, gliotransmission and proinflammatory activity via RAGE-NF-κB pathway. In addition, astrocytes play an important role in the metabolism of tau and clearance of Aß through the glymphatic system. In this review, we will discuss novel pharmacological and non-pharmacological treatments focused on astrocytes as therapeutic targets for AD. These interventions include effects on anti-inflammatory/antioxidant systems, glutamate activity, lipid metabolism, neurovascular coupling and glymphatic system, calcium dysregulation, and in the release of peptides which affects glial and neuronal function. According to the AD stage, these therapies may be of benefit in either preventing or delaying the progression of the disease.

Taurine and Astrocytes: A Homeostatic and Neuroprotective Relationship.

Taurine is considered the most abundant free amino acid in the brain. Even though there are endogenous mechanisms for taurine production in neural cells, an exogenous supply of taurine is required to meet physiological needs. Taurine is required for optimal postnatal brain development; however, its brain concentration decreases with age. Synthesis of taurine in the central nervous system (CNS) occurs predominantly in astrocytes. A metabolic coupling between astrocytes and neurons has been reported, in which astrocytes provide neurons with hypotaurine as a substrate for taurine production. Taurine has antioxidative, osmoregulatory, and anti-inflammatory functions, among other cytoprotective properties. Astrocytes release taurine as a gliotransmitter, promoting both extracellular and intracellular effects in neurons. The extracellular effects include binding to neuronal GABAA and glycine receptors, with subsequent cellular hyperpolarization, and attenuation of N-methyl-D-aspartic acid (NMDA)-mediated glutamate excitotoxicity. Taurine intracellular effects are directed toward calcium homeostatic pathway, reducing calcium overload and thus preventing excitotoxicity, mitochondrial stress, and apoptosis. However, several physiological aspects of taurine remain unclear, such as the existence or not of a specific taurine receptor. Therefore, further research is needed not only in astrocytes and neurons, but also in other glial cells in order to fully comprehend taurine metabolism and function in the brain. Nonetheless, astrocyte's role in taurine-induced neuroprotective functions should be considered as a promising therapeutic target of several neuroinflammatory, neurodegenerative and psychiatric diseases in the near future. This review provides an overview of the significant relationship between taurine and astrocytes, as well as its homeostatic and neuroprotective role in the nervous system.

Laminin as a Biomarker of Blood-Brain Barrier Disruption under Neuroinflammation: A Systematic Review.

Laminin, a non-collagenous glycoprotein present in the brain extracellular matrix, helps to maintain blood-brain barrier (BBB) integrity and regulation. Neuroinflammation can compromise laminin structure and function, increasing BBB permeability. The aim of this paper is to determine if neuroinflammation-induced laminin functional changes may serve as a potential biomarker of alterations in the BBB. The 38 publications included evaluated neuroinflammation, BBB disruption, and laminin, and were assessed for quality and risk of bias (protocol registered in PROSPERO; CRD42020212547). We found that laminin may be a good indicator of BBB overall structural integrity, although changes in expression are dependent on the pathologic or experimental model used. In ischemic stroke, permanent vascular damage correlates with increased laminin expression (ß and γ subunits), while transient damage correlates with reduced laminin expression (α subunits). Laminin was reduced in traumatic brain injury and cerebral hemorrhage studies but increased in multiple sclerosis and status epilepticus studies. Despite these observations, there is limited knowledge about the role played by different subunits or isoforms (such as 411 or 511) of laminin in maintaining structural architecture of the BBB under neuroinflammation. Further studies may clarify this aspect and the possibility of using laminin as a biomarker in different pathologies, which have alterations in BBB function in common.

Screening for Interacting Proteins with Peptide Biomarker of Blood-Brain Barrier Alteration under Inflammatory Conditions.

Neurodegenerative diseases are characterized by increased permeability of the blood-brain barrier (BBB) due to alterations in cellular and structural components of the neurovascular unit, particularly in association with neuroinflammation. A previous screening study of peptide ligands to identify molecular alterations of the BBB in neuroinflammation by phage-display, revealed that phage clone 88 presented specific binding affinity to endothelial cells under inflammatory conditions in vivo and in vitro. Here, we aimed to identify the possible target receptor of the peptide ligand 88 expressed under inflammatory conditions. A cross-link test between phage-peptide-88 with IL-1ß-stimulated human hCMEC cells, followed by mass spectrometry analysis, was used to identify the target of peptide-88. We modeled the epitope-receptor molecular interaction between peptide-88 and its target by using docking simulations. Three proteins were selected as potential target candidates and tested in enzyme-linked immunosorbent assays with peptide-88: fibronectin, laminin subunit α5 and laminin subunit ß-1. Among them, only laminin subunit ß-1 presented measurable interaction with peptide-88. Peptide-88 showed specific interaction with laminin subunit ß-1, highlighting its importance as a potential biomarker of the laminin changes that may occur at the BBB endothelial cells under pathological inflammation conditions.

Pathophysiological Mechanisms of Cognitive Impairment and Neurodegeneration by Toxoplasma gondii Infection.

Toxoplasma gondii is an obligate intracellular parasite considered one of the most successful pathogens in the world, owing to its ability to produce long-lasting infections and to persist in the central nervous system (CNS) in most warm-blooded animals, including humans. This parasite has a preference to invade neurons and affect the functioning of glial cells. This could lead to neurological and behavioral changes associated with cognitive impairment. Although several studies in humans and animal models have reported controversial results about the relationship between toxoplasmosis and the onset of dementia as a causal factor, two recent meta-analyses have shown a relative association with Alzheimer's disease (AD). AD is characterized by amyloid-ß (Aß) peptide accumulation, neurofibrillary tangles, and neuroinflammation. Different authors have found that toxoplasmosis may affect Aß production in brain areas linked with memory functioning, and can induce a central immune response and neurotransmitter imbalance, which in turn, affect the nervous system microenvironment. In contrast, other studies have revealed a reduction of Aß plaques and hyperphosphorylated tau protein formation in animal models, which might cause some protective effects. The aim of this article is to summarize and review the newest data in regard to different pathophysiological mechanisms of cerebral toxoplasmosis and their relationship with the development of AD and cognitive impairment. All these associations should be investigated further through clinical and experimental studies.

Effects of Moringa oleifera on Glycaemia and Insulin Levels: A Review of Animal and Human Studies.

Diabetes and related neurological complications are serious worldwide public health problems. The increasing number of affected individuals make it necessary to implement novel nutritional and therapeutic interventions. The tree Moringa oleifera (MO) has been used as a food source and for traditional medicine purposes due to possible antihyperglycemic, antioxidant, anti-inflammatory, and lipid regulating properties. These properties may be explained by the presence of numerous phytochemicals in the leaves, fruits, roots and, oil of the tree. The evidence for acute antihyperglycemic effects of MO extract on diabetic animal models seems to be robust, but more chronic and long-term studies are needed. In contrast, the hypoglycemic effects of MO on humans are not as clear. The scarce number of human studies, together with a diverse range of methodologies and MO doses, may explain this. In addition, evidence regarding changes in insulin levels due to MO intervention is ambiguous, both in animal and human studies. Therefore, more structured studies are needed to clarify if MO has an effect on insulin levels or activity.

Visual Features in Alzheimer's Disease: From Basic Mechanisms to Clinical Overview.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. It compromises patients' daily activities owing to progressive cognitive deterioration, which has elevated direct and indirect costs. Although AD has several risk factors, aging is considered the most important. Unfortunately, clinical diagnosis is usually performed at an advanced disease stage when dementia is established, making implementation of successful therapeutic interventions difficult. Current biomarkers tend to be expensive, insufficient, or invasive, raising the need for novel, improved tools aimed at early disease detection. AD is characterized by brain atrophy due to neuronal and synaptic loss, extracellular amyloid plaques composed of amyloid-beta peptide (Aß), and neurofibrillary tangles of hyperphosphorylated tau protein. The visual system and central nervous system share many functional components. Thus, it is plausible that damage induced by Aß, tau, and neuroinflammation may be observed in visual components such as the retina, even at an early disease stage. This underscores the importance of implementing ophthalmological examinations, less invasive and expensive than other biomarkers, as useful measures to assess disease progression and severity in individuals with or at risk of AD. Here, we review functional and morphological changes of the retina and visual pathway in AD from pathophysiological and clinical perspectives.

Astroglial role in the pathophysiology of status epilepticus: an overview.

Status epilepticus is a medical emergency with elevated morbidity and mortality rates, and represents a leading cause of epilepsy-related deaths. Though status epilepticus can occur at any age, it manifests more likely in children and elderly people. Despite the common prevalence of epileptic disorders, a complete explanation for the mechanisms leading to development of self-limited or long lasting seizures (as in status epilepticus) are still lacking. Apart from neurons, research evidence suggests the involvement of immune and glial cells in epileptogenesis. Among glial cells, astrocytes represent an ideal target for the study of the pathophysiology of status epilepticus, due to their key role in homeostatic balance of the central nervous system. During status epilepticus, astroglial cells are activated by the presence of cytokines, damage associated molecular patterns and reactive oxygen species. The persistent activation of astrocytes leads to a decrease in glutamate clearance with a corresponding accumulation in the synaptic extracellular space, increasing the chance of neuronal excitotoxicity. Moreover, major alterations in astrocytic gap junction coupling, inflammation and receptor expression, facilitate the generation of seizures. Astrocytes are also involved in dysregulation of inhibitory transmission in the central nervous system and directly participate in ionic homeostatic alterations during status epilepticus. In the present review, we focus on the functional and structural changes in astrocytic activity that participate in the development and maintenance of status epilepticus, with special attention on concurrent inflammatory alterations. We also include potential astrocytic treatment targets for status epilepticus.

Situation Awareness Performance in Healthy Young Adults Is Associated With a Serotonin Transporter Gene Polymorphism.

Background Situation awareness (SA) is defined in three levels: SA1 is the perception of the elements in a specific context, SA2 is the comprehension of their meaning, and SA3 is the projection of their status. Purpose To analyze the possible association of a genetic polymorphism in the serotonin transporter ( SLC6A4) gene and performance on the Situational Awareness test (SAtest). Methods SAtest was applied to a sample of 230 healthy Colombian subjects, using the Psychology Experiment Building Language platform and a functional polymorphism in the SLC6A4 gene was genotyped by polymerase chain reaction. Results In the SA1 level, s/s genotype carriers had worse accuracy, in comparison with s/l and l/l genotypes. At SA2 level, l/l genotype carriers had better accuracy than s/s and s/l individuals and that in the SA3 level, l/l carriers also had better accuracy. These associations were significant after correction for multiple testing. Conclusions It is possible that l/l carriers have a better ability to perceive and focus their attention on the elements of their environment and to have the capacity to understand and predict what will happen with those elements. This is the first genetic study of SA performance in healthy participants. Additional investigations of other genes could contribute to the understanding of the molecular correlates of SA in healthy subjects and in neuropsychiatric patients.

Astrocyte´s RAGE: More Than Just a Question of Mood.

BACKGROUND: Adequate function of the nervous system depends on the balance of glianeuron complex interactions. Astrocytes, in particular, are key elements in this process due to the significant participation of these cells in essential properties of the nervous system such as neuroinflammation, regulation of neurotransmitters, release of gliotransmitters and control of synaptic plasticity, among others. Astrocytes express the receptor for advanced glycation end products (RAGE) which is very important in the recognition of endogenous molecules released in the context of infection, physiological stress or chronic inflammation. RAGE can bind several advanced glycation end products, S100 proteins, HMGB1, amyloid-ß and other additional DAMP molecules. The nuclear factorkappa B (NF-κB) transcription pathway is the main intracellular signaling pathway activated by the RAGE receptor, inducing an increase in the expression and release of proinflammatory cytokines. Due to its numerous interactions, RAGE is suspected to be involved in various physiological and pathological processes. CONCLUSION: It is plausible that a prolonged exposure to RAGE ligands or abnormally increased concentrations of some ligands may induce lengthy periods of intracellular proinflammatory activation, which may induce the appearance of reactive astrocytes involved in the development and/or progression of neurodegenerative disorders. Blocking or reducing the duration of activation of RAGE/NF-κB signaling in astrocytes may become an important therapeutic alternative for the treatment of neurodegenerative disorders in the future.

Involvement of Astrocytes in Alzheimer's Disease from a Neuroinflammatory and Oxidative Stress Perspective.

Alzheimer disease (AD) is a frequent and devastating neurodegenerative disease in humans, but still no curative treatment has been developed. Although many explicative theories have been proposed, precise pathophysiological mechanisms are unknown. Due to the importance of astrocytes in brain homeostasis they have become interesting targets for the study of AD. Changes in astrocyte function have been observed in brains from individuals with AD, as well as in AD in vitro and in vivo animal models. The presence of amyloid beta (Aß) has been shown to disrupt gliotransmission, neurotransmitter uptake, and alter calcium signaling in astrocytes. Furthermore, astrocytes express apolipoprotein E and are involved in the production, degradation and removal of Aß. As well, changes in astrocytes that precede other pathological characteristics observed in AD, point to an early contribution of astroglia in this disease. Astrocytes participate in the inflammatory/immune responses of the central nervous system. The presence of Aß activates different cell receptors and intracellular signaling pathways, mainly the advanced glycation end products receptor/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, responsible for the transcription of pro-inflammatory cytokines and chemokines in astrocytes. The release of these pro-inflammatory agents may induce cellular damage or even stimulate the production of Aß in astrocytes. Additionally, Aß induces the appearance of oxidative stress (OS) and production of reactive oxygen species and reactive nitrogen species in astrocytes, affecting among others, intracellular calcium levels, NADPH oxidase (NOX), NF-κB signaling, glutamate uptake (increasing the risk of excitotoxicity) and mitochondrial function. Excessive neuroinflammation and OS are observed in AD, and astrocytes seem to be involved in both. The Aß/NF-κB interaction in astrocytes may play a central role in these inflammatory and OS changes present in AD. In this paper, we also discuss therapeutic measures highlighting the importance of astrocytes in AD pathology. Several new therapeutic approaches involving phenols (curcumin), phytoestrogens (genistein), neuroesteroids and other natural phytochemicals have been explored in astrocytes, obtaining some promising results regarding cognitive improvements and attenuation of neuroinflammation. Novel strategies comprising astrocytes and aimed to reduce OS in AD have also been proposed. These include estrogen receptor agonists (pelargonidin), Bambusae concretio Salicea, Monascin, and various antioxidatives such as resveratrol, tocotrienol, anthocyanins, and epicatechin, showing beneficial effects in AD models.

A functional variant in MIR137, a candidate gene for schizophrenia, affects Stroop test performance in young adults.

MIR137, a brain expressed miRNA, has been identified as a top novel susceptibility gene for schizophrenia (SZ). 230 healthy participants completed the Stroop test and were genotyped for a functional Variable Number Tandem Repeat (VNTR) in MIR137 gene. MIR137 VNTR genotypes were associated with differences in Stroop facilitation and accuracies in congruent trials and for the total number of errors. This is the first study of the functional VNTR in MIR137 gene and Stroop test performance in healthy subjects. Our results could have important implications for the identification of genetic candidates for endophenotypes for SZ.

Alterations in Glucose Metabolism on Cognition: A Possible Link Between Diabetes and Dementia.

The use of the carbohydrate glucose as an energetic source is essential for an adequate function of the human body. The complex regulation of this molecule involves the coordinated action of various organs such as pancreas, liver and brain. Any disruption of this physiological balance may result in a dangerous compromise of general metabolic activities increasing the possibility of developing T1DM, T2DM and possibly AD. Astrocytes convert glucose into lactate and transfer it to neurons. This lactate is essential for neuronal metabolism and for various processes including the formation of synapses, dendrites and the expression of genes involved in memory. The brain is highly susceptible to variations in glucose blood levels, and both hypoglycemia and hyperglycemia can be dangerous. Pathological hyperglycemia induces changes in plasmatic osmotic pressure, mitochondrial production of free radicals, oxidative stress and activation of neuronal apoptosis, among others. Both AD and diabetes are chronic diseases having age as an important risk factor. As the brain ages, it seems to become much more susceptible to cellular damage induced by excess of circulating glucose and this could explain the appearance of cognitive changes observed in some patients with diabetes. Excessive circulation of pro-inflammatory agents has been observed in insulin resistance and is likely that some of these mediators may cross the bloodbrain barrier and induce abnormal neuroinflammation. GSK-3 is overexpressed in diabetes and also has been reported to regulate tau phosphorylation and production of Aß peptides in the brain. Currently, diabetes (hyperglycemia) is considered as a risk factor for the development of AD. A novel therapeutic approach, using intranasal insulin and anti-diabetic medications in patients suffering from AD is being explored and is discussed in this review.

Differences in planning performance, a neurocognitive endophenotype, are associated with a functional variant in PER3 gene.

Performance alterations in executive function have been studied as potential endophenotypes for several neuropsychiatric diseases. Planning is an important component of executive function and has been shown to be affected in diseases such as attention deficit hyperactivity disorder, schizophrenia, obsessive-compulsive disorder and Parkinson's disease. Several genes related to dopaminergic systems, such as COMT, have been explored as candidates for influencing planning performance. The circadian clock gene PERIOD3 (PER3) has been shown to be associated with several complex behaviors in humans and could be involved in different signaling mechanisms. In this study, we evaluated the possible association between a functional polymorphism in the PER3 gene (PER3-VNTR, rs57875989) and performance in a commonly used test of planning (Tower of London, TOL) in 229 healthy subjects from Bogotá, Colombia. PER3-VNTR genotyping was carried out with conventional PCR and all participants completed the TOL test using the computerized Psychology Experiment Building Language (PEBL) battery. A linear regression model was used for the analysis of association with the SNPStats program. We found that 4/4 genotype carriers showed a better performance and made fewer moves, in comparison to 4/5 and 5/5 genotype carriers (p = 0.003). These results appear to be independent from effects of this polymorphism on self-reported average hours of sleep during work days in our sample. This is the first evidence of an association between PER3-VNTR and planning performance in a sample of healthy subjects and our results are consistent from previous findings for alterations in other cognitive domains. Future studies examining additional genes could lead to the identification of novel molecular underpinnings of planning in healthy subjects and in patients with neuropsychiatric disorders.

Noradrenaline acting at central beta-adrenoceptors induces interleukin-10 and suppressor of cytokine signaling-3 expression in rat brain: implications for neurodegeneration.

Evidence indicates that the monoamine neurotransmitter noradrenaline elicits anti-inflammatory actions in the central nervous system (CNS), and consequently may play a neuroprotective role where inflammatory events contribute to CNS pathology. Here we examined the ability of pharmacologically enhancing central noradrenergic tone to induce expression of anti-inflammatory cytokines in rat brain. Administration of the noradrenaline reuptake inhibitor reboxetine (15mg/kg; ip) combined with the alpha(2)-adrenoceptor antagonist idazoxan (1mg/kg; ip) induced interleukin-10 (IL-10) expression in rat cortex and hippocampus. In addition, these drug treatments induced IL-10 signaling as indicated by increased STAT3 phosphorylation and suppressor of cytokine signaling-3 (SOCS-3) mRNA expression. In contrast to the profound increase in IL-10 induced by the reboxetine/idazoxan combination, the other two broad spectrum anti-inflammatory cytokines IL-4 and TGF-beta were not induced by this treatment. The ability of combined treatment with reboxetine and idazoxan to induce IL-10 and SOCS3 expression was mediated by beta-adrenoceptor activation, as their induction was blocked by pre-treatment with the beta-adrenoceptor antagonist propranolol. Moreover, administration of the brain penetrant beta(2)-adrenoceptor agonist clenbuterol induced a time- and dose-dependent increase in central IL-10 and SOCS3 expression, and the ability of clenbuterol to induce IL-10 and SOCS-3 expression was blocked by the centrally acting beta-adrenoceptor antagonist, propranolol, and was mimicked by the highly selective beta(2)-adrenoceptor agonist formoterol. In all, these data indicate that increasing central noradrenergic tone induces IL-10 production and signaling in the CNS, which may protect against neurodegeneration.

The psychostimulant modafinil facilitates water maze performance and augments synaptic potentiation in dentate gyrus.

Modafinil is a psychostimulant drug used widely for the treatment of narcolepsy, which also has additional positive effects on cognition. Here, we investigate the effects of modafinil on behavioural performance and synaptic plasticity in rats. Improved acquisition in the water maze task was observed in animals that underwent chronic treatment with modafinil. We found that the distance traveled and escape latency were reduced after the first day in chronically-treated rats, compared to controls. Importantly, swim velocity was similar for both groups, excluding pharmacological effects on motor skills. We also found that modafinil increases synaptic plasticity in the dentate gyrus of urethane-anaesthetized rats; modafinil induced a robust augmentation of the population spike, evident after application of 2 bursts of 200 Hz high-frequency stimulation. Furthermore, the modafinil-dependent enhancement of postsynaptic potentials correlated selectively with theta rhythm augmentation. We propose that modafinil may facilitate hippocampal-associated spatial representation via increased theta-related hippocampal plasticity.