Intrinsic diving reflex induces potent antioxidative response by activation of NRF2 signaling.

Aims: This study aims to elucidate the underlying mechanisms of diving reflex, a powerful endogenous mechanism supporting underwater mammalian survival. Antioxidative responses, observed in marine mammals, may be contributing factors. Using a multi-organ approach, this study assesses whether acute and chronic diving reflex activate nuclear factor-erythroid-2-related factor 2 (NRF2) signaling pathways, which regulate cellular antioxidant responses. Methods: Male Sprague-Dawley rats ( n =38) underwent either a single diving session to elicit acute diving reflex, or daily diving sessions for 4-weeks to produce chronic diving reflex. NRF2 (total, nuclear, phosphorylated), NRF2-downstream genes, and malondialdehyde were assessed via Western blot, immunofluorescence, RT-PCR, and ELISA in brain, lung, kidney, and serum. Results: Diving reflex increased nuclear NRF2, phosphorylated NRF2, and antioxidative gene expression, in an organ-specific and exposure time-specific manner. Comparing organs, the brain had the highest increase of phosphorylated NRF2 expression, while kidney had the highest degree of nuclear NRF2 expression. Comparing acute and chronic sessions, phosphorylated NRF2 increased the most with chronic diving reflex, but acute diving reflex had the highest antioxidative gene expression. Notably, calcitonin gene-related peptide appears to mediate diving reflex' effects on NRF2 activation. Conclusions: Acute and chronic diving reflex activate potent NRF2 signaling in the brain and peripheral organs. Interestingly, acute diving reflex induces higher expression of downstream antioxidative genes compared to chronic diving reflex. This result contradicts previous assumptions requiring chronic exposure to diving for induction of antioxidative effects and implies that the diving reflex has a strong translational potential during preconditioning and postconditioning therapies. Key Points: Diving reflex activates potent NRF2 signaling via multiple mechanisms, including phosphorylation, nuclear translocation, and KEAP1 downregulation with both acute and chronic exposure.Diving reflex activates NRF2 via differential pathways in the brain and other organs; phosphorylated NRF2 increases more in the brain, while nuclear NRF2 increases more in the peripheral organs.Acute diving reflex exposure induces a more pronounced antioxidative effect than chronic diving reflex exposure, indicating that the antioxidative response activated by diving reflex is not dependent upon chronic adaptive responses and supports diving reflex as both a preconditioning and postconditioning treatment.

Dominance hierarchy regulates social behavior during spatial movement.

Rodents establish dominance hierarchy as a social ranking system in which one subject acts as dominant over all the other subordinate individuals. Dominance hierarchy regulates food access and mating opportunities, but little is known about its significance in other social behaviors, for instance during collective navigation for foraging or migration. Here, we implemented a simplified goal-directed spatial task in mice, in which animals navigated individually or collectively with their littermates foraging for food. We compared between conditions and found that the social condition exerts significant influence on individual displacement patterns, even when efficient navigation rules leading to reward had been previously learned. Thus, movement patterns and consequent task performance were strongly dependent on contingent social interactions arising during collective displacement, yet their influence on individual behavior was determined by dominance hierarchy. Dominant animals did not behave as leaders during collective displacement; conversely, they were most sensitive to the social environment adjusting their performance accordingly. Social ranking in turn was associated with specific spontaneous neural activity patterns in the prefrontal cortex and hippocampus, with dominant mice showing higher firing rates, larger ripple oscillations, and stronger neuronal entrainment by ripples than subordinate animals. Moreover, dominant animals selectively increased their cortical spiking activity during collective movement, while subordinate mice did not modify their firing rates, consistent with dominant animals being more sensitive to the social context. These results suggest that dominance hierarchy influences behavioral performance during contingent social interactions, likely supported by the coordinated activity in the hippocampal-prefrontal circuit.

Neurobehavioral Impairments Predict Specific Cerebral Damage in Rat Model of Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a severe form of stroke that can cause unpredictable and diffuse cerebral damage, which is difficult to detect until it becomes irreversible. Therefore, there is a need for a reliable method to identify dysfunctional regions and initiate treatment before permanent damage occurs. Neurobehavioral assessments have been suggested as a possible tool to detect and approximately localize dysfunctional cerebral regions. In this study, we hypothesized that a neurobehavioral assessment battery could be a sensitive and specific method for detecting damage in discrete cerebral regions following SAH. To test this hypothesis, a behavioral battery was employed at multiple time points after SAH induced via an endovascular perforation, and brain damage was confirmed via postmortem histopathological analysis. Our results demonstrate that impairment of sensorimotor function accurately predict damage in the cerebral cortex (AUC 0.905; sensitivity 81.8%; specificity 90.9%) and striatum (AUC 0.913; sensitivity 90.1%; specificity 100%), while impaired novel object recognition is a more accurate indicator of damage to the hippocampus (AUC 0.902; sensitivity 74.1%; specificity 83.3%) than impaired reference memory (AUC 0.746; sensitivity 72.2%; specificity 58.0%). Tests for anxiety-like and depression-like behaviors predict damage to the amygdala (AUC 0.900; sensitivity 77.0%; specificity 81.7%) and thalamus (AUC 0.963; sensitivity 86.3%; specificity 87.8%), respectively. This study suggests that recurring behavioral testing can accurately predict damage in specific brain regions, which could be developed into a clinical battery for early detection of SAH damage in humans, potentially improving early treatment and outcomes.

Neurobehavioral impairments predict specific cerebral damage in rat model of subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a severe form of stroke that can cause unpredictable and diffuse cerebral damage, which is difficult to detect until it becomes irreversible. Therefore, there is a need for a reliable method to identify dysfunctional regions and initiate treatment before permanent damage occurs. Neurobehavioral assessments have been suggested as a possible tool to detect and approximately localize dysfunctional cerebral regions. In this study, we hypothesized that a neurobehavioral assessment battery could be a sensitive and specific early warning for damage in discrete cerebral regions following SAH. To test this hypothesis, a behavioral battery was employed at multiple time points after SAH induced via an endovascular perforation, and brain damage was confirmed via postmortem histopathological analysis. Our results demonstrate that impairment of sensorimotor function accurately predict damage in the cerebral cortex (AUC: 0.905; sensitivity: 81.8%; specificity: 90.9%) and striatum (AUC: 0.913; sensitivity: 90.1%; specificity: 100%), while impaired novel object recognition is a more accurate indicator of damage to the hippocampus (AUC: 0.902; sensitivity: 74.1%; specificity: 83.3%) than impaired reference memory (AUC: 0.746; sensitivity: 72.2%; specificity: 58.0%). Tests for anxiety-like and depression-like behaviors predict damage to the amygdala (AUC: 0.900; sensitivity: 77.0%; specificity: 81.7%) and thalamus (AUC: 0.963; sensitivity: 86.3%; specificity: 87.8%), respectively. This study suggests that recurring behavioral testing can accurately predict damage in specific brain regions, which could be developed into a clinical battery for early detection of SAH damage in humans, potentially improving early treatment and outcomes.

In utero exposure to maternal anti-aquaporin-4 antibodies alters brain vasculature and neural dynamics in male mouse offspring.

The fetal brain is constantly exposed to maternal IgG before the formation of an effective blood-brain barrier (BBB). Here, we studied the consequences of fetal brain exposure to an antibody to the astrocytic protein aquaporin-4 (AQP4-IgG) in mice. AQP4-IgG was cloned from a patient with neuromyelitis optica spectrum disorder (NMOSD), an autoimmune disease that can affect women of childbearing age. We found that embryonic radial glia cells in neocortex express AQP4. These cells are critical for blood vessel and BBB formation through modulation of the WNT signaling pathway. Male fetuses exposed to AQP4-IgG had abnormal cortical vasculature and lower expression of WNT signaling molecules Wnt5a and Wnt7a. Positron emission tomography of adult male mice exposed in utero to AQP4-IgG revealed increased blood flow and BBB leakiness in the entorhinal cortex. Adult male mice exposed in utero to AQP4-IgG had abnormal cortical vessels, fewer dendritic spines in pyramidal and stellate neurons, and more S100ß+ astrocytes in the entorhinal cortex. Behaviorally, they showed impairments in the object-place memory task. Neural recordings indicated that their grid cell system, within the medial entorhinal cortex, did not map the local environment appropriately. Collectively, these data implicate in utero binding of AQP4-IgG to radial glia cells as a mechanism for alterations of the developing male brain and adds NMOSD to the conditions in which maternal IgG may cause persistent brain dysfunction in offspring.

Relación del estado nutricional de las madres y la alteración de los factores de riesgo cardiovascular de sus hijos / Relationship between mothers' nutritional status and alterations in cardiovascular risk factors of their offsprings

RESUMEN: ANTECEDENTES: La obesidad infantil es uno de los principales problemas de salud pública, y es el mejor predictor de obesidad adulta, que conlleva a futuras consecuencias, como enfermedades cardiovasculares. OBJETIVO: Este estudio pretende relacionar el estado nutricional de las madres con los factores de riesgo cardiovascular (FRCV) de sus hijos con malnutrición por exceso (MNPE). MÉTODOS: Estudio descriptivo de corte transversal y muestreo de tipo no probabilístico por conveniencia, se efectuó en 100 diadas madres/hijos con MNPE. En cada diada se efectuaron mediciones antropométricas, peso, talla, estado nutricional según índice de masa corporal (IMC) y perímetro cintura (PC). En escolares se determinó presión arterial (PA), glicemia y consumo alimentario. El análisis estadístico incluyó Riesgo relativo (RR) y regresión logística. Su usó el software Stata 14. RESULTADOS: Los promedios encontrados en los hijos fueron: edad 8.8 años, IMC/edad 21.1 kg/mt2. En las madres, la edad promedio fue 36,9 años y el IMC 29,0 kg/mt2. En relación con los FRCV, los escolares presentaron glicemias y presión arterial alteradas y obesidad abdominal. La malnutrición por exceso y la alteración de la percepción de las madres sobre el estado nutricional de sus hijos aumentó el RR de presentar alteración de la glicemia en 1,31 veces. La obesidad según IMC/edad presentó un RR de 1,5 y una relación positiva OR de 5,73. CONCLUCIONES: Existe una asociación positiva entre la MNPE de las madres y la obesidad de sus hijos. Se observó un aumento en los factores de riesgo cardiovascular de los escolares, quienes presentaban obesidad abdominal y presión arterial y glicemia alteradas.

ABSTRACT: BACKGROUP: Childhood obesity is one of the main public health problems. It is the best predictor of adult obesity, leading to adverse consequences, especially in relation to cardiovascular diseases. OBJETIVE: This study aims to relate the nutritional status of mothers to the cardiovascular risk factors (CVRF) of their offsprings with excess MNPE. Methods: A descriptive, cross-sectional study with non-probabilistic convenience sampling included 100 mother/child dyads with MNPE. Anthropometric measurements and determination of weight, height, nutritional status (body mass index (BMI) and waist circumference (WC)), as well as blood pressure (BP), glycemia and food consumption were evaluated in schoolchildren. The statistical analysis included Relative Risk (RR) and logistic regression, using the Stata 14 software. RESULTS: Average results in children included: age 8.8 years, BMI/age 21.1 kg/mt2. In mothers, mean age was 36.9 years and BMI 29.0 kg/mt2. In relation to CVRF, schoolchildren presented altered glycemia, higher blood pressure and abdominal obesity. The MNPE and the alteration of mothers' perception of the nutritional status of their children increased the RR of altered glycemia 1.31 fold. Obesity according to BMI/age presented a RR of 1.5 and a positive OR 5.73. CONCLUSIONS: There was a positive association between the mothers' MNPE and elevated cardiovascular risk factors in school children including abdominal obesity, higher blood pressure and altered glycemia.

Framework for automated sorting of neural spikes from Neuralynx-acquired tetrode recordings in freely-moving mice.

BACKGROUND: Extracellular recording represents a crucial electrophysiological technique in neuroscience for studying the activity of single neurons and neuronal populations. The electrodes capture voltage traces that, with the help of analytical tools, reveal action potentials ('spikes') as well as local field potentials. The process of spike sorting is used for the extraction of action potentials generated by individual neurons. Until recently, spike sorting was performed with manual techniques, which are laborious and unreliable due to inherent operator bias. As neuroscientists add multiple electrodes to their probes, the high-density devices can record hundreds to thousands of neurons simultaneously, making the manual spike sorting process increasingly difficult. The advent of automated spike sorting software has offered a compelling solution to this issue and, in this study, we present a simple-to-execute framework for running an automated spike sorter. METHODS: Tetrode recordings of freely-moving mice are obtained from the CA1 region of the hippocampus as they navigate a linear track. Tetrode recordings are also acquired from the prelimbic cortex, a region of the medial prefrontal cortex, while the mice are tested in a T maze. All animals are implanted with custom-designed, 3D-printed microdrives that carry 16 electrodes, which are bundled in a 4-tetrode geometry. RESULTS: We provide an overview of a framework for analyzing single-unit data in which we have concatenated the acquisition system (Cheetah, Neuralynx) with analytical software (MATLAB) and an automated spike sorting pipeline (MountainSort). We give precise instructions on how to implement the different steps of the framework, as well as explanations of our design logic. We validate this framework by comparing manually-sorted spikes against automatically-sorted spikes, using neural recordings of the hippocampus and prelimbic cortex in freely-moving mice. CONCLUSIONS: We have efficiently integrated the MountainSort spike sorter with Neuralynx-acquired neural recordings. Our framework is easy to implement and provides a high-throughput solution. We predict that within the broad field of bioelectronic medicine, those teams that incorporate high-density neural recording devices to their armamentarium might find our framework quite valuable as they expand their analytical footprint.

Contributions of Sex Chromosomes and Gonadal Hormones to the Male Bias in a Maternal Antibody-Induced Model of Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental conditions that is four times more commonly diagnosed in males than females. While susceptibility genes located in the sex chromosomes have been identified in ASD, it is unclear whether they are sufficient to explain the male bias or whether gonadal hormones also play a key role. We evaluated the sex chromosomal and hormonal influences on the male bias in a murine model of ASD, in which mice are exposed in utero to a maternal antibody reactive to contactin-associated protein-like 2 (Caspr2), which was originally cloned from a mother of a child with ASD (termed C6 mice henceforth). In this model, only male mice are affected. We used the four-core-genotypes (FCG) model in which the Sry gene is deleted from the Y chromosome (Y-) and inserted into autosome 3 (TgSry). Thus, by combining the C6 and FCG models, we were able to differentiate the contributions of sex chromosomes and gonadal hormones to the development of fetal brain and adult behavioral phenotypes. We show that the presence of the Y chromosome, or lack of two X chromosomes, irrespective of gonadal sex, increased the susceptibility to C6-induced phenotypes including the abnormal growth of the developing fetal cerebral cortex, as well as a behavioral pattern of decreased open-field exploration in adult mice. Our results indicate that sex chromosomes are the main determinant of the male bias in the maternal C6-induced model of ASD. The less dominant hormonal effect may be due to modulation by sex chromosome genes of factors involved in gonadal hormone pathways in the brain.

Reversible dysregulation of renal circadian rhythm in lupus nephritis.

BACKGROUND: We have found disruption of expression of major transcriptional regulators of circadian rhythm in the kidneys of several mouse models of lupus nephritis. Here we define the consequence of this disturbance with respect to circadian gene expression and renal homeostatic function in a mouse model of lupus nephritis. METHODS: Molecular profiling of kidneys from 47 young and 41 nephritic female NZB/W F1 mice was performed at 4 hourly intervals over a 24 h period. Disruption of major circadian transcriptional regulators was confirmed by qPCR. Molecular data was normalized and analyzed for rhythmicity using RAIN analysis. Serum aldosterone and glucose and urine sodium and potassium were measured at 4 hourly intervals in pre-nephritic and nephritic mice and blood pressure was measured every 4 h. Analyses were repeated after induction of complete remission of nephritis using combination cyclophosphamide and costimulatory blockade. RESULTS: We show a profound alteration of renal circadian rhythms in mice with lupus nephritis affecting multiple renal pathways. Using Cosinor analysis we identified consequent alterations of renal homeostasis and metabolism as well as blood pressure dipper status. This circadian dysregulation was partially reversed by remission induction therapy. CONCLUSIONS: Our studies indicate the role of inflammation in causing the circadian disruption and suggest that screening for loss of normal blood pressure dipping should be incorporated into LN management. The data also suggest a potential role for circadian agonists in the treatment of lupus nephritis.

Alteración de la percepción materna sobre el estado nutricional de sus hijos ¿nuevo factor de riesgo cardiovascular? / Perception of child nutritional status by their mothers: a new cardiovascular risk factor?

ANTECEDENTES: La obesidad infantil es un trastorno de prevalencia creciente que predispone a la obesidad, diabetes y enfermedades cardiovasculares en el adulto. Investigaciones recientes relacionan la percepción materna con el estado nutricional real de los niños, encontrando una distorsión entre imagen corporal de sus hijos con malnutrición por exceso (MNPE). MÉTODOS: Estudio descriptivo de corte transversal. La población objetivo fue 320 madres de escolares de 6 a 10 años y se utilizó un muestreo por conveniencia. Se incluyeron madres de hijos con MNPE. Se evaluó la percepción de las madres a través de un pictograma. Se efectuaron mediciones antropométricas de peso, talla y perímetro de cintura (PC), presión arterial (PA), glicemia y colesterol total. En el análisis estadístico se usó Stata 14 y Epidat 4.2. RESULTADOS: La muestra fue conformada por 100 díadas madre/hijo con MNPE. 69% de las madres presentaron escolaridad de enseñanza media, y 68% tenían nivel socioeconómico bajo. Respecto de los niños, 52% eran de sexo femenino, 38% presentaban riesgo de obesidad abdominal y el 47% tenían obesidad abdominal. La glicemia en ayunas estaba alterada en 35%, el colesterol total alterado en 12% y 31% presentaban PA elevada. El 60% de las madres de niños con MNPE subestimaron el estado nutricional de sus hijos. CONCLUSIONES: En relación a los factores de riesgo cardiovascular de los escolares, un alto porcentaje presenta índices de riesgo cardiovascular elevado: obesidad abdominal, PA alterada, colesterol total y glicemias alteradas. La alteración de la percepción materna sobre el estado nutricional de sus hijos, puede repercutir en forma significativa para el desarrollo y mantenimiento de la MNPE y, por consiguiente, constituye un factor de riesgo cardiovascular, estableciendo un punto clave de intervención.

BACKGROUND: Overnutrition in children is increasingly more prevalent and leads to obesity, diabetes and cardiovascular disease in adults. Recent research links distorted maternal perception of nutritional status in their children with the presence of obesity in adulthood). METHODS: A descriptive cross-sectional study was performed on mothers and their schoolchildren aged 6 to 10 years old. A basic inclusion criteria was the presence of overnutrition in children and the study related maternal perception with the actual degree of overnutrition in her child. Perception was evaluated using a pictogram. Weight, height, waist circumference, blood pressure (BP), blood sugar level and total cholesterol were measured in children Stata 14 and Epidat 2.0 were used for statistical analysis. RESULTS: 100 mother-child pairs were studied. All children had overnutrition. 69% of mothers had high-school level education and 68% belonged in the low socio-economic stratum. There were 52% of girls. According to waist circumference 38% were at risk of malnutrition and 47% already had abdominal obesity. 35% had an altered fasting blood sugar level, 12% an elevated total cholesterol, 31% an increased blood pressure. 60% of mothers of children with overnutrition underestimated the actual nutritional status (overnutrion) of their children. CONCLUSIONS: The presence of overnutrition and obesity indicators were high in this population. This occurred along with increased levels of BP, total cholesterol and altered blood sugar levels. The maternal perception of their children severely under estimated the level of overnutrition. This fact can have a significant impact on the development and maintenance of the excess type malnutrition and subsequent development of other cardiovascular risk factors. Therefore, improving the perception of mothers regarding the nutritional status of their children should be an important element for diminishing cardiovascular risk longterm.

In utero exposure to endogenous maternal polyclonal anti-Caspr2 antibody leads to behavioral abnormalities resembling autism spectrum disorder in male mice.

The concept that exposure in utero to maternal anti-brain antibodies contributes to the development of autism spectrum disorders (ASD) has been entertained for over a decade. We determined that antibodies targeting Caspr2 are present at high frequency in mothers with brain-reactive serology and a child with ASD, and further demonstrated that exposure in utero to a monoclonal anti-Caspr2 antibody, derived from a mother of an ASD child, led to an-ASD like phenotype in male offspring. Now we propose a new model to study the effects of in utero exposure to anti-Caspr2 antibody. Dams immunized with the extracellular portion of Caspr2 express anti-Caspr2 antibodies throughout gestation to better mimic the human condition. Male but not female mice born to dams harboring polyclonal anti-Caspr2 antibodies showed abnormal cortical development, decreased dendritic complexity of excitatory neurons and reduced numbers of inhibitory neurons in the hippocampus, as well as repetitive behaviors and impairments in novelty interest in the social preference test as adults. These data supporting the pathogenicity of anti-Caspr2 antibodies are consistent with the concept that anti-brain antibodies present in women during gestation can alter fetal brain development, and confirm that males are peculiarly susceptible.

Key role of MIF-related neuroinflammation in neurodegeneration and cognitive impairment in Alzheimer's disease.

BACKGROUND: Macrophage Migration Inhibitory Factor (MIF) is a potent proinflammatory cytokine that promotes the production of other immune mediators. MIF is produced by most cell types in the brain including microglia, astrocytes and neurons. Enhanced expression of MIF might contribute to the persistent activation of glial, chronic neuroinflammation and neurodegeneration. Here, we investigated the effect of MIF on inflammatory markers and spatial learning in a mouse model of sporadic AD and on tau pathology in AD patients. METHODS: We examined the effects of MIF deficiency and pharmacological MIF inhibition in vitro and in vivo. In vitro, quantitative PCR and ELISA were used to assess cytokine production of STZ-treated glial cells. In vivo, C57BL/6 mice were subjected to intracerebroventricular streptozotocin injection (3 mg/kg, ICV-STZ). Neuroinflammation and contextual learning performance were assessed using quantitative PCR and fear conditioning, respectively. Pharmacological MIF inhibition was achieved with intraperitoneal injections of ISO-1 (daily, IP, 20 mg/kg in 5% DMSO in 0.9% NaCl) for 4 weeks following ICV-STZ injection. The findings from ISO-1 treated mice were confirmed in MIF knockout C57BL/6. To assess the role of MIF in human AD, cerebrospinal fluid levels of MIF and hyperphosphorylated tau were measured using ELISA. RESULTS: Administration ICV-STZ resulted in hippocampal dependent cognitive impairment. MIF inhibition with ISO-1 significantly improved the STZ-induced impairment in contextual memory performance, indicating MIF-related inflammation as a major contributor to ICV-STZ-induced memory deficits. Furthermore, inhibition of the MIF resulted in reduced cytokine production in vitro and in vivo. In human subjects with AD at early clinical stages, cerebrospinal fluid levels of MIF were increased in comparison with age-matched controls, and correlated with biomarkers of tau hyper-phosphorylation and neuronal injury hinting at MIF levels as a potential biomarker for early-stage AD. CONCLUSIONS: The present study indicates the key role of MIF in controlling the chronic cytokine release in neuroinflammation related to tau hyperphosphorylation, neurodegeneration, and clinical manifestations of AD, suggesting the potential of MIF inhibition as therapeutic strategy to slow down neurodegeneration and clinical disease progression.

Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory.

Patients with Systemic lupus erythematosus (SLE) experience various peripheral and central nervous system manifestations including spatial memory impairment. A subset of autoantibodies (DNRAbs) cross-react with the GluN2A and GluN2B subunits of the NMDA receptor (NMDAR). We find that these DNRAbs act as positive allosteric modulators on NMDARs with GluN2A-containing NMDARs, even those containing a single GluN2A subunit, exhibiting a much greater sensitivity to DNRAbs than those with exclusively GluN2B. Accordingly, GluN2A-specific antagonists provide greater protection from DNRAb-mediated neuronal cell death than GluN2B antagonists. Using transgenic mice to perturb expression of either GluN2A or GluN2B in vivo, we find that DNRAb-mediated disruption of spatial memory characterized by early neuronal cell death and subsequent microglia-dependent pathologies requires GluN2A-containing NMDARs. Our results indicate that GluN2A-specific antagonists or negative allosteric modulators are strong candidates to treat SLE patients with nervous system dysfunction.

Endogenous retroviruses are associated with hippocampus-based memory impairment.

Retrotransposons compose a staggering 40% of the mammalian genome. Among them, endogenous retroviruses (ERV) represent sequences that closely resemble the proviruses created from exogenous retroviral infection. ERVs make up 8 to 10% of human and mouse genomes and range from evolutionarily ancient sequences to recent acquisitions. Studies in Drosophila have provided a causal link between genomic retroviral elements and cognitive decline; however, in mammals, the role of ERVs in learning and memory remains unclear. Here we studied 2 independent murine models for ERV activation: muMT strain (lacking B cells and antibody production) and intracerebroventricular injection of streptozotocin (ICVI-STZ). We conducted behavioral assessments (contextual fear memory and spatial learning), as well as gene and protein analysis (RNA sequencing, PCR, immunohistochemistry, and western blot assays). Mice lacking mitochondrial antiviral-signaling protein (MAVS) and mice lacking stimulator of IFN genes protein (STING), 2 downstream sensors of ERV activation, provided confirmation of ERV impact. We found that muMT mice and ICVI-STZ mice induced hippocampal ERV activation, as shown by increased gene and protein expression of the Gag sequence of the transposable element intracisternal A-particle. ERV activation was accompanied by significant hippocampus-related memory impairment in both models. Notably, the deficiency of the MAVS pathway was protective against ICVI-STZ-induced cognitive pathology. Overall, our results demonstrate that ERV activation is associated with cognitive impairment in mice. Moreover, they provide a molecular target for strategies aimed at attenuating retroviral element sensing, via MAVS, to treat dementia and neuropsychiatric disorders.

Factores de riesgo cardiovascular en población adolescente aymara. Rol de la occidentalización de la nutrición / Risk factors in Aymara adolescents: influence of western type nutrition

RESUMEN ANTECEDENTES: La obesidad es una epidemia mundial que provoca una alta frecuencia de factores de riesgo cardiovascular (FRCV). Se ha observado que la aculturación está incidiendo en los pueblos originarios, como consecuencia de una dieta occidentalizada, lo cual predispone la obesidad, desarrollo de enfermedades cardiovasculares (ECV) y diabetes. En general la población aymara adulta presenta un bajo riesgo cardiovascular innato, lo cual lleva a una baja incidencia de ECV. Objetivos: Conocer la influencia de la occidentalización de la nutrición y evaluar riesgo cardiovascular de la población adolescente aymara de la comuna de Camiña. Método: Estudio descriptivo de corte transversal, en población aymara entre 11 y 18 años de la comuna de Camiña. Muestra probabilística aleatoria simple constituida por 94 individuos. Se aplica una encuesta alimentaria de tendencia de consumo cuantificada, medición antropométrica y exámenes de glicemia y perfil lipídico. Resultados: Se evaluaron 94 participantes 57,4 % mujeres. Malnutrición por exceso presenta 41%; riesgo cardiovascular según medición de perímetro de cintura (PC) 55,2%; colesterol total alterado 52,6% y triglicéridos alterados 89,5%. Mediante encuesta alimentaria se pudo conocer que 71,7% mantenían una dieta hipercalórica, 69,8 % una dieta hiperglucídica, 45% una dieta hiperlipídica. Conclusión: En la población adolescente aymara estudiada se encontraron factores de riesgo cardiovascular alterados, como malnutrición por exceso, PC aumentado, Colesterol total y Triglicéridos elevados. Su alimentación era "de tipo occidental", consumiendo alimentos procesados y elaborados con dietas hipercalóricas, hiperglucídicas e hiperlipídicas.

ABSTRACT BACKGROUND. Obesity is widely known to lead to increased cardiovascular risk factors (RF). Cultural changes observed in native populations, including the adoption of a western type nutrition, leads to obesity, increased levels of RF ,cardiovascular diseases and diabetes. Aim: To determine the influence of a western type nutrition on RF among adolescent Aymaras in northern Chile. Methods: A cross sectional descriptive study was performed in Camiña (northern Chile), including Aymaras aged 11 to 18 years-old. A quantified alimentary consumption questionnaire, anthropometric measurements, blood glucose levels and lipid profile were obtained. Results: 94 subjects (57% women) were studied. Excess malnutrition (obesity) was present in 41%, abnormally high waist circumference in 55%, high cholesterol levels in 53%, and high triglycerides in 90% of subjects. The contents of the diet being consumed was high in calories in 72%, high in sugar in 70% and high in lipids in 45%. Conclusion: A high prevalence of cardiovascular RF was present in adolescent Aymaras of northern Chile. This finding was related to the consumption of a western type diet, rich in calories, lipids and sugar, leading to obesity

Large-Scale Validation of the Paddling Pool Task in the Clockmaze for Studying Hippocampus-Based Spatial Cognition in Mice.

Rationally designed behavioral tests are important tools to assess the function of specific brain regions. The hippocampus is a crucial neural substrate for spatial cognition, and many studies have linked hippocampal dysfunction with defects on spatial learning and memory in neurological conditions ranging from Alzheimer's disease to autoimmune syndromes, such as neuropsychiatric lupus. While our understanding of hippocampal function, from the molecular to the system levels, has increased dramatically over the last decades, this effort has not yet translated into efficacious therapies for cognitive impairment. We think that the availability of highly validated behavioral paradigms to measure cognition in mouse models is likely to enhance the potential success of preclinical therapeutic modalities. Here, we present an extensive study of the paddling pool task (PPT), first reported by Deacon and Rawlins, in which mice learn to escape from shallow water through a peripheral exit in a circular arena dubbed the clockmaze. We show that the PPT provides highly reliable results when assaying spatial cognition in C57/BL6 mice (120 males, 40 females) and BALB/c mice (40 males, 90 females). Additionally, we develop a robust algorithm for the assessment of escape strategies with clearly quantifiable readouts, enabling fine-granular phenotyping. Notably, the use of spatial strategy increases linearly across trials in the PPT. In a separate cohort of mice, we apply muscimol injections to silence the dorsal CA1 region of the hippocampus and show that the use of the spatial strategy in the PPT relies on the integrity of the dorsal hippocampus. Additionally, we compare directly the PPT and the Morris water maze (MWM) task in C57/BL6 mice (20 males, 20 females) and BALB/c mice (20 males, 20 females) and we find that the PPT induces significantly lower anxiety, exhaustion and hypothermia than the MWM. We conclude that the PPT provides a robust assessment of spatial cognition in mice, which can be applied in conjunction with other tests, to facilitate hypothesis testing and drug development to combat cognitive impairment.

Extracellular cold inducible RNA-binding protein mediates binge alcohol-induced brain hypoactivity and impaired cognition in mice.

BACKGROUND: Alcohol abuse affects the brain regions responsible for memory, coordination and emotional processing. Binge alcohol drinking has shown reductions in brain activity, but the molecular targets have not been completely elucidated. We hypothesized that brain cells respond to excessive alcohol by releasing a novel inflammatory mediator, called cold inducible RNA-binding protein (CIRP), which is critical for the decreased brain metabolic activity and impaired cognition. METHODS: Male wild type (WT) mice and mice deficient in CIRP (CIRP-/-) were studied before and after exposure to binge alcohol level by assessment of relative brain glucose metabolism with fluorodeoxyglucose (18FDG) and positron emission tomography (PET). Mice were also examined for object-place memory (OPM) and open field (OF) tasks. RESULTS: Statistical Parametric Analysis (SPM) of 18FDG-PET uptake revealed marked decreases in relative glucose metabolism in distinct brain regions of WT mice after binge alcohol. Regional analysis (post hoc) revealed that while activity in the temporal (secondary visual) and limbic (entorhinal/perirhinal) cortices was decreased in WT mice, relative glucose metabolic activity was less suppressed in the CIRP-/- mice. Group and condition interaction analysis revealed differing responses in relative glucose metabolism (decrease in WT mice but increase in CIRP-/- mice) after alcohol in brain regions including the hippocampus and the cortical amygdala where the percent changes in metabolic activity correlated with changes in object discrimination performance. Behaviorally, alcohol-treated WT mice were impaired in exploring a repositioned object in the OPM task, and were more anxious in the OF task, whereas CIRP-/- mice were not impaired in these tasks. CONCLUSION: CIRP released from brain cells could be responsible for regional brain metabolic hypoactivity leading to cognitive impairment under binge alcohol conditions.

Assessment of glutamatergic synaptic transmission and plasticity in brain slices: relevance to bioelectronic approaches.

BACKGROUND: Glutamatergic neurons represent the largest neuronal class in the brain and are responsible for the bulk of excitatory synaptic transmission and plasticity. Abnormalities in glutamatergic neurons are linked to several brain disorders and their modulation represents a potential opportunity for emerging bioelectronic medicine (BEM) approaches. Here, we have used a set of electrophysiological assays to identify the effect of the pyrimidine nucleoside uridine on glutamatergic systems in ex vivo brain slices. An improved understanding of glutamatergic synaptic transmission and plasticity, through this type of examination, is critical to the development of potential neuromodulation strategies. METHODS: Ex vivo hippocampal slices (400 µm thick) were prepared from mouse brain. We recorded field excitatory postsynaptic potentials (fEPSP) in the CA1's stratum radiatum by stimulation of the CA3 Schaeffer collateral/commissural axons. Uridine was applied at concentrations (3, 30, 300 µM) representing the physiological range present in brain tissue. Synaptic function was studied with input-output (I-O) functions, as well as paired-pulse facilitation (PPF). Synaptic plasticity was studied by applying tetanic stimulation to induce post-tetanic potentiation (PTP), short-term potentiation (STP) and long-term potentiation (LTP). Additionally, we determined whether uridine affected synaptic responses carried solely by n-methyl-d-aspartate receptors (NMDARs), particularly during the oxygen-glucose deprivation (OGD) paradigm. RESULTS: The presence of uridine altered glutamatergic synaptic transmission and plasticity. We found that uridine affected STP and LTP in a concentration-dependent manner. Low-dose uridine (3 µM) had no effect, but higher doses (30 and 300 µM) impaired STP and LTP. Moreover, uridine (300 µM) decreased NMDAR-mediated synaptic responses. Conversely, uridine (at all concentrations tested) had a negligible effect on PPF and basal synaptic transmission, which is mediated primarily by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). In addition, uridine (100 µM) exerted a protective effect when the hippocampal slices were challenged with OGD, a widely used model of cerebral ischemia. CONCLUSIONS: Using a wide set of electrophysiological assays, we identify that uridine interacts with glutamatergic neurons to alter NMDAR-mediated responses, impair synaptic STP and LTP in a dose-dependent manner, and has a protective effect against OGD insult. This work outlines a strategy to identify deficits in glutamatergic mechanisms for signaling and plasticity that may be critical for targeting these same systems with BEM device-based approaches. To improve the efficacy of potential neuromodulation approaches for treating brain dysfunction, we need to improve our understanding of glutamatergic systems in the brain, including the effects of modulators such as uridine.

Correlación entre estudios electrocardiográficos y cinecoronariográficos en enfermedades coronarias / Connection between electrocardiographic and cinecoronariographic studies in coronary diseases

Las enfermedades cardiovasculares son la principal causa de muerte en Chile. Los Síndromes Coronarios Agudos (SCA), obligan a los sistemas de salud a destinar recursos de elevado costo para su diagnóstico. Procedimientos como el electrocardiograma (ECG) y la cinecoronariografía (CCG) orientan en el diagnóstico de dichas patologías, siendo el ECG un examen no invasivo de fácil ejecución y de bajo costo. El objetivo de este estudio fue relacionar el examen ECG con la CCG para mejorar la precisión diagnóstica de obstrucción coronaria. El estudio fue de tipo descriptivo de corte transversal, constituido por 44 pacientes adultos de ambos sexos que presentaron infarto de miocardio con elevación de segmento ST (STEMI), derivados al Servicio de Hemodinamia de la Clínica Iquique, Chile, para intervención coronaria. Los 44 pacientes tenían un ECG previo y se les realizó una CCG. Los resultados establecieron una fuerte correlación entre los diagnósticos por ECG y por CCG del total de las arterias obstruidas (según prueba de Correlación de Pearson = 0,80; p < 0,001). Se demostró relación entre ambos exámenes en un 92,3 % (p = 0,001) para la obstrucción de la arteria coronaria derecha (ACD) con hallazgo electrocardiográfico que correspondía a infarto de pared inferior. Relación de 100 % para la obstrucción de la rama circunfleja de la arteria coronaria izquierda (ACI) (p = 0,036) y 100 % para la obstrucción de la rama interventricular anterior de la ACI o arteria coronaria descendente anterior (p = 0,001) correspondiente a infarto de pared lateral. Se concluyó que existe relación significativa entre el infarto de pared anterior según los hallazgos electrocardiográficos y la obstrucción de la ACD y la rama circunfleja de la ACI según CCG; además, la relación es significativa entre los infartos de pared lateral y pared anterior con hallazgos por ECG y la obstrucción de la rama interventricular anterior de la arteria coronaria izquierda diagnosticada por CCG. Es fundamental la interpretación correcta del ECG para mejorar la atención del infarto agudo al miocardio.

Cardiovascular diseases are the leading cause of death in Chile. Acute Coronary Syndrome (ACS) forces health systems to allocate high-cost resources for diagnosis. Procedures like Electrocardiogram (ECG) and cinecoronariography (CCG) guide the diagnosis of these pathologies, with ECG being a noninvasive exam easy to perform and of low cost. The aim of this study was to connect ECG exams with CCG to improve the diagnostic accuracy of coronary obstruction. This was a descriptive cross-sectional study, consisting of 44 adult patients of both sexes which presented myocardial infarction with ST-segment elevation (STEMI) referred to the Hemodynamic Service from Iquique Clinic, Chile, for coronary operation. All 44 patients had previous ECG and they were conducted a CCG. Results established a strong correlation between ECG and CCG diagnosis from the total of Clogged Arteries (according to Pearson correlation test = 0.80; p < 0.001). The correlation demonstrated in both exams was 92.3 % (p = 0.001) for blockage in the right coronary artery (RCA) with electrocardiographic finding corresponding to inferior wall infarction. 100 % relationship for the obstruction of the circumflex branch of the left coronary artery (LCA) (p = 0.036) and 100 % for the obstruction of RCA anterior interventricular branch or anterior descending coronary artery (p = 0.001) corresponding to a lateral wall infarction. It is concluded that there is a significant relationship between anterior wall infarction according to electrocardiographic findings and RCA obstruction and LCA circumflex branch according to CCG. In addition, there is a significant relationship between lateral wall infarction and interior walls by ECG findings and the obstruction of the anterior interventricular branch of the left coronary artery diagnosed by CCG. The correct interpretation of ECG is essential to improve the care of acute myocardial infarction.

Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors.

Cognitive impairment occurs in 40-90% of patients with systemic lupus erythematosus (SLE), which is characterized by autoantibodies to nuclear antigens, especially DNA. We discovered that a subset of anti-DNA antibodies, termed DNRAbs, cross reacts with the N-methyl-d-aspartate receptor (NMDAR) and enhances NMDAR signaling. In patients, DNRAb presence associates with spatial memory impairment. In a mouse model, DNRAb-mediated brain pathology proceeds through an acute phase of excitotoxic neuron loss, followed by persistent alteration in neuronal integrity and spatial memory impairment. The latter pathology becomes evident only after DNRAbs are no longer detectable in the brain. Here we investigate the mechanism of long-term neuronal dysfunction mediated by transient exposure to antibody. We show that activated microglia and C1q are critical mediators of neuronal damage. We further show that centrally acting inhibitors of angiotensin-converting enzyme (ACE) can prevent microglial activation and preserve neuronal function and cognitive performance. Thus, ACE inhibition represents a strong candidate for clinical trials aimed at mitigating cognitive dysfunction.