Diffusion tensor imaging analysis along the perivascular space in the UK biobank.

BACKGROUND: The recently discovered glymphatic system may support the removal of neurotoxic proteins, mainly during sleep, that are associated with neurodegenerative diseases such as Alzheimer's and Parkinson's Disease. Diffusion tensor image analysis along the perivascular space (DTI-ALPS) has been suggested as a method to index the health of glymphatic system (with higher values indicating a more intact glymphatic system). Indeed, in small-scale studies the DTI-ALPS index has been shown to correlate with age, cognitive health, and sleep, and is higher in females than males. OBJECTIVE: To determine whether these relationships are stable we replicated previous findings associating the DTI-ALPS index with demographic, sleep-related, and cognitive markers in a large sample of participants from the UK Biobank. METHODS: We calculated the DTI-ALPS index in UK Biobank participants (n = 17723). Using Bayesian and Frequentist analysis approaches, we replicate previously reported relationships between the DTI-ALPS index. RESULTS: We found the predicted associations between the DTI-ALPS index and age, longest uninterrupted sleep window (LUSWT) on a typical night, cognitive performance, and sex. However, these effects were substantially smaller than those found in previous studies. Parameter estimates from this study may be used as priors in subsequent studies using a Bayesian approach. These results suggest that the DTI-ALPS index is consistently, and therefore predictably, associated with demographics, LUWST, and cognition. CONCLUSION: We propose that the metric, calculated for the first time in a large-scale, population-based cohort, is a stable measure, but one for which stronger links to glymphatic system function are needed before it can be used to understand the relationships between glymphatic system function and health outcomes reported in the UK Biobank.

ArcKR expression modifies synaptic plasticity following epileptic activity: Differential effects with in vitro and in vivo seizure-induction protocols.

OBJECTIVES: Pathological forms of neural activity, such as epileptic seizures, modify the expression pattern of multiple proteins, leading to persistent changes in brain function. One such protein is activity-regulated cytoskeleton-associated protein (Arc), which is critically involved in protein-synthesis-dependent synaptic plasticity underlying learning and memory. In the present study, we have investigated how the expression of ArcKR, a form of Arc in which the ubiquitination sites have been mutated, resulting in slowed Arc degradation, modifies group I metabotropic glutamate receptor-mediated long-term depression (G1-mGluR-LTD) following seizures. METHODS: We used a knock-in mice line that express ArcKR and two hyperexcitation models: an in vitro model, where hippocampal slices were exposed to zero Mg2+, 6 mM K+; and an in vivo model, where kainic acid was injected unilaterally into the hippocampus. In both models, field excitatory postsynaptic potentials (fEPSPs) were recorded from the CA1 region of hippocampal slices in response to Schaffer collateral stimulation and G1-mGluR-LTD was induced chemically with the group 1 mGluR agonist DHPG. RESULTS: In the in vitro model, ArcKR expression enhanced the effects of seizure activity and increased the magnitude of G1-mGluR LTD, an effect that could be blocked with the mGluR5 antagonist MTEP. In the in vivo model, fEPSPs were significantly smaller in slices from ArcKR mice and were less contaminated by population spikes. In this model, the amount of G1-mGluR-LTD was significantly less in epileptic slices from ArcKR mice as compared to wildtype (WT) mice. SIGNIFICANCE: We have shown that expression of ArcKR, a form of Arc in which degradation is reduced, significantly modulates the magnitude of G1-mGluR-LTD following epileptic seizures. However, the effect of ArcKR on LTD depends on the epileptic model used, with enhancement of LTD in an in vitro model and a reduction in the kainate mouse model.

Impairments in sleep and brain molecular clearance in people with cognitive deterioration and biological evidence of AD: a report of four cases.

BACKGROUND: Recent evidence suggests that the failure of the glymphatic system - the brain's waste clearance system, which is active during sleep - plays a key role in the pathophysiology of Alzheimer's Disease (AD). Glymphatic function can be investigated using serial MRIs after intrathecal gadobutrol injection. This technique can reveal the health of the glymphatic system, but has not yet been used in participants with cognitive impairment due to AD. CASE REPORT: This report describes the sleep and gadobutrol tracer clearance patterns of four participants diagnosed with mild to moderate cognitive impairment with evidence of AD pathology (pathological levels of Ab and p-tau in cerebrospinal fluid). We performed polysomnography and MRI studies before tracer injection and MRI scans at 1.5-2 h, 5-6 h, and 48 h after injection. Despite participants reporting no sleep problems, polysomnography revealed that all participants had moderate to severe sleep disturbances, including reduced sleep efficiency during the study and obstructive sleep apnea. Severe side-effects related to tracer administration were observed, impeding the completion of the protocol in two participants. Participants who finished the protocol displayed delayed and persistent tracer enrichment in the cortex and white matter, even 48 h after injection. These outcomes have not been observed in previous studies in participants without AD. CONCLUSION: The findings suggest that brains with sleep impairment and AD pathology have poor glymphatic function, and therefore cannot clear the contrast tracer efficiently. This is likely to have caused the severe side effects in our participants, that have not been reported in healthy individuals. Our results may therefore represent the only available data acquired with this technique in participants with AD pathology.

Arc expression regulates long-term potentiation magnitude and metaplasticity in area CA1 of the hippocampus in ArcKR mice.

Expression of the immediate early gene Arc/Arg3.1 (Arc), a key mediator of synaptic plasticity, is enhanced by neural activity and then reduced by proteasome-dependent degradation. We have previously shown that the disruption of Arc degradation, in an Arc knock-in mouse (ArcKR), where the predominant Arc ubiquitination sites were mutated, reduced the threshold to induce, and also enhanced, the strength of Group I metabotropic glutamate receptor-mediated long-term depression (DHPG-LTD). Here, we have investigated if ArcKR expression changes long-term potentiation (LTP) in CA1 area of the hippocampus. As previously reported, there was no change in basal synaptic transmission at Schaffer collateral/commissural-CA1 (SC-CA1) synapses in ArcKR versus wild-type (WT) mice. There was, however, a significant increase in the amplitude of synaptically induced (with low frequency paired-pulse stimulation) LTD in ArcKR mice. Theta burst stimulation (TBS)-evoked LTP at SC-CA1 synapses was significantly reduced in ArcKR versus WT mice (after 2 h). Group 1 mGluR priming of LTP was abolished in ArcKR mice, which could also potentially contribute to a depression of LTP. Although high frequency stimulation (HFS)-induced LTP was not significantly different in ArcKR compared with WT mice (after 1 h), there was a phenotype in environmentally enriched mice, with the ratio of LTP to short-term potentiation (STP) significantly reduced in ArcKR mice. These findings support the hypothesis that Arc ubiquitination supports the induction and expression of LTP, likely via limiting Arc-dependent removal of AMPA receptors at synapses.

The MK2 cascade mediates transient alteration in mGluR-LTD and spatial learning in a murine model of Alzheimer's disease.

A key aim of Alzheimer disease research is to develop efficient therapies to prevent and/or delay the irreversible progression of cognitive impairments. Early deficits in long-term potentiation (LTP) are associated with the accumulation of amyloid beta in rodent models of the disease; however, less is known about how mGluR-mediated long-term depression (mGluR-LTD) is affected. In this study, we have found that mGluR-LTD is enhanced in the APPswe /PS1dE9 mouse at 7 but returns to wild-type levels at 13 months of age. This transient over-activation of mGluR signalling is coupled with impaired LTP and shifts the dynamic range of synapses towards depression. These alterations in synaptic plasticity are associated with an inability to utilize cues in a spatial learning task. The transient dysregulation of plasticity can be prevented by genetic deletion of the MAP kinase-activated protein kinase 2 (MK2), a substrate of p38 MAPK, demonstrating that manipulating the mGluR-p38 MAPK-MK2 cascade at 7 months can prevent the shift in synapse dynamic range. Our work reveals the MK2 cascade as a potential pharmacological target to correct the over-activation of mGluR signalling.

Clathrin adaptor AP-1-mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments.

One of the hallmarks of Alzheimer's disease is the accumulation of toxic amyloid-ß (Aß) peptides in extracellular plaques. The direct precursor of Aß is the carboxyl-terminal fragment ß (or C99) of the amyloid precursor protein (APP). C99 is detected at elevated levels in Alzheimer's disease brains, and its intracellular accumulation has been linked to early neurotoxicity independently of Aß. Despite this, the causes of increased C99 levels are poorly understood. Here, we demonstrate that APP interacts with the clathrin vesicle adaptor AP-1 (adaptor protein 1), and we map the interaction sites on both proteins. Using quantitative kinetic trafficking assays, established cell lines and primary neurons, we also show that this interaction is required for the transport of APP from the trans-Golgi network to endosomes. In addition, disrupting AP-1-mediated transport of APP alters APP processing and degradation, ultimately leading to increased C99 production and Aß release. Our results indicate that AP-1 regulates the subcellular distribution of APP, altering its processing into neurotoxic fragments.

The p38MAPK-MK2 Signaling Axis as a Critical Link Between Inflammation and Synaptic Transmission.

p38 is a mitogen-activated protein kinase (MAPK), that responds primarily to stress stimuli. p38 has a number of targets for phosphorylation, including MAPK-activated protein kinase 2 (MK2). MK2 primarily functions as a master regulator of RNA-binding proteins, indirectly controlling gene expression at the level of translation. The role of MK2 in regulating the synthesis of pro-inflammatory cytokines downstream of inflammation and cellular stress is well-described. A significant amount of evidence, however, now points to a role for the p38MAPK-MK2 signaling axis in mediating synaptic plasticity through control of AMPA receptor trafficking and the morphology of dendritic spines. These processes are mediated through control of cytoskeletal dynamics via the activation of cofilin-1 and possibly control of the expression of Arc/Arg3.1. There is evidence that MK2 is necessary for group I metabotropic glutamate receptors long-term depression (mGluR-LTD). Disruption of this signaling may play an important role in mediating cognitive dysfunction in neurological disorders such as fragile X syndrome and Alzheimer's disease. To date, the role of neuronal MK2 mediating synaptic plasticity in response to inflammatory stimuli has not yet been investigated. In immune cells, it is clear that MK2 is phosphorylated following activation of a broad range of cell surface receptors for cytokines and other inflammatory mediators. We propose that neuronal MK2 may be an important player in the link between inflammatory states and dysregulation of synaptic plasticity underlying cognitive functions. Finally, we discuss the potential of the p38MAPK-MK2 signaling axis as target for therapeutic intervention in a number of neurological disorders.

Web-based searching for abortion information during health emergencies: a case study of Brazil during the 2015/2016 Zika outbreak.

Sexual and reproductive health needs and access are often neglected during health emergencies. The 2015/2016 Zika epidemic is an example of priorities shifting to the detriment of women's health needs. The internet is a key tool for abortion knowledge sharing and seeking in countries where abortion is not legally available and it is also a key resource for tele-health. Yet, we know very little about how people use the internet, and the type of information searched for, to access abortion information and services. The aim of this study is to analyse to what extent and how the internet was used as a resource for abortion information during the Zika outbreak and its aftermath in Brazil in 2015/2016. Using Google Trends and Analytics data, we analyse contextually-specific abortion searches using standardised terms that reflect the overall representation of searches at that time alongside weekly levels of Zika incidence. The results show a heightened use of combined search terms for abortion and Zika, as well as abortion and microcephaly, suggesting a rise in abortion information searching linked to the epidemic. These searches were highly correlated with the level of Zika incidence. This study confirms the use of the internet for information seeking during a public health emergency. It demonstrates the need for appropriate internet resources to improve access to abortion information, especially in countries where abortion is highly restricted and stigmatised.

Analysing the intersection between health emergencies and abortion during Zika in Brazil, El Salvador and Colombia.

The Zika outbreak of 2015-7 is a lens to analyse the positioning of abortion within in global health security. The sequelae of the virus almost exclusively affected newborn children, manifested through Congenital Zika Syndrome (CZS), and a focus on women at risk of, planning or being pregnant. At the global level, debate considered whether Zika would provide impetus for regulatory change for reproductive rights in Latin America, a region with some of the most restrictive abortion regulation in the world. However, regulatory change for abortion did not occur. We analyse why the Zika health emergency did not lead to any changes in abortion regulation through multi-method analysis of the intersection between Zika, health emergencies and abortion in Brazil, Colombia and El Salvador. These case study countries were purposefully selected; each had Zika infected women (albeit with differing incidence) yet represent diverse regulatory environments for abortion. Our comparative research is multi-method: framework analysis of key informant interviews (n = 49); content analysis of women's enquiries to a medical abortion telemedicine provider; and, policy analysis of (inter)national-level Zika response and abortion policies. We consider this within literature on global health security, and the prioritisation of a particular approach to epidemic control. Within this securitized landscape, despite increased public debate about abortion regulatory change, no meaningful change occurred, due to a dominant epidemiological approach to the Zika health emergency in all three countries and prominent conservative forces in government and within anti-abortion rights movements. Simultaneously, we demonstrate that regulation did not deter all women from seeking such service clandestinely.

Aprendizagem significativa de conceitos da biomecânica nas aulas de educação física / Meaningful learning of biomechanical concepts in physical education classes / La aprendizaje significativo del conceptos biomecánicos en clases de educación física

O objetivo do estudo foi analisar as possibilidades de inserção de conceitos de Biomecânica nas aulas de Educação Física partir da aplicação de um projeto educacional fundamentado na teoria da aprendizagem significativa. Foi realizada uma pesquisa qualitativa para avaliar a aplicação do projeto educacional, no qual participaram 17 estudantes do Ensino Fundamental. A análise dos questionários e das observações realizadas permitiram verificar que os participantes ampliaram suas ideias iniciais e atribuíram significado aos conceitos ensinados. Os conteúdos selecionados são passíveis de inserção na Educação Física e as estratégias de ensino foram adequadas para que a aprendizagem significativa ocorresse, contribuindo assim para a construção do currículo escolar

The aim of this study was to analyze the insertion possibilities of Biomechanics concepts in Physical Education classes with the implementation of an educational project based on the theory of meaningful learning. A qualitative research was performed to evaluate the implementation of the educational project, which involved 17 students of elementary school. The questionnaires and observations analysis allowed to verify that participants increased their initial ideas and gave meaning to the taught concepts. The selected content was suitable to inclusion in physical education and the teaching strategies were adequate for meaningful learning, contributing tothe construction of the school curriculum

El objetivo de este estudio fue analizar las posibilidades de inserción de los conceptos del Biomecánica en las clases de Educación Física con la implementación de un proyecto educativo basado en la teoría del aprendizaje significativo. Se realizó una investigación cualitativa para evaluar la ejecución del proyecto educativo, con la participación del 17 estudiantes de la escuela primaria. El análisis de los cuestionarios y las observaciones permitió verificar que los participantes Alteraron sus concepciones iniciales y asignado significado a los conceptos enseñados. El contenido seleccionado era coherente para su inclusión en la educación física y las estrategias de enseñanza eran adecuadas para el aprendizaje significativo, lo que contribuye a la construcción del curriculum

NMDA receptor-dependent signalling pathways regulate arginine vasopressin expression in the paraventricular nucleus of the rat.

The antidiuretic hormone arginine vasopressin (AVP) regulates water homeostasis, blood pressure and a range of stress responses. It is synthesized in the hypothalamus and released from the posterior pituitary into the general circulation upon a range of stimuli. While the mechanisms leading to AVP secretion have been widely investigated, the molecular mechanisms regulating AVP gene expression are mostly unclear. Here we investigated the neurotransmitters and signal transduction pathways that activate AVP gene expression in the paraventricular nucleus (PVN) of the rat using acute brain slices and quantitative real-time PCR. We show that stimulation with l-glutamate robustly induced AVP gene expression in acute hypothalamic brain slices containing the PVN. More specifically, we show that AVP transcription was stimulated by NMDA. Using pharmacological treatments, our data further reveal that the activation of ERK1/2 (PD184352), CaMKII (KN-62) and PI3K (LY294002; 740 Y-P) is involved in the NMDA-induced AVP gene expression in the PVN. Together, this study identifies NMDA-mediated cell signalling pathways that regulate AVP gene expression in the rat PVN.

Zika, abortion and health emergencies: a review of contemporary debates.

BACKGROUND: The Zika outbreak provides pertinent case study for considering the impact of health emergencies on abortion decision-making and/or for positioning abortion in global health security debates. MAIN BODY: This paper provides a baseline of contemporary debates taking place in the intersection of two key health policy areas, and seeks to understand how health emergency preparedness frameworks and the broader global health security infrastructure is prepared to respond to future crises which implicate sexual and reproductive rights. Our paper suggests there are three key themes that emerge from the literature; 1) the lack of consideration of sexual and reproductive health (SRH) services in outbreak response 2) structural inequalities permeate the landscape of health emergencies, epitomised by Zika, and 3) the need for rights based approaches to health. CONCLUSION: Global health security planning and response should specifically include programmatic activity for SRH provision during health emergencies.

The MK2 cascade regulates mGluR-dependent synaptic plasticity and reversal learning.

The ability to either erase or update the memories of a previously learned spatial task is an essential process that is required to modify behaviour in a changing environment. Current evidence suggests that the neural representation of such cognitive flexibility involves the balancing of synaptic potentiation (acquisition of memories) with synaptic depression (modulation and updating previously acquired memories). Here we demonstrate that the p38 MAPK/MAPK-activated protein kinase 2 (MK2) cascade is required to maintain the precise tuning of long-term potentiation and long-term depression at CA1 synapses of the hippocampus which is correlated with efficient reversal learning. Using the MK2 knockout (KO) mouse, we show that mGluR-LTD, but not NMDAR-LTD, is markedly impaired in mice aged between 4 and 5 weeks (juvenile) to 7 months (mature adult). Although the amplitude of LTP was the same as in wildtype mice, priming of LTP by the activation of group I metabotropic receptors was impaired in MK2 KO mice. Consistent with unaltered LTP amplitude and compromised mGluR-LTD, MK2 KO mice had intact spatial learning when performing the Barnes maze task, but showed specific deficits in selecting the most efficient combination of search strategies to perform the task reversal. Findings from this study suggest that the mGluR-p38-MK2 cascade is important for cognitive flexibility by regulating LTD amplitude and the priming of LTP.

The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility.

Neuronal activity regulates the transcription and translation of the immediate-early gene Arc/Arg3.1, a key mediator of synaptic plasticity. Proteasome-dependent degradation of Arc tightly limits its temporal expression, yet the significance of this regulation remains unknown. We disrupted the temporal control of Arc degradation by creating an Arc knockin mouse (ArcKR) where the predominant Arc ubiquitination sites were mutated. ArcKR mice had intact spatial learning but showed specific deficits in selecting an optimal strategy during reversal learning. This cognitive inflexibility was coupled to changes in Arc mRNA and protein expression resulting in a reduced threshold to induce mGluR-LTD and enhanced mGluR-LTD amplitude. These findings show that the abnormal persistence of Arc protein limits the dynamic range of Arc signaling pathways specifically during reversal learning. Our work illuminates how the precise temporal control of activity-dependent molecules, such as Arc, regulates synaptic plasticity and is crucial for cognition.

The mechanistic link between Arc/Arg3.1 expression and AMPA receptor endocytosis.

The activity-regulated cytoskeleton associated protein (Arc/Arg3.1) plays a key role in determining synaptic strength through facilitation of AMPA receptor (AMPAR) endocytosis. Although there is considerable data on the mechanism by which Arc induction controls synaptic plasticity and learning behaviours, several key mechanistic questions remain. Here we review data on the link between Arc expression and the clathrin-mediated endocytic pathway which internalises AMPARs and discuss the significance of Arc binding to the clathrin adaptor protein 2 (AP-2) and to endophilin/dynamin. We consider which AMPAR subunits are selected for Arc-mediated internalisation, implications for synaptic function and consider Arc as a therapeutic target.

MSK1 regulates transcriptional induction of Arc/Arg3.1 in response to neurotrophins.

The immediate early gene activity-regulated cytoskeletal protein (Arc)/Arg3.1 and the neurotrophin brain-derived neurotrophic factor (BDNF) play important roles in synaptic plasticity and learning and memory in the mammalian brain. However, the mechanisms by which BDNF regulates the expression of Arc/Arg3.1 are unclear. In this study, we show that BDNF acts via the ERK1/2 pathway to activate the nuclear kinase mitogen- and stress-activated protein kinase 1 (MSK1). MSK1 then induces Arc/Arg3.1 expression via the phosphorylation of histone H3 at the Arc/Arg3.1 promoter. MSK1 can also phosphorylate the transcription factor cyclic-AMP response element-binding protein (CREB) on Ser133. However, this is not required for BDNF-induced Arc.Arg3.1 transcription as a Ser133Ala knockin mutation had no effect on Arc/Arg3.1 induction. In parallel, ERK1/2 directly activates Arc/Arg3.1 mRNA transcription via at least one serum response element on the promoter, which bind a complex of the Serum Response Factor (SRF) and a Ternary Complex Factor (TCF).

Human biological and nonbiological point-light movements: Creation and validation of the dataset.

Human action perception is so powerful that people can identify movement efficiently in the absence of pictorial information, such as in point-light displays. Interest is growing in this type of stimulus for research in neuroscience. This interest stems from the advantage of separating the component of pure human action kinematics from other pictorial information, such as facial expression and muscle contraction. Although several groups have previously developed datasets of human point-light actions, due to the lack of datasets composed of daily actions with short durations, we developed 20 biological and 40 control (scrambled) point-light movements by using the technique of recording people wearing reflector patches. The videos are about 1 s long. Subsequently, we performed a judgment task in which 100 participants (50 male and 50 female) evaluated each video according to three categories: human action resemblance, performed action, and gender of actor. We present the mean scores of each evaluation for each video, and further propose a selection of the most suitable videos to be used as human point-light action displays and scrambled point-light displays for control. Finally, we discuss our findings on the gender attributions of the point-light displays.

Reform of abortion law in Uruguay: context, process and lessons learned.

In October 2012, a new law was approved in Uruguay that allows abortion on demand during the first 12 weeks of pregnancy, 14 weeks in the case of rape, and without a time limit when the woman's health is at risk or in the case of foetal anomalies. This paper analyses this legal reform. It is based on 27 individual and group interviews with key informants, and on review of primary documents and the literature. The factors explaining the reform include: secular values in society, favourable public opinion, a persistent feminist movement, effective coalition building, particular party politics, and a vocal public health sector. The content of the new law reflects the tensions between a feminist perspective of women's rights and public health arguments that stop short of fully recognizing women's autonomy. The Uruguayan reform shows that, even in Latin America, abortion can be addressed politically without electoral cost to the parties that promote it. On the other hand, the prevailing public health rationale and conditionalities built into the law during the negotiation process resulted in a law that cannot be interpreted as a full recognition of women's rights, but rather as a modified protectionist approach that circumscribes women's autonomy.