Suchergebnisse

This work was supported by grants from the French Agence Nationale de la Recherche (ANR-12-JSH2-0004-01 and ANR AI-REPS–18-CE37-0007-01), the Fyssen foundation, and the Université Paul Sabatier, Toulouse, France (BQR, 2009 and Appel à Projets de Recherche Labellisés, 2013), to L.R., the European Research Council (ERC Consolidator Grant P-Cycles number 614244), the French Agence Nationale de la Recherche (ANR OSCI-DEEP ANR-19-NEUC-0004), and an ANITI (Artificial and Natural Intelligence Toulouse Institute) Research Chair (ANR-19-PI3A-0004) to R.V., the Studienstiftung des Deutschen Volkes (German Academic Scholarship Foundation) to B.Z., the European Union (ERC Grant Agreement n. 339490 "Cortic_al_gorithms" and grant agreements 720270 and 785907 "Human Brain Project SGA1 and SGA2') and the Friends Foundation of the Netherlands Institute for Neuroscience to P.R.R. ; The ability to maintain a sequence of items in memory is a fundamental cognitive function. In the rodent hippocampus, the representation of sequentially organized spatial locations is reflected by the phase of action potentials relative to the theta oscillation (phase precession). We investigated whether the timing of neuronal activity relative to the theta brain oscillation also reflects sequence order in the medial temporal lobe of humans. We used a task in which human participants learned a fixed sequence of pictures and recorded single neuron and local field potential activity with implanted electrodes. We report that spikes for three consecutive items in the sequence (the preferred stimulus for each cell, as well as the stimuli immediately preceding and following it) were phase-locked at distinct phases of the theta oscillation. Consistent with phase precession, spikes were fired at progressively earlier phases as the sequence advanced. These findings generalize previous findings in the rodent hippocampus to the human temporal lobe and suggest that encoding stimulus information at distinct oscillatory phases may play a role in maintaining sequential order in memory. ; Publisher PDF ; Peer reviewed

Support from the Wellcome Trust, Medical Research Council, European Union Seventh Framework Programme (FP7/2007-2013) under grant agreements no. 604102 (HBP), 241995 (GENCODYS), 242498 (EUROSPIN), 242167 (SYNSYS). ; The molecular features of synapses in the hippocampus underpin current models of learning and cognition. Although synapse ultra-structural diversity has been described in the canonical hippocampal circuitry, our knowledge of sub-synaptic organisation of synaptic molecules remains largely unknown. To address this, mice were engineered to express Post Synaptic Density 95 protein (PSD95) fused to either eGFP or mEos2 and imaged with two orthogonal super-resolution methods: gated stimulated emission depletion (g-STED) microscopy and photoactivated localisation microscopy (PALM). Large-scale analysis of ~100,000 synapses in 7 hippocampal sub-regions revealed they comprised discrete PSD95 nanoclusters that were spatially organised into single and multi-nanocluster PSDs. Synapses in different sub-regions, cell-types and locations along the dendritic tree of CA1 pyramidal neurons, showed diversity characterised by the number of nanoclusters per synapse. Multi-nanocluster synapses were frequently found in the CA3 and dentate gyrus sub-regions, corresponding to large thorny excrescence synapses. Although the structure of individual nanoclusters remained relatively conserved across all sub-regions, PSD95 packing into nanoclusters also varied between sub-regions determined from nanocluster fluorescence intensity. These data identify PSD95 nanoclusters as a basic structural unit, or building block, of excitatory synapses and their number characterizes synapse size and structural diversity. ; Publisher PDF ; Peer reviewed

This work was supported by Goethe University Frankfurt; Deutsche Forschungsgemeinschaft (DFG), grant EXC115; European Union FP7 grant "EUTrigTreat and German Research Council (DFG) Grant MI 685/2-1. ; Genetically encoded calcium indicators (GECIs) are powerful tools for systems neuroscience. Here we describe red, single-wavelength GECIs, "RCaMPs," engineered from circular permutation of the thermostable red fluorescent protein mRuby. High-resolution crystal structures of mRuby, the red sensor RCaMP, and the recently published red GECI R-GECO1 give insight into the chromophore environments of the Ca(2+)-bound state of the sensors and the engineered protein domain interfaces of the different indicators. We characterized the biophysical properties and performance of RCaMP sensors in vitro and in vivo in Caenorhabditis elegans, Drosophila larvae, and larval zebrafish. Further, we demonstrate 2-color calcium imaging both within the same cell (registering mitochondrial and somatic [Ca(2+)]) and between two populations of cells: neurons and astrocytes. Finally, we perform integrated optogenetics experiments, wherein neural activation via channelrhodopsin-2 (ChR2) or a red-shifted variant, and activity imaging via RCaMP or GCaMP, are conducted simultaneously, with the ChR2/RCaMP pair providing independently addressable spectral channels. Using this paradigm, we measure calcium responses of naturalistic and ChR2-evoked muscle contractions in vivo in crawling C. elegans. We systematically compare the RCaMP sensors to R-GECO1, in terms of action potential-evoked fluorescence increases in neurons, photobleaching, and photoswitching. R-GECO1 displays higher Ca(2+) affinity and larger dynamic range than RCaMP, but exhibits significant photoactivation with blue and green light, suggesting that integrated channelrhodopsin-based optogenetics using R-GECO1 may be subject to artifact. Finally, we create and test blue, cyan, and yellow variants engineered from GCaMP by rational design. This engineered set of chromatic variants facilitates new experiments in functional imaging and optogenetics. ; Publisher PDF ; Peer reviewed

IR and LZ were funded by the European Union, Seventh Framework Programme (FP7/2007–2013), by the European Union and Greek National Funds through the operational program "Education and Lifelong Learning" of the National Strategic Reference Framework, funding program: ARISTEIA II, and by Fondation Santé. ; Cholinergic neuromodulation has been described throughout the brain and has been implicated in various functions including attention, food intake and response to stress. Cholinergic modulation is also thought to be important for regulating motor systems, as revealed by studies of large cholinergic synapses on spinal motor neurons, called C boutons, which seem to control motor neuron excitability in a task-dependent manner. C boutons on spinal motor neurons stem from spinal interneurons that express the transcription factor Pitx2. C boutons have also been identified on the motor neurons of specific cranial nuclei. However, the source and roles of cranial C boutons are less clear. Previous studies suggest that they originate from Pitx2+ and Pitx2− neurons, in contrast to spinal cord C boutons that originate solely from Pitx2 neurons. Here, we address this controversy using mouse genetics, and demonstrate that brainstem C boutons are Pitx2+ derived. We also identify new Pitx2 populations and map the cholinergic Pitx2 neurons of the mouse brain. Taken together, our data present important new information about the anatomical organization of cholinergic systems which impact motor systems of the brainstem. These findings will enable further analyses of the specific roles of cholinergic modulation in motor control. ; Publisher PDF ; Peer reviewed

Authors would like to acknowledge the following funders: Motor Neurone Disease (MND) Association UK (Miles/Apr18/863-791), the Euan MacDonald Centre and Chief Scientist Office, The European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (695568 SYNNOVATE), Simons Foundation Autism Research Initiative (529085), and the Wellcome Trust (Technology Development grant 202932). ; Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder. Separate lines of evidence suggest that synapses and astrocytes play a role in the pathological mechanisms underlying ALS. Given that astrocytes make specialised contacts with some synapses, called tripartite synapses, we hypothesise that tripartite synapses could act as the fulcrum of disease in ALS. To test this hypothesis, we have performed an extensive microscopy-based investigation of synapses and tripartite synapses in the spinal cord of ALS model mice and post-mortem human tissue from ALS cases. We reveal widescale synaptic changes at the early symptomatic stages of the SOD1G93a mouse model. Super-resolution microscopy reveals that large complex postsynaptic structures are lost in ALS mice. Most surprisingly, tripartite synapses are selectively lost, while non-tripartite synapses remain in equal number to healthy controls. Finally, we also observe a similar selective loss of tripartite synapses in human post-mortem ALS spinal cords. From these data we conclude that tripartite synaptopathy is a key hallmark of ALS. ; Publisher PDF ; Peer reviewed

PC, AM, NHK and SGNG were supported by the Wellcome Trust Genes to Cognition programme and European Union programs (Project GENCODYS no. 241995, Project EUROSPIN no. 242498 and Project SYNSYS no. 242167) and SJE was supported by the CARMEN e-science project (www.carmen.org.uk) funded by the EPSRC (EP/E002331/1). ; The function of the nervous system depends on the integrity of synapses and the patterning of electrical activity in brain circuits. The rapid advances in genome sequencing reveal a large number of mutations disrupting synaptic proteins, which potentially result in diseases known as synaptopathies. However, it is also evident that every normal individual carries hundreds of potentially damaging mutations. Although genetic studies in several organisms show that mutations can be masked during development by a process known as canalization, it is unknown if this occurs in the development of the electrical activity in the brain. Using longitudinal recordings of primary cultured neurons on multi-electrode arrays from mice carrying knockout mutations we report evidence of canalization in development of spontaneous activity patterns. Phenotypes in the activity patterns in young cultures from mice lacking the Gria1 subunit of the AMPA receptor were ameliorated as cultures matured. Similarly, the effects of chronic pharmacological NMDA receptor blockade diminished as cultures matured. Moreover, disturbances in activity patterns by simultaneous disruption of Gria1 and NMDA receptors were also canalized by three weeks in culture. Additional mutations and genetic variations also appeared to be canalized to varying degrees. These findings indicate that neuronal network canalization is a form of nervous system plasticity that provides resilience to developmental disruption. ; Publisher PDF ; Peer reviewed

Funding: UK Medical Research Council, grant number: MC_PC_17217), and the Scottish Government via the Scottish Learning Disabilities Observatory. ; Objectives To investigate mortality in adults with intellectual disabilities: rates, causes, place, demographic and clinical predictors. Design Cohort study with record linkage to death data. Setting General community. Participants 961/1023 (94%) adults (16–83 years; mean=44.1 years; 54.6% male) with intellectual disabilities, clinically examined in 2001–2004; subsequently record-linked to their National Health Service number, allowing linkage to death certificate data, 2018. Outcome measures Standardised mortality ratios (SMRs), underlying and all contributing causes of death, avoidable deaths, place, and demographic and clinical predictors of death. Results 294/961 (30.6%) had died; 64/179 (35.8%) with Down syndrome, 230/783 (29.4%) without Down syndrome. SMR overall=2.24 (1.98, 2.49); Down syndrome adults=5.28 (3.98, 6.57), adults without Down syndrome=1.93 (1.68, 2.18); male=1.69 (1.42, 1.95), female=3.48 (2.90, 4.06). SMRs decreased as age increased. More severe intellectual disabilities increased SMR, but ability was not retained in the multivariable model. SMRs were higher for most International Statistical Classification of Diseases and Related Health Problems, 10th Revision chapters. For adults without Down syndrome, aspiration/reflux/choking and respiratory infection were the the most common underlying causes of mortality; for Down syndrome adults 'Down syndrome', and dementia were most common. Amenable deaths (29.8%) were double that in the general population (14%); 60.3% died in hospital. Mortality risk related to percutaneous endoscopic gastrostomy/tube fed, Down syndrome, diabetes, lower respiratory tract infection at cohort-entry, smoking, epilepsy, hearing impairment, increasing number of prescribed drugs, increasing age. Bowel incontinence reduced mortality risk. Conclusions Adults with intellectual disabilities with and without Down syndrome have different SMRs and causes of death which should be separately reported. Both die younger, from different causes than other people. Some mortality risks are similar to other people, with earlier mortality reflecting more multimorbidity; amenable deaths are also common. This should inform actions to reduce early mortality, for example, training to avoid aspiration/choking, pain identification to address problems before they are advanced, and reasonable adjustments to improve healthcare quality. ; Publisher PDF ; Peer reviewed

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

The possible role of aluminium in the pathogenesis of Alzheimer's disease (AD) has been hotly debated over the past few decades. Although the so‐called 'aluminium hypothesis' was popular in the 1970s and 1980s, it has gradually fallen out of favour in the past few years possibly following a number of inconclusive and contradictory human environmental/clinical studies. Nevertheless, there have from time to time been reminders in the media of environmental accidents; these have prevented the topic from disappearing completely from public memory. One such accident occurred on July 6th 1988 in Camelford, Cornwall when 20 tonnes of aluminium sulphate was mistakenly discharged into the mains water supply. Twenty thousand people were exposed to concentrations of aluminium which were 500–3000 times the acceptable limit under European Union legislation. Over the subsequent years there have been UK government inquiries into the supposed environmental impact and occasional clinical follow‐up studies documenting declining cerebral function in those exposed to the contaminated water but very little neuropathological data has been published. To our knowledge, the case described here is only the second neuropathological description.

This study was funded by the European Union Seventh Framework Program, under grant agreement number 305697 (the Observational Prolonged Trial In Myotonic dystrophy type 1 to Improve Quality of Life Standards, a Target Identification Collaboration [OPTIMISTIC] project). We thank Marie Kierkegaard (Karolinska University Hospital, Karolinska Institutet, Department of Physical Therapy, Sweden) and Don MacKenzie (Marigold Foundation, Calgary, AB, Canada) as members of the external advisory board for their continued monitoring and recommendations for improvement of our study. The Health Services Research Unit (University of Aberdeen, Aberdeen, UK) receives core funding from the Chief Scientist Office of the Scottish Government Health Directorates. We acknowledge the contribution to this study made by the Tayside Clinical Trials Unit, University of Dundee (Dundee, UK). ; Peer reviewed ; Postprint

Background: This consensus statement was developed because there are concerns about the appropriate use of opioids for acute pain management, with opposing views in the literature. Consensus statement on policies for system-level interventions may help inform organisations such as management structures, government agencies and funding bodies. Methods: We conducted a multi-stakeholder survey using a modified Delphi methodology focusing on policies, at the system level, rather than at the prescriber or patient level. We aimed to provide consensus statements for current developments and priorities for future developments. Results: Twenty-five experts from a variety of fields with experience in acute pain management were invited to join a review panel, of whom 23 completed a modified Delphi survey of policies designed to improve the safety and quality of opioids prescribing for acute pain in the secondary care setting. Strong agreement, defined as consistent among> 75% of panellists, was observed for ten statements. Conclusions: Using a modified Delphi study, we found agreement among a multidisciplinary panel, including patient representation, on prioritisation of policies for system-level interventions, to improve governance, pain management, patient/consumers care, safety and engagement. ; Publisher PDF ; Peer reviewed

We acknowledge support from the ERC Starting Grant ABLASE (640012), the Scottish Funding Council (via SUPA), and the European Union Marie Curie Career Integration Grant (PCIG12-GA-2012-334407). MS acknowledges funding by the European Commission through a Marie Sklodowska-Curie Individual Fellowship (659213). MK and PL acknowledge funding from the EPSRC DTG (EP/M506631/1 and EP/L505079/1). ; Reliable methods to individually track large numbers of cells in real time are urgently needed to advance our understanding of important biological processes like cancer metastasis, neuronal network development and wound healing. It has recently been suggested to introduce microscopic whispering gallery mode lasers into the cytoplasm of cells and to use their characteristic, size dependent emission spectrum as optical barcode but so far there is no evidence that this approach is generally applicable. Here, we describe a method that drastically improves intracellular delivery of resonators for several cell types, including mitotic and non-phagocytic cells. In addition, we characterize the influence of resonator size on the spectral characteristics of the emitted laser light and identify an optimum size range that facilitates tagging and tracking of thousands of cells simultaneously. Finally, we observe that the microresonators remain internalized by cells during cell division, which enables tagging several generations of cells. ; Publisher PDF ; Peer reviewed

Background: Understanding patient experiences of detention under mental health legislation is crucial to efforts to reform policy and practice. Aims: To synthesise qualitative evidence on patients' experiences of assessment and detention under mental health legislation. Method: Five bibliographic databases were searched, supplemented by reference list screening and citation tracking. Studies were included if they reported on patient experiences of assessment or detention under mental health legislation; reported on patients aged 18 years or older; collected data using qualitative methods; and were reported in peer-reviewed journals. Findings were analysed and synthesised using thematic synthesis. Results: The review included 56 papers. Themes were generally consistent across studies and related to information and involvement in care, the environment and relationships with staff, as well as the impact of detention on feelings of self-worth and emotional state. The emotional impact of detention and views of its appropriateness varied, but a frequent theme was fear and distress during detention, including in relation to the use of force and restraint. Where staff were perceived as striving to form caring and collaborative relationships with patients despite the coercive nature of treatment, and when clear information was delivered, the negative impact of involuntary care seemed to be reduced. Conclusions: Findings suggest that involuntary in-patient care is often frightening and distressing, but certain factors were identified that can help reduce negative experiences. Coproduction models may be fruitful in developing new ways of working on in-patient wards that provide more voice to patients and staff, and physical and social environments that are more conducive to recovery.

A systematic review and meta-ethnographic synthesis exploring the experiences of people with schizophrenia and healthcare professionals (HCPs) towards physical activity was undertaken. Major electronic databases were searched from inception until January 2014. Studies were eligible if they considered the experiences and perceptions of people with schizophrenia or the perceptions of HCPs towards physical activity. All included studies were synthesised within a meta-ethnographic approach, including completing a methodological quality assessment. The search strategy identified 106 articles, 11 of which were included in the final analysis. Eight articles considered patients׳ experiences and perceptions, and three articles considered the experiences and perceptions of HCPs. A total of 108 patients and 65 HCPs were included. Three main themes were identified: (1) the influence of identity, culture and the environment on physical activity engagement, (2) access and barriers to participation in physical activity, and (3) the benefits of engaging in physical activity. Aspects within the built, social and political environment as well as aspects of social cognition and perceptual biases influence participation in physical activity for individuals with schizophrenia. Specific recommendations for HCPs are given to help promote physical activity in this population group.

Studies in human and non-human primates indicate that basic socio-cognitive operations are inherently linked to the power of gaze in capturing reflexively the attention of an observer. Although monkey studies indicate that the automatic tendency to follow the gaze of a conspecific is modulated by the leader-follower social status, evidence for such effects in humans is meager. Here, we used a gaze following paradigm where the directional gaze of right- or left-wing Italian political characters could influence the oculomotor behavior of ingroup or outgroup voters. We show that the gaze of Berlusconi, the right-wing leader currently dominating the Italian political landscape, potentiates and inhibits gaze following behavior in ingroup and outgroup voters, respectively. Importantly, the higher the perceived similarity in personality traits between voters and Berlusconi, the stronger the gaze interference effect. Thus, higher-order social variables such as political leadership and affiliation prepotently affect reflexive shifts of attention.