The NEWMEDS rodent touchscreen test battery for cognition relevant to schizophrenia.

RATIONALE: The NEWMEDS initiative (Novel Methods leading to New Medications in Depression and Schizophrenia, http://www.newmeds-europe.com ) is a large industrial-academic collaborative project aimed at developing new methods for drug discovery for schizophrenia. As part of this project, Work package 2 (WP02) has developed and validated a comprehensive battery of novel touchscreen tasks for rats and mice for assessing cognitive domains relevant to schizophrenia. OBJECTIVES: This article provides a review of the touchscreen battery of tasks for rats and mice for assessing cognitive domains relevant to schizophrenia and highlights validation data presented in several primary articles in this issue and elsewhere. METHODS: The battery consists of the five-choice serial reaction time task and a novel rodent continuous performance task for measuring attention, a three-stimulus visual reversal and the serial visual reversal task for measuring cognitive flexibility, novel non-matching to sample-based tasks for measuring spatial working memory and paired-associates learning for measuring long-term memory. RESULTS: The rodent (i.e. both rats and mice) touchscreen operant chamber and battery has high translational value across species due to its emphasis on construct as well as face validity. In addition, it offers cognitive profiling of models of diseases with cognitive symptoms (not limited to schizophrenia) through a battery approach, whereby multiple cognitive constructs can be measured using the same apparatus, enabling comparisons of performance across tasks. CONCLUSION: This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.This work was supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). The authors thank Charlotte Oomen for valuable comments on the manuscript.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00213-015-4007-

Circulating microparticles: square the circle

Background: The present review summarizes current knowledge about microparticles (MPs) and provides a systematic overview of last 20 years of research on circulating MPs, with particular focus on their clinical relevance. Results: MPs are a heterogeneous population of cell-derived vesicles, with sizes ranging between 50 and 1000 nm. MPs are capable of transferring peptides, proteins, lipid components, microRNA, mRNA, and DNA from one cell to another without direct cell-to-cell contact. Growing evidence suggests that MPs present in peripheral blood and body fluids contribute to the development and progression of cancer, and are of pathophysiological relevance for autoimmune, inflammatory, infectious, cardiovascular, hematological, and other diseases. MPs have large diagnostic potential as biomarkers; however, due to current technological limitations in purification of MPs and an absence of standardized methods of MP detection, challenges remain in validating the potential of MPs as a non-invasive and early diagnostic platform. Conclusions: Improvements in the effective deciphering of MP molecular signatures will be critical not only for diagnostics, but also for the evaluation of treatment regimens and predicting disease outcomes

Antenatal glucocorticoid treatment induces adaptations in adult midbrain dopamine neurons, which underpin sexually dimorphic behavioral resilience

We demonstrated previously that antenatal glucocorticoid treatment (AGT, gestational days 16-19) altered the size and organization of the adult rat midbrain dopaminergic (DA) populations. Here we investigated the consequences of these AGT-induced cytoarchitectural disturbances on indices of DA function in adult rats. We show that in adulthood, enrichment of striatal DA fiber density paralleled AGT-induced increases in the numbers of midbrain DA neurons, which retained normal basal electrophysiological properties. This was co-incident with changes in (i) striatal D2-type receptor levels (increased, both sexes); (ii) D1-type receptor levels (males decreased; females increased); (iii) DA transporter levels (males increased; females decreased) in striatal regions; and (iv) amphetamine-induced mesolimbic DA release (males increased; females decreased). However, despite these profound, sexually dimorphic changes in markers of DA neurotransmission, in-utero glucocorticoid overexposure had a modest or no effect on a range of conditioned and unconditioned appetitive behaviors known to depend on mesolimbic DA activity. These findings provide empirical evidence for enduring AGT-induced adaptive mechanisms within the midbrain DA circuitry, which preserve some, but not all, functions, thereby casting further light on the vulnerability of these systems to environmental perturbations. Furthermore, they demonstrate these effects are achieved by different, often opponent, adaptive mechanisms in males and females, with translational implications for sex biases commonly found in midbrain DA-associated disorders

Trends in parameterization, economics and host behaviour in influenza pandemic modelling: a review and reporting protocol.

BACKGROUND: The volume of influenza pandemic modelling studies has increased dramatically in the last decade. Many models incorporate now sophisticated parameterization and validation techniques, economic analyses and the behaviour of individuals. METHODS: We reviewed trends in these aspects in models for influenza pandemic preparedness that aimed to generate policy insights for epidemic management and were published from 2000 to September 2011, i.e. before and after the 2009 pandemic. RESULTS: We find that many influenza pandemics models rely on parameters from previous modelling studies, models are rarely validated using observed data and are seldom applied to low-income countries. Mechanisms for international data sharing would be necessary to facilitate a wider adoption of model validation. The variety of modelling decisions makes it difficult to compare and evaluate models systematically. CONCLUSIONS: We propose a model Characteristics, Construction, Parameterization and Validation aspects protocol (CCPV protocol) to contribute to the systematisation of the reporting of models with an emphasis on the incorporation of economic aspects and host behaviour. Model reporting, as already exists in many other fields of modelling, would increase confidence in model results, and transparency in their assessment and comparison

Discrete and Effortful Imagined Movements Do Not Specifically Activate the Autonomic Nervous System

International audienceBACKGROUND: The autonomic nervous system (ANS) is activated in parallel with the motor system during cyclical and effortful imagined actions. However, it is not clear whether the ANS is activated during motor imagery of discrete movements and whether this activation is specific to the movement being imagined. Here, we explored these topics by studying the baroreflex control of the cardiovascular system. METHODOLOGY/PRINCIPAL FINDINGS: Arterial pressure and heart rate were recorded in ten subjects who executed or imagined trunk or leg movements against gravity. Trunk and leg movements result in different physiological reactions (orthostatic hypotension phenomenon) when they are executed. Interestingly, ANS activation significantly, but similarly, increased during imagined trunk and leg movements. Furthermore, we did not observe any physiological modulation during a control mental-arithmetic task or during motor imagery of effortless movements (horizontal wrist displacements). CONCLUSIONS/SIGNIFICANCE: We concluded that ANS activation during motor imagery is general and not specific and physiologically prepares the organism for the upcoming effortful action

Anomalous visual experience is linked to perceptual uncertainty and visual imagery vividness

An imbalance between top-down and bottom-up processing on perception (specifically, over-reliance on top-down processing) can lead to anomalous perception, such as illusions. One factor that may be involved in anomalous perception is visual mental imagery, which is the experience of “seeing” with the mind’s eye. There are vast individual differences in self-reported imagery vividness, and more vivid imagery is linked to a more sensory-like experience. We, therefore, hypothesized that susceptibility to anomalous perception is linked to individual imagery vividness. To investigate this, we adopted a paradigm that is known to elicit the perception of faces in pure visual noise (pareidolia). In four experiments, we explored how imagery vividness contributes to this experience under different response instructions and environments. We found strong evidence that people with more vivid imagery were more likely to see faces in the noise, although removing suggestive instructions weakened this relationship. Analyses from the first two experiments led us to explore confidence as another factor in pareidolia proneness. We, therefore, modulated environment noise and added a confidence rating in a novel design. We found strong evidence that pareidolia proneness is correlated with uncertainty about real percepts. Decreasing perceptual ambiguity abolished the relationship between pareidolia proneness and both imagery vividness and confidence. The results cannot be explained by incidental face-like patterns in the noise, individual variations in response bias, perceptual sensitivity, subjective perceptual thresholds, viewing distance, testing environments, motivation, gender, or prosopagnosia. This indicates a critical role of mental imagery vividness and perceptual uncertainty in anomalous perceptual experience. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00426-020-01364-7) contains supplementary material, which is available to authorized users

Patients with schizophrenia show deficits of working memory maintenance components in circuit-specific tasks

Working memory (WM) deficits are a neuropsychological core finding in patients with schizophrenia and also supposed to be a potential endophenotype of schizophrenia. Yet, there is a large heterogeneity between different WM tasks which is partly due to the lack of process specificity of the tasks applied. Therefore, we investigated WM functioning in patients with schizophrenia using process- and circuit-specific tasks. Thirty-one patients with schizophrenia and 47 controls were tested with respect to different aspects of verbal and visuospatial working memory using modified Sternberg paradigms in a computer-based behavioural experiment. Total group analysis revealed significant impairment of patients with schizophrenia in each of the tested WM components. Furthermore, we were able to identify subgroups of patients showing different patterns of selective deficits. Patients with schizophrenia exhibit specific and, in part, selective WM deficits with indirect but conclusive evidence of dysfunctions of the underlying neural networks. These deficits are present in tasks requiring only maintenance of verbal or visuospatial information. In contrast to a seemingly global working memory deficit, individual analysis revealed differential patterns of working memory impairments in patients with schizophrenia

The Sensory Consequences of Speaking: Parametric Neural Cancellation during Speech in Auditory Cortex

When we speak, we provide ourselves with auditory speech input. Efficient monitoring of speech is often hypothesized to depend on matching the predicted sensory consequences from internal motor commands (forward model) with actual sensory feedback. In this paper we tested the forward model hypothesis using functional Magnetic Resonance Imaging. We administered an overt picture naming task in which we parametrically reduced the quality of verbal feedback by noise masking. Presentation of the same auditory input in the absence of overt speech served as listening control condition. Our results suggest that a match between predicted and actual sensory feedback results in inhibition of cancellation of auditory activity because speaking with normal unmasked feedback reduced activity in the auditory cortex compared to listening control conditions. Moreover, during self-generated speech, activation in auditory cortex increased as the feedback quality of the self-generated speech decreased. We conclude that during speaking early auditory cortex is involved in matching external signals with an internally generated model or prediction of sensory consequences, the locus of which may reside in auditory or higher order brain areas. Matching at early auditory cortex may provide a very sensitive monitoring mechanism that highlights speech production errors at very early levels of processing and may efficiently determine the self-agency of speech input

A small TAT-TrkB peptide prevents BDNF receptor cleavage and restores synaptic physiology in Alzheimer\u27s disease

Copyright \ua9 2024 The Author(s). Published by Elsevier Inc. All rights reserved. In Alzheimer\u27s disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, and synaptic transmission and plasticity. Using cerebrospinal fluid and postmortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as a function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aβ in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential to be a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD