Sylics Synaptologics BV

Amsterdam, Netherlands

Sylics Synaptologics BV

Amsterdam, Netherlands
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Remmelink E.,Sylics Synaptologics B.V. | Remmelink E.,VU University Amsterdam | Chau U.,Sylics Synaptologics B.V. | Smit A.B.,VU University Amsterdam | And 2 more authors.
Scientific Reports | Year: 2017

Many psychiatric disorders emerge during adolescence. The study of executive functions in animal models of these disorders critically requires short-duration tasks measuring these functions before the animal ages. Here, a novel 5-choice serial reaction time task (5-CSRTT) protocol is presented, to measure attention and impulsivity within one week, without scheduled food deprivation and with little animal handling. Mice were allowed 24-h/day task access from their home-cage, during which they could self-pace task progression and earn unlimited food rewards depending on task performance. Manipulation of task parameters in this self-paced 5-CSRTT protocol (SP-5C) affected attentional performance and impulsivity to a similar extent as previously observed in the 5-CSRTT. Task activity followed intrinsic circadian rhythm, distinctive for the SP-5C protocol, with task performance stable over the day. The sensitivity of the SP-5C protocol to detect strain differences between C57BL/6J, DBA/2 J, BXD16 and BXD62 mice was demonstrated as well as its suitability for testing adolescent mice. Acute administration of the muscarinic acetylcholine receptor antagonist scopolamine impaired attentional performance, providing initial pharmacological validation of the task. The SP-5C substantially shortens the assessment of impulsivity and attention, increases test efficiency and enables the assessment of adolescent mouse models of psychiatric disorders. © 2017 The Author(s).


Loos M.,VU University Amsterdam | Loos M.,Sylics Synaptologics BV | Mueller T.,Max Delbrück Center for Molecular Medicine | Gouwenberg Y.,VU University Amsterdam | And 7 more authors.
Biological Psychiatry | Year: 2014

Background A deficit in impulse control is a prominent, heritable symptom in several psychiatric disorders, such as addiction, attention-deficit/hyperactivity disorder, and schizophrenia. Here, we aimed to identify genes regulating impulsivity, specifically of impulsive action, in mice. Methods Using the widely used 5-choice serial reaction time task, we measured impulsive action in 1) a panel of 41 BXD recombinant inbred strains of mice (n = 13.7 ±.8 per strain; n = 654 total) to detect underlying genetic loci; 2) congenic mice (n = 23) to replicate the identified locus; 3) mice overexpressing the Nrg3 candidate gene in the medial prefrontal cortex (n = 21); and 4) a Nrg3 loss-of-function mutant (n = 59) to functionally implicate the Nrg3 candidate gene in impulsivity. Results Genetic mapping of impulsive action in the BXD panel identified a locus on chromosome 14 (34.5-41.4 Mb), syntenic with the human 10q22-q23 schizophrenia-susceptibility locus. Congenic mice carrying the impulsivity locus (Impu1) confirmed its influence on impulsive action. Increased impulsivity was associated with increased Nrg3 gene expression in the medial prefrontal cortex (mPFC). Viral overexpression of Nrg3 in the mPFC increased impulsivity, whereas a constitutive Nrg3 loss-of-function mutation decreased it. Conclusions The causal relation between Nrg3 expression in the mPFC and level of impulsive action shown here provides a mechanism by which polymorphism in NRG3 in humans contributes to a specific cognitive deficit seen in several psychiatric diseases, such as addiction, attention-deficit/hyperactivity disorder, and schizophrenia. © 2014 Society of Biological Psychiatry.


Seigers R.,Netherlands Cancer Institute | Loos M.,Sylics Synaptologics BV | Van Tellingen O.,Netherlands Cancer Institute | Boogerd W.,Netherlands Cancer Institute | And 2 more authors.
Behavioural Brain Research | Year: 2016

Cognitive deficit is a frequently reported side-effect of adjuvant chemotherapy. A large number of animal studies has been performed to examine the neurobiological mechanisms underlying this phenomenon, however, definite conclusions from these studies are restricted due to differences in experimental set-up.We systematically investigated the effects of 6 cytotoxic agents on various neurobiological parameters. C57Bl/6J mice were treated with cyclophosphamide, docetaxel, doxorubicin, 5-fluorouracil, methotrexate, or topotecan. The animals were sacrificed 3 or 15 weeks after treatment and the effect on neurogenesis, blood vessel density, and neuroinflammation was analyzed using immunohistochemistry. None of the cytostatic agents tested affected neurogenesis (cell survival or cell proliferation). Blood vessel density was increased in the hippocampus and prefrontal cortex 3 weeks after treatment with docetaxel and doxorubicin compared with control animals. A decrease in the number of microglial cells was observed in the prefrontal cortex after treatment with cyclophosphamide, docetaxel, 5-FU, and topotecan compared with control mice. The observed decrease in microglia cells is indicative of inflammation that occurred after treatment.Overall, the magnitude of the effects was relatively modest. Therefore, we conducted a similar study with topotecan in Abcg2;. Abcb1a/b knock out and wildtype FVB mice. Animals were sacrificed 3 weeks after treatment and no notable effect was seen in hippocampal cell differentiation (DCX), microglia activation, or blood vessel density. Perhaps the FVB strain is more resistant to the neurotoxic effects of topotecan which makes this not the correct model to study the mechanism of chemotherapy-induced cognitive impairment. © 2015 Elsevier B.V.


Kramvis I.,VU University Amsterdam | Kramvis I.,Sylics Synaptologics BV | Mansvelder H.D.,VU University Amsterdam | Loos M.,Sylics Synaptologics BV | And 2 more authors.
Frontiers in Behavioral Neuroscience | Year: 2013

Attentional deficits and executive function impairments are common to many neurodevelopmental disorders of intellectual disability and autism, including Fragile X syndrome (FXS). In the knockout mouse model for FXS, significant changes in synaptic plasticity and connectivity are found in the prefrontal cortex (PFC)-a prominent region for attentional processing and executive control. Given these alterations in PFC synaptic function, we tested whether adult Fragile X knockout mice exhibited corresponding impairments in inhibitory control, perseveration, and sustained attention. Furthermore, we investigated individual performance during attentional rule acquisition. Using the 5-choice serial reaction time task, our results show no impairments in inhibitory control and sustained attention. Fragile X knockout mice exhibited enhanced levels of correct and incorrect responding, as well as perseveration of responding during initial phases of rule acquisition, that normalized with training. For both knockout and wild type mice, pharmacological attenuation of metabotropic glutamate receptor 5 signaling did not affect response accuracy but reduced impulsive responses and increased omission errors. Upon rule reversal, Fragile X knockout mice made more correct and incorrect responses, similar to the initial phases of rule acquisition. Analogous to heightened activity upon novel rule acquisition, Fragile X knockout mice were transiently hyperactive in both a novel open field (OF) arena and novel home cage. Hyperactivity ceased with familiarization to the environment. Our findings demonstrate normal inhibitory control and sustained attention but heightened perseveration, responding, and hyperactivity during novel rule acquisition and during exposure to novel environments in Fragile X knockout mice. We therefore provide evidence for subtle but significant differences in the processing of novel stimuli in the mouse model for the FXS. © 2013 Kramvis, Mansvelder, Loos and Meredith.


Remmelink E.,Sylics Synaptologics B.V. | Remmelink E.,VU University Amsterdam | Loos M.,Sylics Synaptologics B.V. | Koopmans B.,Sylics Synaptologics B.V. | And 3 more authors.
Behavioural Brain Research | Year: 2015

Individuals are able to change their behavior based on its consequences, a process involving instrumental learning. Studying instrumental learning in mice can provide new insights in this elementary aspect of cognition. Conventional appetitive operant learning tasks that facilitate the study of this form of learning in mice, as well as more complex operant paradigms, require labor-intensive handling and food deprivation to motivate the animals. Here, we describe a 1-night operant learning protocol that exploits the advantages of automated home-cage testing and circumvents the interfering effects of food restriction. The task builds on behavior that is part of the spontaneous exploratory repertoire during the days before the task. We compared the behavior of C57BL/6J, BALB/cJ and DBA/2J mice and found various differences in behavior during this task, but no differences in learning curves. BALB/cJ mice showed the largest instrumental learning response, providing a superior dynamic range and statistical power to study instrumental learning by using this protocol. Insights gained with this home-cage-based learning protocol without food restriction will be valuable for the development of other, more complex, cognitive tasks in automated home-cages. © 2015 Elsevier B.V.


Koopmans B.,Sylics Synaptologics BV | Smit A.B.,VU University Amsterdam | Verhage M.,VU University Amsterdam | Loos M.,Sylics Synaptologics BV
BMC Bioinformatics | Year: 2017

Background: Systematic, standardized and in-depth phenotyping and data analyses of rodent behaviour empowers gene-function studies, drug testing and therapy design. However, no data repositories are currently available for standardized quality control, data analysis and mining at the resolution of individual mice. Description: Here, we present AHCODA-DB, a public data repository with standardized quality control and exclusion criteria aimed to enhance robustness of data, enabled with web-based mining tools for the analysis of individually and group-wise collected mouse phenotypic data. AHCODA-DB allows monitoring in vivo effects of compounds collected from conventional behavioural tests and from automated home-cage experiments assessing spontaneous behaviour, anxiety and cognition without human interference. AHCODA-DB includes such data from mutant mice (transgenics, knock-out, knock-in), (recombinant) inbred strains, and compound effects in wildtype mice and disease models. AHCODA-DB provides real time statistical analyses with single mouse resolution and versatile suite of data presentation tools. On March 9th, 2017 AHCODA-DB contained 650 k data points on 2419 parameters from 1563 mice. Conclusion: AHCODA-DB provides users with tools to systematically explore mouse behavioural data, both with positive and negative outcome, published and unpublished, across time and experiments with single mouse resolution. The standardized (automated) experimental settings and the large current dataset (1563 mice) in AHCODA-DB provide a unique framework for the interpretation of behavioural data and drug effects. The use of common ontologies allows data export to other databases such as the Mouse Phenome Database. Unbiased presentation of positive and negative data obtained under the highly standardized screening conditions increase cost efficiency of publicly funded mouse screening projects and help to reach consensus conclusions on drug responses and mouse behavioural phenotypes. The website is publicly accessible through https://public.sylics.comand can be viewed in every recent version of all commonly used browsers. © 2017 The Author(s).


Remmelink E.,Sylics Synaptologics B.V. | Remmelink E.,VU University Amsterdam | Smit A.B.,VU University Amsterdam | Verhage M.,VU University Amsterdam | Loos M.,Sylics Synaptologics B.V.
Learning and Memory | Year: 2016

Many neurological and psychiatric disorders are characterized by deficits in cognitive flexibility. Modeling cognitive flexibility in mice enables the investigation of mechanisms underlying these deficits. The majority of currently available behavioral tests targeting this cognitive domain are reversal learning tasks that require scheduled food restriction, extended training periods and labor-intensive, and stress-inducing animal handling. Here, we describe a novel 4-day (4-d) continuously running task measuring discrimination- and reversal learning in an automated home cage (CognitionWall DL/RL task) that largely eliminates these limitations. In this task, mice can earn unlimited number of food rewards by passing through the correct hole of the three-holed CognitionWall. To assess the validity and sensitivity of this novel task, the performance of C57BL/6J mice, amyloid precursor protein/presenilin1 transgenic (APP/PS1) mice, a-calmodulin kinase-II (aCaMKII) T305D knock-in mice, and mice with an orbitofrontal cortex lesion were examined. We found that C57BL/6J mice reach stable performance levels within the 4 d of the task, while experiencing only slight reductions in weight and no major effects on circadian rhythm. The task detected learning deficits in APP/PS1 transgenic and aCaMKII T305D mutant mice. Additionally, we established that the orbitofrontal cortex underlies reversal learning performance in our task. Because of its short duration and the absence of food deprivation and concurrent weight loss, this novel automated home-cage task substantially improves comprehensive preclinical assessment of cognitive functions in mouse models of psychiatric and neurological disorders and also enables analysis during specific developmental stages. © 2016 Remmelink et al.


Maroteaux G.,VU University Amsterdam | Loos M.,VU University Amsterdam | Loos M.,Sylics Synaptologics BV | van der Sluis S.,VU University Amsterdam | And 9 more authors.
Genes, Brain and Behavior | Year: 2012

Marked cognitive responses in 3, but not other inbred mouse lines in automated avoidance learning screening. Recognizing and avoiding aversive situations are central aspects of mammalian cognition. These abilities are essential for health and survival and are expected to have a prominent genetic basis. We modeled these abilities in eight common mouse inbred strains covering ∼75% of the species' natural variation and in gene-trap mice (>2000 mice), using an unsupervised, automated assay with an instrumented home cage (PhenoTyper) containing a shelter with two entrances. Mice visited this shelter for 20-1200 times/24 h and 71% of all mice developed a significant and often strong preference for one entrance. Subsequently, a mild aversive stimulus (shelter illumination) was automatically delivered when mice used their preferred entrance. Different genotypes developed different coping strategies. Firstly, the number of entries via the preferred entrance decreased in DBA/2J, C57BL/6J and 129S1/SvImJ, indicating that these genotypes associated one specific entrance with the aversive stimulus. Secondly, mice started sleeping outside (C57BL/6J, DBA/2J), indicating they associated the shelter, in general, with the aversive stimulus. Some mice showed no evidence for an association between the entrance and the aversive light, but did show markedly shorter shelter residence times in response to illumination, indicating they did perceive illumination as aversive. Finally, using this assay, we screened 43 different mutants, which yielded a novel gene, specc1/cytospinB. This mutant showed profound and specific delay in avoidance learning. Together, these data suggest that different genotypes express distinct learning and/or memory of associations between shelter entrance and aversive stimuli, and that specc1/cytospinB is involved in this aspect of cognition. © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.


Seigers R.,Netherlands Cancer Institute | Loos M.,Sylics Synaptologics BV | Van Tellingen O.,Netherlands Cancer Institute | Boogerd W.,Netherlands Cancer Institute | And 2 more authors.
Psychopharmacology | Year: 2015

Rationale and objectives: Adjuvant chemotherapy is associated with changes in cognition in a subgroup of cancer patients. Chemotherapy is generally given as a combination of cytotoxic agents, which makes it hard to define the agent responsible for these observed changes. Literature on animal experiments has been difficult to interpret due to variance in experimental setup. Methods: We examined the effects of cytotoxic agents administered separately on various cognitive measures in a standardized animal model. Male C57Bl/6 mice received cyclophosphamide, docetaxel, doxorubicin, 5-fluorouracil, methotrexate, or topotecan. These agents represent different compound classes based on their working mechanism and are frequently prescribed in the clinic. A control group received saline. Behavioral testing started 2 or 15 weeks after treatment and included testing general measures of behavior and cognitive task performance: spontaneous behavior in an automated home cage, open field, novel location recognition (NLR), novel object recognition (NOR), Barnes maze, contextual fear conditioning, and a simple choice reaction time task (SCRTT). Results: Cyclophosphamide, docetaxel, and doxorubicin administration affected spontaneous activity in the automated home cage. All cytotoxic agents affected memory (NLR and/or NOR). Spatial memory measured in the Barnes maze was affected after administration with doxorubicin, 5-fluorouracil, and topotecan. Decreased inhibition in the SCRTT was observed after treatment with cyclophosphamide, docetaxel, and topotecan. Conclusions: Our data show that, in mice, a single treatment with a cytotoxic agent causes cognitive impairment. Not all cytotoxic agents affected the same cognitive domains, which might be explained by differences in working mechanisms of the various agents. © Springer-Verlag 2014.


Geerts C.J.,VU University Amsterdam | Plomp J.J.,Leiden University | Koopmans B.,Sylics Synaptologics BV | Loos M.,Sylics Synaptologics BV | And 4 more authors.
Brain Structure and Function | Year: 2015

Tomosyn-1 (STXBP5) is a soluble NSF attachment protein receptor complex-binding protein that inhibits vesicle fusion, but the role of tomosyn-2 (STXBP5L) in the mammalian nervous system is still unclear. Here we generated tomosyn-2 null (Tom2KO/KO) mice, which showed impaired motor performance. This was accompanied by synaptic changes at the neuromuscular junction, including enhanced spontaneous acetylcholine release frequency and faster depression of muscle motor endplate potentials during repetitive stimulation. The postsynaptic geometric arrangement and function of acetylcholine receptors were normal. We conclude that tomosyn-2 supports motor performance by regulation of transmitter release willingness to sustain synaptic strength during high-frequency transmission, which makes this gene a candidate for involvement in neuromuscular disorders. © 2014, Springer-Verlag Berlin Heidelberg.

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