Publications by authors named "York Winter"

53 Publications

Learning Set Formation and Reversal Learning in Mice During High-Throughput Home-Cage-Based Olfactory Discrimination.

Front Behav Neurosci 2021 9;15:684936. Epub 2021 Jun 9.

Institute for Biology, Humboldt Universität, Berlin, Germany.

Rodent behavioral tasks are crucial to understanding the nature and underlying biology of cognition and cognitive deficits observed in psychiatric and neurological pathologies. Olfaction, as the primary sensory modality in rodents, is widely used to investigate cognition in rodents. In recent years, automation of olfactory tasks has made it possible to conduct olfactory experiments in a time- and labor-efficient manner while also minimizing experimenter-induced variability. In this study, we bring automation to the next level in two ways: First, by incorporating a radio frequency identification-based sorter that automatically isolates individuals for the experimental session. Thus, we can not only test animals during defined experimental sessions throughout the day but also prevent cagemate interference during task performance. Second, by implementing software that advances individuals to the next test stage as soon as performance criteria are reached. Thus, we can prevent overtraining, a known confounder especially in cognitive flexibility tasks. With this system in hand, we trained mice on a series of four odor pair discrimination tasks as well as their respective reversals. Due to performance-based advancement, mice normally advanced to the next stage in less than a day. Over the series of subsequent odor pair discriminations, the number of errors to criterion decreased significantly, thus indicating the formation of a learning set. As expected, errors to criterion were higher during reversals. Our results confirm that the system allows investigating higher-order cognitive functions such as learning set formation (which is understudied in mice) and reversal learning (which is a measure of cognitive flexibility and impaired in many clinical populations). Therefore, our system will facilitate investigations into the nature of cognition and cognitive deficits in pathological conditions by providing a high-throughput and labor-efficient experimental approach without the risks of overtraining or cagemate interference.
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http://dx.doi.org/10.3389/fnbeh.2021.684936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219855PMC
June 2021

Two-dimensional reward evaluation in mice.

Anim Cogn 2021 Sep 15;24(5):981-998. Epub 2021 Mar 15.

Institute of Biology, Humboldt University, Philippstr. 13, 10099, Berlin, Germany.

When choosing among multi-attribute options, integrating the full information may be computationally costly and time-consuming. So-called non-compensatory decision rules only rely on partial information, for example when a difference on a single attribute overrides all others. Such rules may be ecologically more advantageous, despite being economically suboptimal. Here, we present a study that investigates to what extent animals rely on integrative rules (using the full information) versus non-compensatory rules when choosing where to forage. Groups of mice were trained to obtain water from dispensers varying along two reward dimensions: volume and probability. The mice's choices over the course of the experiment suggested an initial reliance on integrative rules, later displaced by a sequential rule, in which volume was evaluated before probability. Our results also demonstrate that while the evaluation of probability differences may depend on the reward volumes, the evaluation of volume differences is seemingly unaffected by the reward probabilities.
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http://dx.doi.org/10.1007/s10071-021-01482-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360905PMC
September 2021

A CRISPR-Cas9-engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions.

Proc Natl Acad Sci U S A 2021 01;118(2)

Institute for Genomic Statistics and Bioinformatics, University of Bonn, 53127 Bonn, Germany;

Pathogenic germline mutations in lead to glycosylphosphatidylinositol biosynthesis deficiency (GPIBD). Individuals with pathogenic biallelic mutations in genes of the glycosylphosphatidylinositol (GPI)-anchor pathway exhibit cognitive impairments, motor delay, and often epilepsy. Thus far, the pathophysiology underlying the disease remains unclear, and suitable rodent models that mirror all symptoms observed in human patients have not been available. Therefore, we used CRISPR-Cas9 to introduce the most prevalent hypomorphic missense mutation in European patients, :c.1022C > A (p.A341E), at a site that is conserved in mice. Mirroring the human pathology, mutant mice exhibited deficits in motor coordination, cognitive impairments, and alterations in sociability and sleep patterns, as well as increased seizure susceptibility. Furthermore, immunohistochemistry revealed reduced synaptophysin immunoreactivity in mice, and electrophysiology recordings showed decreased hippocampal synaptic transmission that could underlie impaired memory formation. In single-cell RNA sequencing, -hippocampal cells exhibited changes in gene expression, most prominently in a subtype of microglia and subicular neurons. A significant reduction in transcript levels in several cell clusters suggested a link to the signaling pathway of GPI-anchored ephrins. We also observed elevated levels of transcripts, which might affect histamine metabolism with consequences for circadian rhythm. This mouse model will not only open the doors to further investigation into the pathophysiology of GPIBD, but will also deepen our understanding of the role of GPI-anchor-related pathways in brain development.
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http://dx.doi.org/10.1073/pnas.2014481118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812744PMC
January 2021

Abnormal brain structure and behavior in MyD88-deficient mice.

Brain Behav Immun 2021 01 28;91:181-193. Epub 2020 Sep 28.

Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address:

While the original protein Toll in Drosophila melanogaster regulates both host defense and morphogenesis, the role of its ortholog Toll-like receptors (TLRs), the interleukin 1 receptor (IL-1R) family, and the associated signaling pathways in mammalian brain development and structure is poorly understood. Because the adaptor protein myeloid differentiation primary response protein 88 (MyD88) is essential for downstream signaling of most TLRs and IL-1R, we systematically investigated the effect of MyD88 deficiency on murine brain structure during development and on behavior. In neonatal Myd88 mice, neocortical thickness was reduced, while density of cortical neurons was increased. In contrast, microglia, astrocyte, oligodendrocyte, and proliferating cell numbers were unchanged in these mice compared to wild-type mice. In adult Myd88 mice, neocortical thickness was unaltered, but neuronal density in neocortex and hippocampus was increased. Neuron arborization was less pronounced in adult Myd88 mice compared to wild-type animals. In addition, numbers of microglia and proliferating cells were increased in the neocortex and subventricular zone, respectively, with unaltered astrocyte and oligodendrocyte numbers, and myelinization was enhanced in the adult Myd88 neocortex. These morphologic changes in the brain of adult Myd88 mice were accompanied by specific behavioral traits, such as decreased locomotor activity, increased anxiety-like behavior, but normal day/light activity, satisfactory learning, short- and long-term spatial memory, potential cognitive inflexibility, and increased hanging and locomotor behavior within their home cage. Taken together, MyD88 deficiency results in morphologic and cellular changes in the mouse brain, as well as in altered natural and specific behaviors. Our data indicate a pathophysiological significance of MyD88 for mammalian CNS development, structure, and function.
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http://dx.doi.org/10.1016/j.bbi.2020.09.024DOI Listing
January 2021

Early-life environmental enrichment generates persistent individualized behavior in mice.

Sci Adv 2020 Aug 26;6(35):eabb1478. Epub 2020 Aug 26.

German Center for Neurodegenerative Diseases (DZNE) Dresden, Tatzberg 41, 01307 Dresden, Germany.

Individuals differ in their response to environmental stimuli, but the stability of individualized behaviors and their associated changes in brain plasticity are poorly understood. We developed a novel model of enriched environment to longitudinally monitor 40 inbred mice exploring 35 connected cages over periods of 3 to 6 months. We show that behavioral individuality that emerged during the first 3 months of environmental enrichment persisted when mice were withdrawn from the enriched environment for 3 additional months. Behavioral trajectories were associated with stable interindividual differences in adult hippocampal neurogenesis and persistent epigenetic effects on neuronal plasticity genes in the hippocampus. Using genome-wide DNA methylation sequencing, we show that one-third of the DNA methylation changes were maintained after withdrawal from the enriched environment. Our results suggest that, even under conditions that control genetic background and shared environment, early-life experiences result in lasting individualized changes in behavior, brain plasticity, and epigenetics.
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http://dx.doi.org/10.1126/sciadv.abb1478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449688PMC
August 2020

Loss of Piccolo Function in Rats Induces Cerebellar Network Dysfunction and Pontocerebellar Hypoplasia Type 3-like Phenotypes.

J Neurosci 2020 04 2;40(14):2943-2959. Epub 2020 Mar 2.

German Center for Neurodegenerative Diseases, Charité Medical University, 10117 Berlin, Germany,

Piccolo, a presynaptic active zone protein, is best known for its role in the regulated assembly and function of vertebrate synapses. Genetic studies suggest a further link to several psychiatric disorders as well as Pontocerebellar Hypoplasia type 3 (PCH3). We have characterized recently generated Piccolo KO ( ) rats. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT ( ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Analysis of the cerebellum and brainstem revealed a reduced granule cell layer and a reduction in size of pontine nuclei. Moreover, the maturation of mossy fiber afferents from pontine neurons and the expression of the α6 GABA receptor subunit at the mossy fiber-granule cell synapse are perturbed, as well as the innervation of Purkinje cells by cerebellar climbing fibers. Ultrastructural and functional studies revealed a reduced size of mossy fiber boutons, with fewer synaptic vesicles and altered synaptic transmission. These data imply that Piccolo is required for the normal development, maturation, and function of neuronal networks formed between the brainstem and cerebellum. Consistently, behavioral studies demonstrated that adult rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Together, these data suggest that loss of Piccolo function in patients with PCH3 could be involved in many of the observed anatomical and behavioral symptoms, and that the further analysis of these animals could provide fundamental mechanistic insights into this devastating disorder. Pontocerebellar Hypoplasia Type 3 is a devastating developmental disorder associated with severe developmental delay, progressive microcephaly with brachycephaly, optic atrophy, seizures, and hypertonia with hyperreflexia. Recent genetic studies have identified non-sense mutations in the coding region of the PCLO gene, suggesting a functional link between this disorder and the presynaptic active zone. Our analysis of Piccolo KO rats supports this hypothesis, formally demonstrating that anatomical and behavioral phenotypes seen in patients with Pontocerebellar Hypoplasia Type 3 are also exhibited by these Piccolo deficient animals.
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http://dx.doi.org/10.1523/JNEUROSCI.2316-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117892PMC
April 2020

Automated radial 8-arm maze: A voluntary and stress-free behavior test to assess spatial learning and memory in mice.

Behav Brain Res 2020 03 10;381:112352. Epub 2019 Nov 10.

Department of Neurology and Department of Experimental Neurology, Neurocure Cluster of Excellence, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; German Federal Institute for Risk Assessment, German Center for the Protection of Laboratory Animals (Bf3R), Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany. Electronic address:

The radial arm maze (RAM) is a common behavioral test to assess spatial working and reference memory in mice. However, conventional RAM experiments require a substantial degree of manual handling and animals are usually subjected to prolonged periods of food or water deprivation to achieve sufficient learning motivation resulting in stress-induced confounding effects and unwanted intra- and inter-subject variation. In a proof-of-concept approach to improve reliability and repeatability of results by refining the conventional maze methodology, we developed a voluntary, fully automated 8-arm RAM and tested its feasibility and usability using both spatial working and combined working/reference memory paradigms in ten female C57BL/6J mice. We demonstrate that experimental procedures of up to 7 days duration could be conducted without any manual animal handling and that mice up to 18 months of age showed robust spatial learning performance without any food or water restrictions being applied. Therefore, a voluntary, automated 8-arm RAM can serve to minimize variation in experimental results by reducing an animal's distress, suffering, and pain, which, in turn, contributes to the comprehensive application of 3R principles.
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http://dx.doi.org/10.1016/j.bbr.2019.112352DOI Listing
March 2020

Wheel running behaviour in group-housed female mice indicates disturbed wellbeing due to DSS colitis.

Lab Anim 2020 Feb 1;54(1):63-72. Epub 2019 Nov 1.

Institute for Laboratory Animal Science, Hannover Medical School, Germany.

Voluntary wheel running (VWR) behaviour is a sensitive indicator of disturbed wellbeing and used for the assessment of individual experimental severity levels in laboratory mice. However, monitoring individual VWR performance usually requires single housing, which itself might have a negative effect on wellbeing. In consideration of the 3Rs principle, VWR behaviour was evaluated under group-housing conditions. To test the applicability for severity assessment, this readout was evaluated in a dextran sodium sulphate (DSS) induced colitis model. For continuous monitoring, an automated system with integrated radio-frequency identification technology was used, enabling detection of individual VWR. After a 14-day adaptation period mice demonstrated a stable running performance. Analysis during DSS treatment in combination with repeated facial vein phlebotomy and faecal sampling procedure resulted in significantly reduced VWR behaviour during the course of colitis and increased VWR during disease recovery. Mice submitted to phlebotomy and faecal sampling but no DSS treatment showed less reduced VWR but a longer-lasting recovery. Application of a cluster model discriminating individual severity levels based on VWR and body weight data revealed the highest severity level in most of the DSS-treated mice on day 7, but a considerable number of control mice also showed elevated severity levels due to sampling procedures alone. In summary, VWR sensitively indicated the course of DSS colitis severity and the impact of sample collection. Therefore, monitoring of VWR is a suitable method for the detection of disturbed wellbeing due to DSS colitis and sampling procedure in group-housed female laboratory mice.
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http://dx.doi.org/10.1177/0023677219879455DOI Listing
February 2020

Inter-individual and inter-strain differences in cognitive and social abilities of Dark Agouti and Wistar Han rats.

Behav Brain Res 2020 01 29;377:112188. Epub 2019 Aug 29.

Humboldt University, Berlin, Germany; Charité University Medicine, Berlin, Germany. Electronic address:

Healthy animals displaying extreme behaviours that resemble human psychiatric symptoms are relevant models to study the natural psychobiological processes of maladapted behaviours. Using a Rat Gambling Task, healthy individuals spontaneously making poor decisions (PDMs) were found to co-express a combination of other cognitive and reward-based characteristics similar to symptoms observed in human patients with impulse-control disorders. The main goals of this study were to 1) confirm the existence of PDMs and their unique behavioural phenotypes in Dark Agouti (DA) and Wistar Han (WH) rats, 2) to extend the behavioural profile of the PDMs to probability-based decision-making and social behaviours and 3) to extract key discriminative traits between DA and WH strains, relevant for biomedical research. We have compared cognitive abilities, natural behaviours and physiological responses in DA and WH rats at the strain and at the individual level. Here we found that the naturally occurring PDM's profile was consistent between both rat lines. Then, although the PDM individuals did not take more risks in probability discounting task, they seemed to be of higher social ranks. Finally and despite their similarities in performance, WH and DA lines differed in degree of reward sensitivity, impulsivity, locomotor activity and open space-occupation. The reproducibility and conservation of the complex phenotypes of PDMs and GDMs (good decision makers) in these two genetically different strains support their translational potential. Both strains, present large phenotypic variation in behaviours pertinent for the study of the underlying mechanisms of poor decision making and associated disorders.
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http://dx.doi.org/10.1016/j.bbr.2019.112188DOI Listing
January 2020

Human gestational N-methyl-d-aspartate receptor autoantibodies impair neonatal murine brain function.

Ann Neurol 2019 11 18;86(5):656-670. Epub 2019 Sep 18.

Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Objective: Maternal autoantibodies are a risk factor for impaired brain development in offspring. Antibodies (ABs) against the NR1 (GluN1) subunit of the N-methyl-d-aspartate receptor (NMDAR) are among the most frequently diagnosed anti-neuronal surface ABs, yet little is known about effects on fetal development during pregnancy.

Methods: We established a murine model of in utero exposure to human recombinant NR1 and isotype-matched nonreactive control ABs. Pregnant C57BL/6J mice were intraperitoneally injected on embryonic days 13 and 17 each with 240μg of human monoclonal ABs. Offspring were investigated for acute and chronic effects on NMDAR function, brain development, and behavior.

Results: Transferred NR1 ABs enriched in the fetus and bound to synaptic structures in the fetal brain. Density of NMDAR was considerably reduced (up to -49.2%) and electrophysiological properties were altered, reflected by decreased amplitudes of spontaneous excitatory postsynaptic currents in young neonates (-34.4%). NR1 AB-treated animals displayed increased early postnatal mortality (+27.2%), impaired neurodevelopmental reflexes, altered blood pH, and reduced bodyweight. During adolescence and adulthood, animals showed hyperactivity (+27.8% median activity over 14 days), lower anxiety, and impaired sensorimotor gating. NR1 ABs caused long-lasting neuropathological effects also in aged mice (10 months), such as reduced volumes of cerebellum, midbrain, and brainstem.

Interpretation: The data collectively support a model in which asymptomatic mothers can harbor low-level pathogenic human NR1 ABs that are diaplacentally transferred, causing neurotoxic effects on neonatal development. Thus, AB-mediated network changes may represent a potentially treatable neurodevelopmental congenital brain disorder contributing to lifelong neuropsychiatric morbidity in affected children. ANN NEUROL 2019;86:656-670.
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http://dx.doi.org/10.1002/ana.25552DOI Listing
November 2019

Nesfatin-1 Injected Intracerebroventricularly Increases Anxiety, Depression-Like Behavior, and Anhedonia in Normal Weight Rats.

Nutrients 2018 Dec 3;10(12). Epub 2018 Dec 3.

Charité Center for Internal Medicine and Dermatology, Department for Psychosomatic Medicine, Charité-Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany.

Nesfatin-1 is a well-established anorexigenic peptide. Recent studies indicated an association between nesfatin-1 and anxiety/depression-like behavior. However, it is unclear whether this effect is retained in obesity. The aim was to investigate the effect of nesfatin-1-the active core of nesfatin-1-on anxiety and depression-like behavior in normal weight (NW) and diet-induced (DIO) obese rats. Male rats were intracerebroventricularly (ICV) cannulated and received nesfatin-1 (0.1, 0.3, or 0.9 nmol/rat) or vehicle 30 min before testing. Nesfatin-1 at a dose of 0.3 nmol reduced sucrose consumption in the sucrose preference test in NW rats compared to vehicle (⁻33%, < 0.05), indicating depression-like/anhedonic behavior. This dose was used for all following experiments. Nesfatin-1 also reduced cookie intake during the novelty-induced hypophagia test (-62%, < 0.05). Moreover, nesfatin-1 reduced the number of entries into the center zone in the open field test (-45%, < 0.01) and the visits of open arms in the elevated zero maze test (-39%, < 0.01) in NW rats indicating anxiety. Interestingly, DIO rats showed no behavioral alterations after the injection of nesfatin-1 ( > 0.05). These results indicate an implication of nesfatin-1 in the mediation of anxiety and depression-like behavior/anhedonia under normal weight conditions, while in DIO rats, a desensitization might occur.
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http://dx.doi.org/10.3390/nu10121889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315806PMC
December 2018

Behavioral and psychological symptoms of dementia (BPSD) and impaired cognition reflect unsuccessful neuronal compensation in the pre-plaque stage and serve as early markers for Alzheimer's disease in the APP23 mouse model.

Behav Brain Res 2018 07 21;347:300-313. Epub 2018 Mar 21.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neurology, Charitéplatz 1, 10117, Berlin, Germany. Electronic address:

Recent research on Alzheimer's disease (AD) focuses on processes prior to amyloid-beta plaque deposition accounting for the progress of the disease. However, early mechanisms of AD are still poorly understood and predictors of the disease in the pre-plaque stage essential for initiating an early therapy are lacking. Behavioral and psychological symptoms of dementia (BPSD) and potentially impaired cognition may serve as predictors and early clinical diagnostic markers for AD. To investigate potential BPSD and cognitive impairments in association with neuronal cell development as such markers for AD in the pre-plaque stage, female APP23 mice at eight, 19 and 31 weeks of age and corresponding control animals were tested for BPSD (elevated zero maze; sucrose preference test), motor coordination (rotarod), spatial memory and reversal learning (Morris water maze) and hippocampal neurogenesis as a neuronal correlate for hippocampus-dependent behavior. To evaluate a potential therapeutic effect of physical, cognitive and social stimulation, animals were exposed to environmental enrichment (EE) for one, twelve or 24 weeks from five weeks of age. In APP23, decreased anxiety accompanied increased agitation from eight weeks of age. Impairment of spatial memory and learning flexibility prior to plaque deposition involved an insufficient use of spatial search strategies associated with an unsuccessful compensatory increase of neurogenesis. EE had an overall beneficial effect on behavior and neurogenesis and thus constitutes a therapeutic tool to slow disease progression. BPSD, cognition and associated impaired neurogenesis complement clinical diagnostic markers for pre-plaque AD and contribute to an early detection essential to halt disease progression.
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http://dx.doi.org/10.1016/j.bbr.2018.03.030DOI Listing
July 2018

The Absence of Sensory Axon Bifurcation Affects Nociception and Termination Fields of Afferents in the Spinal Cord.

Front Mol Neurosci 2018 8;11:19. Epub 2018 Feb 8.

Developmental Neurobiology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.

A cGMP signaling cascade composed of C-type natriuretic peptide, the guanylyl cyclase receptor Npr2 and cGMP-dependent protein kinase I (cGKI) controls the bifurcation of sensory axons upon entering the spinal cord during embryonic development. However, the impact of axon bifurcation on sensory processing in adulthood remains poorly understood. To investigate the functional consequences of impaired axon bifurcation during adult stages we generated conditional mouse mutants of Npr2 and cGKI ( and ) that lack sensory axon bifurcation in the absence of additional phenotypes observed in the global knockout mice. Cholera toxin labeling in digits of the hind paw demonstrated an altered shape of sensory neuron termination fields in the spinal cord of conditional Npr2 mouse mutants. Behavioral testing of both sexes indicated that noxious heat sensation and nociception induced by chemical irritants are impaired in the mutants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are not affected. Recordings from C-fiber nociceptors in the hind limb skin showed that Npr2 function was not required to maintain normal heat sensitivity of peripheral nociceptors. Thus, the altered behavioral responses to noxious heat found in mice is not due to an impaired C-fiber function. Overall, these data point to a critical role of axonal bifurcation for the processing of pain induced by heat or chemical stimuli.
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http://dx.doi.org/10.3389/fnmol.2018.00019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809486PMC
February 2018

Longitudinal intravital imaging of the femoral bone marrow reveals plasticity within marrow vasculature.

Nat Commun 2017 12 18;8(1):2153. Epub 2017 Dec 18.

Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Charitéplatz 1, 10117, Berlin, Germany.

The bone marrow is a central organ of the immune system, which hosts complex interactions of bone and immune compartments critical for hematopoiesis, immunological memory, and bone regeneration. Although these processes take place over months, most existing imaging techniques allow us to follow snapshots of only a few hours, at subcellular resolution. Here, we develop a microendoscopic multi-photon imaging approach called LIMB (longitudinal intravital imaging of the bone marrow) to analyze cellular dynamics within the deep marrow. The approach consists of a biocompatible plate surgically fixated to the mouse femur containing a gradient refractive index lens. This microendoscope allows highly resolved imaging, repeatedly at the same regions within marrow tissue, over months. LIMB reveals extensive vascular plasticity during bone healing and steady-state homeostasis. To our knowledge, this vascular plasticity is unique among mammalian tissues, and we expect this insight will decisively change our understanding of essential phenomena occurring within the bone marrow.
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http://dx.doi.org/10.1038/s41467-017-01538-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735140PMC
December 2017

Principles of Economic Rationality in Mice.

Sci Rep 2017 12 12;7(1):17441. Epub 2017 Dec 12.

Department of Biology, Humboldt University, Philippstr. 13, Berlin, 10099, Germany.

Humans and non-human animals frequently violate principles of economic rationality, such as transitivity, independence of irrelevant alternatives, and regularity. The conditions that lead to these violations are not completely understood. Here we report a study on mice tested in automated home-cage setups using rewards of drinking water. Rewards differed in one of two dimensions, volume or probability. Our results suggest that mouse choice conforms to the principles of economic rationality for options that differ along a single reward dimension. A psychometric analysis of mouse choices further revealed that mice responded more strongly to differences in probability than to differences in volume, despite equivalence in return rates. This study also demonstrates the synergistic effect between the principles of economic rationality and psychophysics in making quantitative predictions about choices of healthy laboratory mice. This opens up new possibilities for the analyses of multi-dimensional choice and the use of mice with cognitive impairments that may violate economic rationality.
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http://dx.doi.org/10.1038/s41598-017-17747-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727109PMC
December 2017

Response to Comment on "Cognition-mediated evolution of low-quality floral nectars".

Science 2017 12;358(6368)

Humboldt University, Berlin, Germany.

Pyke and Waser claim that our virtual pollination ecology model makes unrealistic assumptions and fails to predict observed nectar concentrations of bat flowers and negative correlations between pollinator body size and sugar concentration. In their comment, crucial model features are misrepresented, misunderstood, or ignored. Sensitivity to the supply/demand ratio explains both the equilibrium concentrations and the selection for lower concentrations by larger pollinators.
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http://dx.doi.org/10.1126/science.aao2622DOI Listing
December 2017

Melatonin restores hippocampal neural precursor cell proliferation and prevents cognitive deficits induced by jet lag simulation in adult mice.

J Pineal Res 2017 May 12;62(4). Epub 2017 Mar 12.

Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Frequent flyers and shift workers undergo circadian dysrhythmia with adverse impact on body and mind. The circadian rhythm disorder "jet lag" disturbs hippocampal neurogenesis and spatial cognition, which represent morphological and functional adult brain plasticity. This raises the question if pro-neurogenic stimuli might prevent those consequences. However, suitable measures to mitigate jet lag-induced adverse effects on brain plasticity have been neglected so far. Here, we used adult C57Bl6 mice to investigate the pro-neurogenic stimuli melatonin (8 mg/kg i.p.) as well as environmental enrichment as potential measures. We applied photoperiod alterations to simulate "jet lag" by shortening the dark period every third day by 6 hours for 3 weeks. We found that "jet lag" simulation reduced hippocampal neural precursor cell proliferation by 24% and impaired spatial memory performance in the water maze indicated by a prolonged swim path to the target (~23%). While melatonin prevented both the cellular (~1%) as well as the cognitive deficits (~5%), environmental enrichment only preserved precursor cell proliferation (~12%). Our results indicate that lifestyle interventions are insufficient to completely compensate jet lag-induced consequences. Instead, melatonin is required to prevent cognitive impairment caused by the same environmental factors to which frequent flyers and shift workers are typically exposed to.
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http://dx.doi.org/10.1111/jpi.12397DOI Listing
May 2017

Spatial cognition in a virtual reality home-cage extension for freely moving rodents.

J Neurophysiol 2017 04 11;117(4):1736-1748. Epub 2017 Jan 11.

Cognitive Neurobiology, Humboldt-Universität zu Berlin, Berlin, Germany;

Virtual reality (VR) environments are a powerful tool to investigate brain mechanisms involved in the behavior of animals. With this technique, animals are usually head fixed or secured in a harness, and training for cognitively more complex VR paradigms is time consuming. A VR apparatus allowing free animal movement and the constant operator-independent training of tasks would enable many new applications. Key prospective usages include brain imaging of animal behavior when carrying a miniaturized mobile device such as a fluorescence microscope or an optetrode. Here, we introduce the Servoball, a spherical VR treadmill based on the closed-loop tracking of a freely moving animal and feedback counterrotation of the ball. Furthermore, we present the complete integration of this experimental system with the animals' group home cage, from which single individuals can voluntarily enter through a tunnel with radio-frequency identification (RFID)-automated access control and commence experiments. This automated animal sorter functions as a mechanical replacement of the experimenter. We automatically trained rats using visual or acoustic cues to solve spatial cognitive tasks and recorded spatially modulated entorhinal cells. When electrophysiological extracellular recordings from awake behaving rats were performed, head fixation can dramatically alter results, so that any complex behavior that requires head movement is impossible to achieve. We circumvented this problem with the use of the Servoball in open-field scenarios, as it allows the combination of open-field behavior with the recording of nerve cells, along with all the flexibility that a virtual environment brings. This integrated home cage with a VR arena experimental system permits highly efficient experimentation for complex cognitive experiments. Virtual reality (VR) environments are a powerful tool for the investigation of brain mechanisms. We introduce the Servoball, a VR treadmill for freely moving rodents. The Servoball is integrated with the animals' group home cage. Single individuals voluntarily enter using automated access control. Training is highly time-efficient, even for cognitively complex VR paradigms.
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http://dx.doi.org/10.1152/jn.00630.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384973PMC
April 2017

An Automated, Experimenter-Free Method for the Standardised, Operant Cognitive Testing of Rats.

PLoS One 2017 6;12(1):e0169476. Epub 2017 Jan 6.

Department of Biology, Humboldt University of Berlin, Berlin, Germany.

Animal models of human pathology are essential for biomedical research. However, a recurring issue in the use of animal models is the poor reproducibility of behavioural and physiological findings within and between laboratories. The most critical factor influencing this issue remains the experimenter themselves. One solution is the use of procedures devoid of human intervention. We present a novel approach to experimenter-free testing cognitive abilities in rats, by combining undisturbed group housing with automated, standardized and individual operant testing. This experimenter-free system consisted of an automated-operant system (Bussey-Saksida rat touch screen) connected to a home cage containing group living rats via an automated animal sorter (PhenoSys). The automated animal sorter, which is based on radio-frequency identification (RFID) technology, functioned as a mechanical replacement of the experimenter. Rats learnt to regularly and individually enter the operant chamber and remained there for the duration of the experimental session only. Self-motivated rats acquired the complex touch screen task of trial-unique non-matching to location (TUNL) in half the time reported for animals that were manually placed into the operant chamber. Rat performance was similar between the two groups within our laboratory, and comparable to previously published results obtained elsewhere. This reproducibility, both within and between laboratories, confirms the validity of this approach. In addition, automation reduced daily experimental time by 80%, eliminated animal handling, and reduced equipment cost. This automated, experimenter-free setup is a promising tool of great potential for testing a large variety of functions with full automation in future studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169476PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5218494PMC
August 2017

Cognition-mediated evolution of low-quality floral nectars.

Science 2017 01;355(6320):75-78

Humboldt University, Berlin, Germany.

Plants pollinated by hummingbirds or bats produce dilute nectars even though these animals prefer more concentrated sugar solutions. This mismatch is an unsolved evolutionary paradox. Here we show that lower quality, or more dilute, nectars evolve when the strength of preferring larger quantities or higher qualities of nectar diminishes as magnitudes of the physical stimuli increase. In a virtual evolution experiment conducted in the tropical rainforest, bats visited computer-automated flowers with simulated genomes that evolved relatively dilute nectars. Simulations replicated this evolution only when value functions, which relate the physical stimuli to subjective sensations, were nonlinear. Selection also depended on the supply/demand ratio; bats selected for more dilute nectar when competition for food was higher. We predict such a pattern to generally occur when decision-makers consider multiple value dimensions simultaneously, and increases of psychological value are not fully proportional to increases in physical magnitude.
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http://dx.doi.org/10.1126/science.aah4219DOI Listing
January 2017

Air-Track: a real-world floating environment for active sensing in head-fixed mice.

J Neurophysiol 2016 10 13;116(4):1542-1553. Epub 2016 Jul 13.

Neurocure Cluster of Excellence, Humboldt-Universität zu Berlin, Berlin, Germany; and

Natural behavior occurs in multiple sensory and motor modalities and in particular is dependent on sensory feedback that constantly adjusts behavior. To investigate the underlying neuronal correlates of natural behavior, it is useful to have access to state-of-the-art recording equipment (e.g., 2-photon imaging, patch recordings, etc.) that frequently requires head fixation. This limitation has been addressed with various approaches such as virtual reality/air ball or treadmill systems. However, achieving multimodal realistic behavior in these systems can be challenging. These systems are often also complex and expensive to implement. Here we present "Air-Track," an easy-to-build head-fixed behavioral environment that requires only minimal computational processing. The Air-Track is a lightweight physical maze floating on an air table that has all the properties of the "real" world, including multiple sensory modalities tightly coupled to motor actions. To test this system, we trained mice in Go/No-Go and two-alternative forced choice tasks in a plus maze. Mice chose lanes and discriminated apertures or textures by moving the Air-Track back and forth and rotating it around themselves. Mice rapidly adapted to moving the track and used visual, auditory, and tactile cues to guide them in performing the tasks. A custom-controlled camera system monitored animal location and generated data that could be used to calculate reaction times in the visual and somatosensory discrimination tasks. We conclude that the Air-Track system is ideal for eliciting natural behavior in concert with virtually any system for monitoring or manipulating brain activity.
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http://dx.doi.org/10.1152/jn.00088.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5144720PMC
October 2016

Only watching others making their experiences is insufficient to enhance adult neurogenesis and water maze performance in mice.

Sci Rep 2015 Sep 15;5:14141. Epub 2015 Sep 15.

Department of Neurology, Charité Universitätsmedizin, Charitéplatz 1, 10117 Berlin.

In the context of television consumption and its opportunity costs the question arises how far experiencing mere representations of the outer world would have the same neural and cognitive consequences than actively interacting with that environment. Here we demonstrate that physical interaction and direct exposition are essential for the beneficial effects of environmental enrichment. In our experiment, the mice living in a simple standard cage placed in the centre of a large enriched environment only indirectly experiencing the stimulus-rich surroundings (IND) did not display increased adult hippocampal neurogenesis. In contrast, the mice living in and directly experiencing the surrounding enriched environment (DIR) and mice living in a similar enriched cage containing an uninhabited inner cage (ENR) showed enhanced neurogenesis compared to mice in control conditions (CTR). Similarly, the beneficial effects of environmental enrichment on learning performance in the Morris Water maze depended on the direct interaction of the individual with the enrichment. In contrast, indirectly experiencing a stimulus-rich environment failed to improve memory functions indicating that direct interaction and activity within the stimulus-rich environment are necessary to induce structural and functional changes in the hippocampus.
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http://dx.doi.org/10.1038/srep14141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642579PMC
September 2015

The wake of hovering flight in bats.

J R Soc Interface 2015 08;12(109):20150357

Department of Biology, Lund University, Lund, Sweden.

Hovering means stationary flight at zero net forward speed, which can be achieved by animals through muscle powered flapping flight. Small bats capable of hovering typically do so with a downstroke in an inclined stroke plane, and with an aerodynamically active outer wing during the upstroke. The magnitude and time history of aerodynamic forces should be reflected by vorticity shed into the wake. We thus expect hovering bats to generate a characteristic wake, but this has until now never been studied. Here we trained nectar-feeding bats, Leptonycteris yerbabuenae, to hover at a feeder and using time-resolved stereoscopic particle image velocimetry in conjunction with high-speed kinematic analysis we show that hovering nectar-feeding bats produce a series of bilateral stacked vortex loops. Vortex visualizations suggest that the downstroke produces the majority of the weight support, but that the upstroke contributes positively to the lift production. However, the relative contributions from downstroke and upstroke could not be determined on the basis of the wake, because wake elements from down- and upstroke mix and interact. We also use a modified actuator disc model to estimate lift force, power and flap efficiency. Based on our quantitative wake-induced velocities, the model accounts for weight support well (108%). Estimates of aerodynamic efficiency suggest hovering flight is less efficient than forward flapping flight, while the overall energy conversion efficiency (mechanical power output/metabolic power) was estimated at 13%.
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http://dx.doi.org/10.1098/rsif.2015.0357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535406PMC
August 2015

Leading edge vortices in lesser long-nosed bats occurring at slow but not fast flight speeds.

Bioinspir Biomim 2014 Jun 22;9(2):025006. Epub 2014 May 22.

Department of Biology, Lund University, Ecology Building, SE-223 62 Lund University, Sweden. Department of Biology, Box 351800, 24 Kincaid Hall, University of Washington, Seattle, WA 98195-1800, USA.

Slow and hovering animal flight creates high demands on the lift production of animal wings. Steady state aerodynamics is unable to explain the forces required and the most commonly used mechanism to enhance the lift production is a leading edge vortex (LEV). Although LEVs increase the lift, they come at the cost of high drag. Here we determine the flow above the wing of lesser long-nosed bats at slow and cruising speed using particle image velocimetry (PIV). We find that a prominent LEV is present during the downstroke at slow speed, but not at cruising speed. Comparison with previously published LEV data from a robotic flapper inspired by lesser long-nosed bats suggests that bats should be able to generate LEVs at cruising speeds, but that they avoid doing so, probably to increase flight efficiency. In addition, at slow flight speeds we find LEVs of opposite spin at the inner and outer wing during the upstroke, potentially providing a control challenge to the animal. We also note that the LEV stays attached to the wing throughout the downstoke and does not show the complex structures found in insects. This suggests that bats are able to control the development of the LEV and potential control mechanisms are discussed.
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http://dx.doi.org/10.1088/1748-3182/9/2/025006DOI Listing
June 2014

A circle-monitor for computerised assessment of visual neglect in peripersonal space.

PLoS One 2013 12;8(12):e82892. Epub 2013 Dec 12.

Department of Biology, Humboldt University Berlin and Cluster of Excellence NeuroCure, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Unlabelled: Current assessment of visual neglect involves paper-and-pencil tests or computer-based tasks. Both have been criticised because of their lack of ecological validity as target stimuli can only be presented in a restricted visual range. This study examined the user-friendliness and diagnostic strength of a new "Circle-Monitor" (CM), which enlarges the range of the peripersonal space, in comparison to a standard paper-and-pencil test (Neglect-Test, NET).

Methods: Ten stroke patients with neglect and ten age-matched healthy controls were examined by the NET and the CM test comprising of four subtests (Star Cancellation, Line Bisection, Dice Task, and Puzzle Test).

Results: The acceptance of the CM in elderly controls and neglect patients was high. Participants rated the examination by CM as clear, safe and more enjoyable than NET. Healthy controls performed at ceiling on all subtests, without any systematic differences between the visual fields. Both NET and CM revealed significant differences between controls and patients in Line Bisection, Star Cancellation and visuo-constructive tasks (NET: Figure Copying, CM: Puzzle Test). Discriminant analyses revealed cross-validated assignment of patients and controls to groups was more precise when based on the CM (hit rate 90%) as compared to the NET (hit rate 70%).

Conclusion: The CM proved to be a sensitive novel tool to diagnose visual neglect symptoms quickly and accurately with superior diagnostic validity compared to a standard neglect test while being well accepted by patients. Due to its upgradable functions the system may also be a valuable tool not only to test for non-visual neglect symptoms, but also to provide treatment and assess its outcome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0082892PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3861461PMC
March 2015

Weber's law, the magnitude effect and discrimination of sugar concentrations in nectar-feeding animals.

PLoS One 2013 10;8(9):e74144. Epub 2013 Sep 10.

Humboldt University, Berlin, Germany.

Weber's law quantifies the perception of difference between stimuli. For instance, it can explain why we are less likely to detect the removal of three nuts from a bowl if the bowl is full than if it is nearly empty. This is an example of the magnitude effect - the phenomenon that the subjective perception of a linear difference between a pair of stimuli progressively diminishes when the average magnitude of the stimuli increases. Although discrimination performances of both human and animal subjects in various sensory modalities exhibit the magnitude effect, results sometimes systematically deviate from the quantitative predictions based on Weber's law. An attempt to reformulate the law to better fit data from acoustic discrimination tasks has been dubbed the "near-miss to Weber's law". Here, we tested the gustatory discrimination performance of nectar-feeding bats (Glossophaga soricina), in order to investigate whether the original version of Weber's law accurately predicts choice behavior in a two-alternative forced choice task. As expected, bats either preferred the sweeter of the two options or showed no preference. In 4 out of 6 bats the near-miss to Weber's law provided a better fit and Weber's law underestimated the magnitude effect. In order to test the generality of this observation in nectar-feeders, we reviewed previously published data on bats, hummingbirds, honeybees, and bumblebees. In all groups of animals the near-miss to Weber's law provided better fits than Weber's law. Furthermore, whereas the magnitude effect was stronger than predicted by Weber's law in vertebrates, it was weaker than predicted in insects. Thus nectar-feeding vertebrates and insects seem to differ in how their choice behavior changes as sugar concentration is increased. We discuss the ecological and evolutionary implications of the observed patterns of sugar concentration discrimination.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0074144PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769339PMC
June 2014

Interval timing behavior in Pallas's long-tongued bat (Glossophaga soricina).

J Comp Psychol 2013 Nov 22;127(4):445-52. Epub 2013 Jul 22.

Berlin School of Mind and Brain, Humboldt University.

Timing behavior in animals and its underlying mechanisms have been investigated extensively in the peak procedure, a variant of fixed interval procedures. In such experiments, individuals typically start responding with high frequency after an initial inactive time interval and continue their responses after peak time if rewards are omitted. This begs the so far unexplored question as to how timing behavior is influenced when such continuous responses are suppressed. Here, we present results from a nectar-feeding bat species, Glossophaga soricina, that was tested in a modified version of the peak procedure at three fixed time intervals (5 s, 11 s, 20 s). In contrast to standard peak procedures we imposed metabolic costs on individual responses which effectively suppressed trains of rapid responses during trials. Under this manipulation, bats' aggregated responses showed clear peaks around the peak time in the 5-s and 11-s schedules. Bats' responses in the 20-s schedule, however, did not peak around the fixed interval time. Crucially, an analysis of time intervals between successive revisits in all schedules revealed that bats revisited feeders at accurately timed intervals in all three conditions. The individual within trial behavioral responses showed clear oscillatory patterns throughout nonrewarded trials. These findings follow predictions from mechanistic timing models, like the striatal beat frequency model, and are discussed with regard to these models.
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http://dx.doi.org/10.1037/a0032528DOI Listing
November 2013

Learning real-life cognitive abilities in a novel 360°-virtual reality supermarket: a neuropsychological study of healthy participants and patients with epilepsy.

J Neuroeng Rehabil 2013 Apr 23;10:42. Epub 2013 Apr 23.

Physiological Psychology, Bielefeld University, P.O, Box 100131, Bielefeld, D-33501, Germany.

Background: To increase the ecological validity of neuropsychological instruments the use of virtual reality (VR) applications can be considered as an effective tool in the field of cognitive neurorehabilitation. Despite the growing use of VR programs, only few studies have considered the application of everyday activities like shopping or travelling in VR training devices.

Methods: We developed a novel 360°-VR supermarket, which is displayed on a circular arrangement of 8 touch-screens--the "OctaVis". In this setting, healthy human adults had to memorize an auditorily presented shopping list (list A) and subsequently buy all remembered products of this list in the VR supermarket. This procedure was accomplished on three consecutive days. On day four, a new shopping list (list B) was introduced and participants had to memorize and buy only products of this list. On day five, participants had to buy all remembered items of list A again, but without new presentation of list A. Additionally, we obtained measures of participants' presence, immersion and figural-spatial memory abilities. We also tested a sample of patients with focal epilepsy with an extended version of our shopping task, which consisted of eight days of training.

Results: We observed a comprehensive and stable effect of learning for the number of correct products, the required time for shopping, and the length of movement trajectories in the VR supermarket in the course of the training program. Task performance was significantly correlated with participants' figural-spatial memory abilities and subjective level of immersion into the VR.

Conclusions: Learning effects in our paradigm extend beyond mere verbal learning of the shopping list as the data show evidence for multi-layered learning (at least visual-spatial, strategic, and verbal) on concordant measures. Importantly, learning also correlated with measures of figural-spatial memory and the degree of immersion into the VR. We propose that cognitive training with the VR supermarket program in the OctaVis will be efficient for the assessment and training of real-life cognitive abilities in healthy subjects and patients with epilepsy. It is most likely that our findings will also apply for patients with cognitive disabilities resulting from other neurological and psychiatric syndromes.
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http://dx.doi.org/10.1186/1743-0003-10-42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637817PMC
April 2013

Compromised fidelity of endocytic synaptic vesicle protein sorting in the absence of stonin 2.

Proc Natl Acad Sci U S A 2013 Feb 23;110(6):E526-35. Epub 2013 Jan 23.

Department of Molecular Pharmacology and Cell Biology, Leibniz Institut für Molekulare Pharmakologie, 13125 Berlin, Germany.

Neurotransmission depends on the exocytic fusion of synaptic vesicles (SVs) and their subsequent reformation either by clathrin-mediated endocytosis or budding from bulk endosomes. How synapses are able to rapidly recycle SVs to maintain SV pool size, yet preserve their compositional identity, is poorly understood. We demonstrate that deletion of the endocytic adaptor stonin 2 (Stn2) in mice compromises the fidelity of SV protein sorting, whereas the apparent speed of SV retrieval is increased. Loss of Stn2 leads to selective missorting of synaptotagmin 1 to the neuronal surface, an elevated SV pool size, and accelerated SV protein endocytosis. The latter phenotype is mimicked by overexpression of endocytosis-defective variants of synaptotagmin 1. Increased speed of SV protein retrieval in the absence of Stn2 correlates with an up-regulation of SV reformation from bulk endosomes. Our results are consistent with a model whereby Stn2 is required to preserve SV protein composition but is dispensable for maintaining the speed of SV recycling.
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http://dx.doi.org/10.1073/pnas.1218432110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568307PMC
February 2013
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