Max Planck Institute for Metabolism Research
Max Planck Institute for Metabolism Research
Kruger L.,German Center for Neurodegenerative Diseases |
Mandelkow E.M.,German Center for Neurodegenerative Diseases |
Mandelkow E.M.,Caesar Research Center |
Mandelkow E.M.,Max Planck Institute for Metabolism Research
Current Opinion in Neurobiology | Year: 2016
Pathological Tau is a hallmark of various neuronal disorders and spreads in the brain of Alzheimer patients in a well-defined manner. Beside Tau's main function in stabilizing microtubules for axonal transport, a variety of novel functions for neurons and glia have emerged recently. Tau regulates the susceptibility to hyperexcitation and plays a role in neuron-glia contact formation. Studies implicate soluble oligomeric species of Tau, rather than insoluble aggregates, as more detrimental to proper neuronal function. Tau is not exclusively intracellular; instead Tau can be released into the extracellular space. This has led to the hypothesis of a prion-disease like mechanism to explain the stereotypical progression of Tau. Targeting pathological Tau with antibodies or aggregation inhibitors may help to prevent pathology. © 2015 Elsevier Ltd.
Difeliceantonio A.G.,Yale University |
Difeliceantonio A.G.,Max Planck Institute for Metabolism Research |
Difeliceantonio A.G.,University of Michigan |
Berridge K.C.,University of Michigan
European Journal of Neuroscience | Year: 2016
Pavlovian cues for rewards can become attractive incentives: approached and 'wanted' as the rewards themselves. The motivational attractiveness of a previously learned cue is not fixed, but can be dynamically amplified during re-encounter by simultaneous activation of brain limbic circuitry. Here it was reported that opioid or dopamine microinjections in the dorsolateral quadrant of the neostriatum (DLS) of rats selectively amplify attraction toward a previously learned Pavlovian cue in an individualized fashion, at the expense of a competing cue. In an autoshaping (sign-tracking vs. goal-tracking) paradigm, microinjection of the mu opioid receptor agonist (DAMGO) or dopamine indirect agonist (amphetamine) in the DLS of sign-tracker individuals selectively enhanced their sign-tracking attraction toward the reward-predictive lever cue. By contrast, DAMGO or amphetamine in the DLS of goal-trackers selectively enhanced prepotent attraction toward the reward-proximal cue of sucrose dish. Amphetamine also enhanced goal-tracking in some sign-tracker individuals (if they ever defected to the dish even once). That DLS enhancement of cue attraction was due to stronger motivation, not stronger habits, was suggested by: (i) sign-trackers flexibly followed their cue to a new location when the lever was suddenly moved after DLS DAMGO microinjection; and (ii) DAMGO in the DLS also made sign-trackers work harder on a new instrumental nose-poke response required to earn presentations of their Pavlovian lever cue (instrumental conditioned reinforcement). Altogether, the current results suggest that DLS circuitry can enhance the incentive salience of a Pavlovian reward cue, selectively making that cue a stronger motivational magnet. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
Kuzmanovic B.,Max Planck Institute for Metabolism Research |
Kuzmanovic B.,Institute of Neuroscience and Medicine |
Kuzmanovic B.,University of Cologne |
Jefferson A.,University of Birmingham |
And 2 more authors.
NeuroImage | Year: 2016
People are motivated to adopt the most favorable beliefs about their future because positive beliefs are experienced as rewarding. However, it is so far inconclusive whether brain regions known to represent reward values are involved in the generation of optimistically biased belief updates. To address this question, we investigated neural correlates of belief updates that result in relatively better future outlooks, and therefore imply a positive subjective value of the judgment outcome. Participants estimated the probability of experiencing different adverse future events. After being provided with population base rates of these events, they had the opportunity to update their initial estimates. Participants made judgments concerning themselves or a similar other, and were confronted with desirable or undesirable base rates (i.e., lower or higher than their initial estimates).Belief updates were smaller following undesirable than desirable information, and this optimism bias was stronger for judgments regarding oneself than others. During updating, the positive value of self-related updates was reflected by neural activity in the subgenual ventromedial prefrontal cortex (vmPFC) that increased both with increasing sizes of favorable updates, and with decreasing sizes of unfavorable updates. During the processing of self-related undesirable base rates, increasing activity in a network including the dorsomedial PFC, hippocampus, thalamus and ventral striatum predicted decreasing update sizes.Thus, key regions of the neural reward circuitry contributed to the generation of optimistically biased self-referential belief updates. While the vmPFC tracked subjective values of belief updates, a network including the ventral striatum was involved in neglecting information calling for unfavorable updates. © 2016 Elsevier Inc.
Wang Y.,German Center for Neurodegenerative Diseases |
Mandelkow E.,German Center for Neurodegenerative Diseases |
Mandelkow E.,Max Planck Institute for Metabolism Research
Nature Reviews Neuroscience | Year: 2016
Tau is a microtubule-associated protein that has a role in stabilizing neuronal microtubules and thus in promoting axonal outgrowth. Structurally, tau is a natively unfolded protein, is highly soluble and shows little tendency for aggregation. However, tau aggregation is characteristic of several neurodegenerative diseases known as tauopathies. The mechanisms underlying tau pathology and tau-mediated neurodegeneration are debated, but considerable progress has been made in the field of tau research in recent years, including the identification of new physiological roles for tau in the brain. Here, we review the expression, post-translational modifications and functions of tau in physiology and in pathophysiology. © 2016 Macmillan Publishers Limited. All rights reserved.
Sevgi M.,Max Planck Institute for Metabolism Research |
Diaconescu A.O.,ETH Zurich |
Tittgemeyer M.,Max Planck Institute for Metabolism Research |
Schilbach L.,Max Planck Institute of Psychiatry |
Schilbach L.,University of Cologne
Biological Psychiatry | Year: 2016
Background Autism is characterized by impairments of social interaction, but the underlying subpersonal processes are still a matter of controversy. It has been suggested that the autistic spectrum might be characterized by alterations of the brain's inference on the causes of socially relevant signals. However, it is unclear at what level of processing such trait-related alterations may occur. Methods We used a reward-based learning task that requires the integration of nonsocial and social cues in conjunction with computational modeling. Healthy subjects (N = 36) were selected based on their Autism Quotient Spectrum (AQ) score, and AQ scores were assessed for correlations with model parameters and task scores. Results Individual differences in AQ were inversely correlated with participants’ task scores (r = −.39, 95% confidence interval [CI] [−.68, −.13]). Moreover, AQ scores were significantly correlated with a social weighting parameter that indicated how strongly the decision was influenced by the social cue (r = −.42, 95% CI [−.66, −.19]), but not with other model parameters. Also, more pronounced social weighting was related to higher scores (r = .50, 95% CI [.20, .86]). Conclusions Our results demonstrate that higher autistic traits in healthy subjects are related to lower scores in a learning task that requires social cue integration. Computational modeling further demonstrates that these trait-related performance differences are not explained by an inability to process the social stimuli and its causes, but rather by the extent to which participants take into account social information during decision making. © 2016 Society of Biological Psychiatry
Stephan K.E.,ETH Zurich |
Stephan K.E.,University College London |
Stephan K.E.,Max Planck Institute for Metabolism Research |
Iglesias S.,ETH Zurich |
And 2 more authors.
Neuron | Year: 2015
Functional neuroimaging has made fundamental contributions to our understanding of brain function. It remains challenging, however, to translate these advances into diagnostic tools for psychiatry. Promising new avenues for translation are provided by computational modeling of neuroimaging data. This article reviews contemporary frameworks for computational neuroimaging, with a focus on forward models linking unobservable brain states to measurements. These approaches-biophysical network models, generative models, and model-based fMRI analyses of neuromodulation-strive to move beyond statistical characterizations and toward mechanistic explanations of neuroimaging data. Focusing on schizophrenia as a paradigmatic spectrum disease, we review applications of these models to psychiatric questions, identify methodological challenges, and highlight trends of convergence among computational neuroimaging approaches. We conclude by outlining a translational neuromodeling strategy, highlighting the importance of openly available datasets from prospective patient studies for evaluating the clinical utility of computational models. Psychiatry lacks diagnostic tools that enable clinical predictions and treatment selection for individual patients. Computational models of neuroimaging data offer a promising new avenue. Focusing on schizophrenia, this article reviews clinical applications, methodological challenges, and future developments of computational neuroimaging. © 2015 Elsevier Inc.
Wensveen F.M.,University of Rijeka |
Jelencic V.,University of Rijeka |
Valentic S.,University of Rijeka |
Sestan M.,University of Rijeka |
And 9 more authors.
Nature Immunology | Year: 2015
An important cause of obesity-induced insulin resistance is chronic systemic inflammation originating in visceral adipose tissue (VAT). VAT inflammation is associated with the accumulation of proinflammatory macrophages in adipose tissue, but the immunological signals that trigger their accumulation remain unknown. We found that a phenotypically distinct population of tissue-resident natural killer (NK) cells represented a crucial link between obesity-induced adipose stress and VAT inflammation. Obesity drove the upregulation of ligands of the NK cell-activating receptor NCR1 on adipocytes; this stimulated NK cell proliferation and interferon-γ (IFN-γ) production, which in turn triggered the differentiation of proinflammatory macrophages and promoted insulin resistance. Deficiency of NK cells, NCR1 or IFN-γ prevented the accumulation of proinflammatory macrophages in VAT and greatly ameliorated insulin sensitivity. Thus NK cells are key regulators of macrophage polarization and insulin resistance in response to obesity-induced adipocyte stress. © 2015 Nature America, Inc. All rights reserved.
Morgan M.,City University London |
Morgan M.,Max Planck Institute for Metabolism Research
Current Biology | Year: 2015
A new experiment shows that the perceived motion path of a textured object is affected both by the path of the object and by the motion of texture within it, but that eye movements attempting to intercept the object are unaffected by the texture movement. © 2015 Elsevier Ltd All rights reserved.
Mauer J.,Max Planck Institute for Metabolism Research |
Denson J.L.,Max Planck Institute for Metabolism Research |
Bruning J.C.,Max Planck Institute for Metabolism Research
Trends in Immunology | Year: 2015
Owing to its abundance in inflammatory settings, interleukin IL-6 is frequently viewed as a proinflammatory cytokine, with functions that parallel those of tumor necrosis factor (TNF) and IL-1β in the context of inflammation. However, accumulating evidence points to a broader role for IL-6 in a variety of (patho)physiological conditions, including functions related to the resolution of inflammation. We review recent findings on the complex biological functions governed by IL-6 signaling, focusing on its role in inflammation-associated cancer and metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM). We propose that the anti-inflammatory functions of IL-6 may extend to multiple settings and cell types, and suggest that these dimensions should be incorporated in therapeutic approaches to these diseases. Finally, we outline important areas of inquiry towards understanding this pleiotropic cytokine. © 2015.
Heiss W.-D.,Max Planck Institute for Metabolism Research
Cerebrovascular Diseases | Year: 2016
Background: Malignant middle cerebral artery infarction is a devastating condition, with up to 80% mortality in conservatively treated patients. The pathophysiology of this stroke is characterized by a large core of severe ischemia and only a relatively small rim of penumbra. Due to the fast development of irreversible morphological damage, cytotoxic edema occurs immediately in a large portion of the ischemic territory. The subsequent damage of the tight junctions leads to the breakdown of the blood brain barrier and vasogenic brain edema, resulting in space-occupying brain swelling. The progressive vasogenic edema reaches its maximum after 1 to several days and exerts a mechanical force on surrounding tissue structures leading to midline shift and transtentorial herniation and finally brain stem compression and death. Summary: Early severe neurological symptoms - hemiparesis, gaze deviation, higher cortical signs - followed by headache, vomiting, papillo edema and reduced consciousness may predict the deleterious course. Imaging supports the suspected diagnosis with hypodense changes on CT extending beyond 50% of the MCA territory. The size of the probably infarcted tissue and a midline shift on CT as well as the size of the lesion on diffusion-weighted MRI are predictive of a malignant course. Reduction of cerebral blood flow below a critical value and volume of irreversible tissue damage detected by positron emission tomography in the early hours after the stroke are indicative of progression to malignant infarction with increased intracranial pressure (ICP) and decreased tissue oxygen tension observed by multimodal neuromonitoring in the later course. Treatment options of malignant infarction include general measures to limit the extent of space-occupying edema, but these therapies have not been efficacious. Only surgical intervention with decompressive hemicraniectomy (DHC) was successful in relieving the effects of increased ICP and of the deleterious shifts of brain tissue. Several controlled clinical trials have proven the efficacy of DHC with a significant decrease in mortality and improved functional outcome. However, DHC must be performed early and with a large diameter, regardless of the age of patients, but in patients beyond 60 years, the higher likelihood of resulting severe disability should be taken into consideration. Key Messages: Malignant MCA infarction can be predicted early with a high sensitivity by neuroimaging. The early diagnosis is mandatory for DHC, which was shown to reduce mortality and improve functional outcome in several controlled clinical trials. © 2015 S. Karger AG, Basel.