Project acronym AMYLOID
Project Identification and modulation of pathogenic Amyloid beta-peptide species
Researcher (PI) Christian Haass
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary The frequency of Alzheimer's disease (AD) will dramatically increase in the ageing western society during the next decades. Currently, about 18 million people suffer worldwide from AD. Since no cure is available, this devastating disorder represents one of the most challenging socio-economical problems of our future. As onset and progression of AD is triggered by the amyloid cascade, I will put particular attention on amyloid ß-peptide (Aß). The reason for this approach is, that even though 20 years ago the Aß generating processing pathway was identified (Haass et al., Nature 1992a & b), the identity of the Aß species, which initiate the deadly cascade is still unknown. I will first tackle this challenge by investigating if a novel and so far completely overlooked proteolytic processing pathway is involved in the generation of Aß species capable to initiate spreading of pathology and neurotoxicity. I will then search for modulating proteins, which could affect generation of pathological Aß species. This includes a genome-wide screen for modifiers of gamma-secretase, one of the proteases involved in Aß generation as well as a targeted search for RNA binding proteins capable to posttranscriptionally regulate beta- and alpha-secretase. In a disease-crossing approach, RNA binding proteins, which were recently found not only to be deposited in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis but also in many AD cases, will be investigated for their potential to modulate Aß aggregation and AD pathology. Modifiers and novel antibodies specifically recognizing neurotoxic Aß assemblies will be validated for their potential not only to prevent amyloid plaque formation, but also spreading of pathology as well as neurotoxicity. In vivo validations include studies in innovative zebrafish models, which allow life imaging of neuronal cell death, as well as the establishment of microPET amyloid imaging for longitudinal studies in individual animals.
Summary
The frequency of Alzheimer's disease (AD) will dramatically increase in the ageing western society during the next decades. Currently, about 18 million people suffer worldwide from AD. Since no cure is available, this devastating disorder represents one of the most challenging socio-economical problems of our future. As onset and progression of AD is triggered by the amyloid cascade, I will put particular attention on amyloid ß-peptide (Aß). The reason for this approach is, that even though 20 years ago the Aß generating processing pathway was identified (Haass et al., Nature 1992a & b), the identity of the Aß species, which initiate the deadly cascade is still unknown. I will first tackle this challenge by investigating if a novel and so far completely overlooked proteolytic processing pathway is involved in the generation of Aß species capable to initiate spreading of pathology and neurotoxicity. I will then search for modulating proteins, which could affect generation of pathological Aß species. This includes a genome-wide screen for modifiers of gamma-secretase, one of the proteases involved in Aß generation as well as a targeted search for RNA binding proteins capable to posttranscriptionally regulate beta- and alpha-secretase. In a disease-crossing approach, RNA binding proteins, which were recently found not only to be deposited in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis but also in many AD cases, will be investigated for their potential to modulate Aß aggregation and AD pathology. Modifiers and novel antibodies specifically recognizing neurotoxic Aß assemblies will be validated for their potential not only to prevent amyloid plaque formation, but also spreading of pathology as well as neurotoxicity. In vivo validations include studies in innovative zebrafish models, which allow life imaging of neuronal cell death, as well as the establishment of microPET amyloid imaging for longitudinal studies in individual animals.
Max ERC Funding
2 497 020 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym BRAINVISIONREHAB
Project ‘Seeing’ with the ears, hands and bionic eyes: from theories about brain organization to visual rehabilitation
Researcher (PI) Amir Amedi
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS5, ERC-2012-StG_20111109
Summary My lab's work ranges from basic science, querying brain plasticity and sensory integration, to technological developments, allowing the blind to be more independent and even “see” using sounds and touch similar to bats and dolphins (a.k.a. Sensory Substitution Devices, SSDs), and back to applying these devices in research. We propose that, with proper training, any brain area or network can change the type of sensory input it uses to retrieve behaviorally task-relevant information within a matter of days. If this is true, it can have far reaching implications also for clinical rehabilitation. To achieve this, we are developing several innovative SSDs which encode the most crucial aspects of vision and increase their accessibility the blind, along with targeted, structured training protocols both in virtual environments and in real life. For instance, the “EyeMusic”, encodes colored complex images using pleasant musical scales and instruments, and the “EyeCane”, a palm-size cane, which encodes distance and depth in several directions accurately and efficiently. We provide preliminary but compelling evidence that following such training, SSDs can enable almost blind to recognize daily objects, colors, faces and facial expressions, read street signs, and aiding mobility and navigation. SSDs can also be used in conjunction with (any) invasive approach for visual rehabilitation. We are developing a novel hybrid Visual Rehabilitation Device which combines SSD and bionic eyes. In this set up, the SSDs is used in training the brain to “see” prior to surgery, in providing explanatory signal after surgery and in augmenting the capabilities of the bionic-eyes using information arriving from the same image. We will chart the dynamics of the plastic changes in the brain by performing unprecedented longitudinal Neuroimaging, Electrophysiological and Neurodisruptive approaches while individuals learn to ‘see’ using each of the visual rehabilitation approaches suggested here.
Summary
My lab's work ranges from basic science, querying brain plasticity and sensory integration, to technological developments, allowing the blind to be more independent and even “see” using sounds and touch similar to bats and dolphins (a.k.a. Sensory Substitution Devices, SSDs), and back to applying these devices in research. We propose that, with proper training, any brain area or network can change the type of sensory input it uses to retrieve behaviorally task-relevant information within a matter of days. If this is true, it can have far reaching implications also for clinical rehabilitation. To achieve this, we are developing several innovative SSDs which encode the most crucial aspects of vision and increase their accessibility the blind, along with targeted, structured training protocols both in virtual environments and in real life. For instance, the “EyeMusic”, encodes colored complex images using pleasant musical scales and instruments, and the “EyeCane”, a palm-size cane, which encodes distance and depth in several directions accurately and efficiently. We provide preliminary but compelling evidence that following such training, SSDs can enable almost blind to recognize daily objects, colors, faces and facial expressions, read street signs, and aiding mobility and navigation. SSDs can also be used in conjunction with (any) invasive approach for visual rehabilitation. We are developing a novel hybrid Visual Rehabilitation Device which combines SSD and bionic eyes. In this set up, the SSDs is used in training the brain to “see” prior to surgery, in providing explanatory signal after surgery and in augmenting the capabilities of the bionic-eyes using information arriving from the same image. We will chart the dynamics of the plastic changes in the brain by performing unprecedented longitudinal Neuroimaging, Electrophysiological and Neurodisruptive approaches while individuals learn to ‘see’ using each of the visual rehabilitation approaches suggested here.
Max ERC Funding
1 499 900 €
Duration
Start date: 2013-09-01, End date: 2018-08-31
Project acronym CHOLINOMIRS
Project CholinomiRs: MicroRNA Regulators of Cholinergic Signalling in the Neuro-Immune Interface
Researcher (PI) Hermona Soreq
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary "Communication between the nervous and the immune system is pivotal for maintaining homeostasis and ensuring rapid and efficient reaction to stress and infection insults. The emergence of microRNAs (miRs) as regulators of gene expression and of acetylcholine (ACh) signalling as regulator of anxiety and inflammation provides a model for studying this interaction. My hypothesis is that 1) a specific sub-group of miRs, designated ""CholinomiRs"", may silence multiple target genes in the neuro-immune interface; 2) these miRs compete with each other on the interaction with their targets, and 3) mutations interfering with miR binding lead to inherited susceptibility to anxiety and inflammation disorders by modifying these interactions. Our preliminary findings have shown that by targeting acetylcholinesterase (AChE), CholinomiR-132 can intensify acute stress, resolve intestinal inflammation and change post-ischemic stroke responses. Further, we have identified clustered single nucleotide polymorphisms (SNPs) interfering with AChE silencing by several miRs which associate with elevated trait anxiety, blood pressure and inflammation. To further study miR regulators of ACh signalling, I plan to: (1) Identify anxiety and inflammation-induced changes in CholinomiRs and their targets in challenged brain and immune cells. (2) Establish the roles of these targets for one selected CholinomiR by tissue-specific manipulations. (3) Study primate-specific CholinomiRs by continued human DNA screens to identify SNPs and in ""humanized"" mice with knocked-in human AChE and transgenic CholinomiR-608. (4) Test if therapeutic modulation of aberrant CholinomiR expression can restore homeostasis. This research will clarify how miRs interact with each other in health and disease, introduce the dimension of complexity of multi-target competition and miR interactions and make a conceptual change in miRs research while enhancing the ability to intervene with diseases involving impaired ACh signalling."
Summary
"Communication between the nervous and the immune system is pivotal for maintaining homeostasis and ensuring rapid and efficient reaction to stress and infection insults. The emergence of microRNAs (miRs) as regulators of gene expression and of acetylcholine (ACh) signalling as regulator of anxiety and inflammation provides a model for studying this interaction. My hypothesis is that 1) a specific sub-group of miRs, designated ""CholinomiRs"", may silence multiple target genes in the neuro-immune interface; 2) these miRs compete with each other on the interaction with their targets, and 3) mutations interfering with miR binding lead to inherited susceptibility to anxiety and inflammation disorders by modifying these interactions. Our preliminary findings have shown that by targeting acetylcholinesterase (AChE), CholinomiR-132 can intensify acute stress, resolve intestinal inflammation and change post-ischemic stroke responses. Further, we have identified clustered single nucleotide polymorphisms (SNPs) interfering with AChE silencing by several miRs which associate with elevated trait anxiety, blood pressure and inflammation. To further study miR regulators of ACh signalling, I plan to: (1) Identify anxiety and inflammation-induced changes in CholinomiRs and their targets in challenged brain and immune cells. (2) Establish the roles of these targets for one selected CholinomiR by tissue-specific manipulations. (3) Study primate-specific CholinomiRs by continued human DNA screens to identify SNPs and in ""humanized"" mice with knocked-in human AChE and transgenic CholinomiR-608. (4) Test if therapeutic modulation of aberrant CholinomiR expression can restore homeostasis. This research will clarify how miRs interact with each other in health and disease, introduce the dimension of complexity of multi-target competition and miR interactions and make a conceptual change in miRs research while enhancing the ability to intervene with diseases involving impaired ACh signalling."
Max ERC Funding
2 375 600 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym CLUE-BGD
Project Closing the Loop between Understanding and Effective Treatment of the Basal Ganglia and their Disorders
Researcher (PI) Hagai Bergman
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary In this project, the basal ganglia are defined as actor-critic reinforcement learning networks that aim at an optimal tradeoff between the maximization of future cumulative rewards and the minimization of the cost (the reinforcement driven multi objective optimization RDMOO model).
This computational model will be tested by multiple neuron recordings in the major basal ganglia structures of monkeys engaged in a similar behavioral task. We will further validate the RMDOO computational model of the basal ganglia by extending our previous studies of neural activity in the MPTP primate model of Parkinson's disease to a primate model of central serotonin depletion and emotional dysregulation disorders. The findings in the primate model of emotional dysregulation will then be compared to electrophysiological recordings carried out in human patients with treatment-resistant major depression and obsessive compulsive disorder during deep brain stimulation (DBS) procedures. I aim to find neural signatures (e.g., synchronous gamma oscillations in the actor part of the basal ganglia as predicted by the RMDOO model) characterizing these emotional disorders and to use them as triggers for closed loop adaptive DBS. Our working hypothesis holds that, as for the MPTP model of Parkinson's disease, closed loop DBS will lead to greater amelioration of the emotional deficits in serotonin depleted monkeys.
This project incorporates extensive collaborations with a team of neurosurgeons, neurologists, psychiatrists, and computer science/ neural network researchers. If successful, the findings will provide a firm understanding of the computational physiology of the basal ganglia networks and their disorders. Importantly, they will pave the way to better treatment of human patients with severe mental disorders.
Summary
In this project, the basal ganglia are defined as actor-critic reinforcement learning networks that aim at an optimal tradeoff between the maximization of future cumulative rewards and the minimization of the cost (the reinforcement driven multi objective optimization RDMOO model).
This computational model will be tested by multiple neuron recordings in the major basal ganglia structures of monkeys engaged in a similar behavioral task. We will further validate the RMDOO computational model of the basal ganglia by extending our previous studies of neural activity in the MPTP primate model of Parkinson's disease to a primate model of central serotonin depletion and emotional dysregulation disorders. The findings in the primate model of emotional dysregulation will then be compared to electrophysiological recordings carried out in human patients with treatment-resistant major depression and obsessive compulsive disorder during deep brain stimulation (DBS) procedures. I aim to find neural signatures (e.g., synchronous gamma oscillations in the actor part of the basal ganglia as predicted by the RMDOO model) characterizing these emotional disorders and to use them as triggers for closed loop adaptive DBS. Our working hypothesis holds that, as for the MPTP model of Parkinson's disease, closed loop DBS will lead to greater amelioration of the emotional deficits in serotonin depleted monkeys.
This project incorporates extensive collaborations with a team of neurosurgeons, neurologists, psychiatrists, and computer science/ neural network researchers. If successful, the findings will provide a firm understanding of the computational physiology of the basal ganglia networks and their disorders. Importantly, they will pave the way to better treatment of human patients with severe mental disorders.
Max ERC Funding
2 476 922 €
Duration
Start date: 2013-12-01, End date: 2018-11-30
Project acronym CORTEX SIMPLEX
Project Function and computation in three-layer cortex
Researcher (PI) Gilles Jean Laurent
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary "Understanding brain function is one of the outstanding challenges of modern biology. Many studies focus on mammalian neocortex, a modular and versatile structure that operates equally well with different sensory inputs and for perception, planning as well as action. Neocortex, however, is remarkably complex. It contains many cell types, six layers, networks with local and long-range connections, and its study is technically challenging. We propose here to address central issues of cortical computation using a simpler experimental system. Neocortex evolved from a more primitive cortex, likely present in the ancestors of all amniotes. Extant reptiles are closest to this putative ancestor: their cortex contains only three layers, two of which are nearly exclusively neuropilar. Reptilian cortex is also closest to mammals’ old cortices (piriform and hippocampus). Like in mammals, reptilian cortex is modular. Its design, however, is considerably simpler and more ubiquitous than in mammals. Indeed, so far as we know, reptilian primary olfactory and visual cortices are very similar to one another. Finally, certain reptiles such as turtles have evolved biochemical and metabolic adaptations to resist long periods of anoxia. Thus, their brains can be studied ex vivo over long periods, giving experimenters access to the entire brain with an intact retina or nasal epithelium. We will use this system to study cortical computation, primarily in visual and olfactory areas. Using electrophysiological, imaging, molecular, behavioral and computational methods, we will discover the representational strategies of these two cortices in vivo, the functional architecture of their microcircuits and the computations that they carry out. This understanding of generic and ancient units of cortical computation will illuminate our studies of more complex and sophisticated cortical circuits."
Summary
"Understanding brain function is one of the outstanding challenges of modern biology. Many studies focus on mammalian neocortex, a modular and versatile structure that operates equally well with different sensory inputs and for perception, planning as well as action. Neocortex, however, is remarkably complex. It contains many cell types, six layers, networks with local and long-range connections, and its study is technically challenging. We propose here to address central issues of cortical computation using a simpler experimental system. Neocortex evolved from a more primitive cortex, likely present in the ancestors of all amniotes. Extant reptiles are closest to this putative ancestor: their cortex contains only three layers, two of which are nearly exclusively neuropilar. Reptilian cortex is also closest to mammals’ old cortices (piriform and hippocampus). Like in mammals, reptilian cortex is modular. Its design, however, is considerably simpler and more ubiquitous than in mammals. Indeed, so far as we know, reptilian primary olfactory and visual cortices are very similar to one another. Finally, certain reptiles such as turtles have evolved biochemical and metabolic adaptations to resist long periods of anoxia. Thus, their brains can be studied ex vivo over long periods, giving experimenters access to the entire brain with an intact retina or nasal epithelium. We will use this system to study cortical computation, primarily in visual and olfactory areas. Using electrophysiological, imaging, molecular, behavioral and computational methods, we will discover the representational strategies of these two cortices in vivo, the functional architecture of their microcircuits and the computations that they carry out. This understanding of generic and ancient units of cortical computation will illuminate our studies of more complex and sophisticated cortical circuits."
Max ERC Funding
2 496 111 €
Duration
Start date: 2013-02-01, End date: 2018-01-31
Project acronym EMOTIONCIRCUITS
Project Circuit mechanics of emotions in the limbic system
Researcher (PI) Wulf Eckhard Haubensak
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Starting Grant (StG), LS5, ERC-2012-StG_20111109
Summary Numerous studies established the role of the limbic system in fear and reward: it integrates sensory information, encodes emotional states and instructs other brain centers to regulate physiology and behavior. The limbic system, however, consists of many distinct and highly interconnected neuronal populations. Resolving how emotions are processed in this network at the level of single neural circuits remains a major challenge.
As entry point into the complexity of emotion circuitry, we propose to study, in exemplary fashion, how fear, as the most basic paradigm for emotions, is processed in key limbic hubs. Genetic manipulation of brain circuitry with electrophysiological methods and Pavlovian conditioning in mice, are powerful tools to explore which and how individual circuits in these hubs control emotional states, and, in turn, how genes and psychoactive drugs modulate circuit activity, emotional states and behavior.
We envision this ERC funded research to uncover general principles of the network organization of both emotions and behaviors. It is our hope that we contribute useful tools and methodological framework for investigating other brain functions in a similar manner.
Summary
Numerous studies established the role of the limbic system in fear and reward: it integrates sensory information, encodes emotional states and instructs other brain centers to regulate physiology and behavior. The limbic system, however, consists of many distinct and highly interconnected neuronal populations. Resolving how emotions are processed in this network at the level of single neural circuits remains a major challenge.
As entry point into the complexity of emotion circuitry, we propose to study, in exemplary fashion, how fear, as the most basic paradigm for emotions, is processed in key limbic hubs. Genetic manipulation of brain circuitry with electrophysiological methods and Pavlovian conditioning in mice, are powerful tools to explore which and how individual circuits in these hubs control emotional states, and, in turn, how genes and psychoactive drugs modulate circuit activity, emotional states and behavior.
We envision this ERC funded research to uncover general principles of the network organization of both emotions and behaviors. It is our hope that we contribute useful tools and methodological framework for investigating other brain functions in a similar manner.
Max ERC Funding
1 499 922 €
Duration
Start date: 2013-01-01, End date: 2018-06-30
Project acronym InVivoSynapse
Project Cellular determinants of neuronal plasticity
on the level of single synapses in vivo
Researcher (PI) Arthur Konnerth
Host Institution (HI) TECHNISCHE UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary The search for the fundamental mechanisms of learning and experience-dependent memory formation in the brain has long been a central quest in neuroscience. The neocortex is a particularly relevant region for plasticity because it is involved in sensory, motor, and cognitive tasks with strong learning components. However, despite many years of intensive research our knowledge of the neuronal mechanisms of plasticity on the level of single synapses in the intact living brain is still very limited.
Here I propose the use of cutting edge technology, including the ultrasensitive LOTOS procedure of in vivo two-photon calcium imaging that was developed in our laboratory, to investigate for the first time the functional properties and the plasticity of signal synapses in auditory cortical pyramidal neurons of layers 2/3, 4 and 5 in vivo. For the study of the cellular determinants of synaptic plasticity we will focus on an associative learning paradigm underlying cued fear conditioning. Importantly, this paradigm can be rapidly and effectively induced not only in awake, but also in anesthetized animals and is therefore ideally suited for these studies. In addition to a comprehensive analysis of wild type animals, we will perform experiments in mouse models of Alzheimer’s disease (AD), aiming to identify the cellular cause of the devastating impairment of memory formation observed in patients suffering from AD.
Summary
The search for the fundamental mechanisms of learning and experience-dependent memory formation in the brain has long been a central quest in neuroscience. The neocortex is a particularly relevant region for plasticity because it is involved in sensory, motor, and cognitive tasks with strong learning components. However, despite many years of intensive research our knowledge of the neuronal mechanisms of plasticity on the level of single synapses in the intact living brain is still very limited.
Here I propose the use of cutting edge technology, including the ultrasensitive LOTOS procedure of in vivo two-photon calcium imaging that was developed in our laboratory, to investigate for the first time the functional properties and the plasticity of signal synapses in auditory cortical pyramidal neurons of layers 2/3, 4 and 5 in vivo. For the study of the cellular determinants of synaptic plasticity we will focus on an associative learning paradigm underlying cued fear conditioning. Importantly, this paradigm can be rapidly and effectively induced not only in awake, but also in anesthetized animals and is therefore ideally suited for these studies. In addition to a comprehensive analysis of wild type animals, we will perform experiments in mouse models of Alzheimer’s disease (AD), aiming to identify the cellular cause of the devastating impairment of memory formation observed in patients suffering from AD.
Max ERC Funding
2 404 800 €
Duration
Start date: 2013-05-01, End date: 2018-04-30
Project acronym IPLASTICITY
Project Induction of juvenile-like plasticity in the adult brain
Researcher (PI) Eero Castrén
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary Neuronal networks are tuned to optimally represent external and internal milieu through neuronal plasticity during critical periods of juvenile life. After the closure of the critical periods, plasticity is considered to be much more limited. In a series of landmark studies, we have shown that critical period-like plasticity can be reactivated in the adult mammalian brain by pharmacological treatment with the antidepressant fluoxetine. These ground-breaking studies establish a new principle, induced juvenile-like plasticity (iPlasticity) and define a new class of drugs, iPlastic drugs. For optimal results, iPlastic drug must be combined with physical or psychological rehabilitation, which guide the plastic networks and together allow better adaptation towards changing environment. iPlasticity may facilitate functional recovery after brain injury and underlie the enhanced efficacy of combined antidepressant treatment and psychotherapy.
We have uncovered iPlasticity as an exciting new concept and established experimental models to study the molecular, cellular and network level mechanisms underlying it. We will here focus on the role of neurotrophin BDNF, because our previous and unpublished work clearly shows that BDNF and its receptors TrkB and p75 are essential and sufficient for iPlasticity. We have found that a major developmental reorganization in TrkB signalling takes place coinciding with the end of critical periods, and its reversal may underlie iPlasticity. We will utilize our resources as a leading lab in BDNF effects in adult brain and through novel controlled transgenic models, genomics and proteomics, we will reveal the role of BDNF signalling through TrkB and p75 in brain maturation, iPlasticity and brain disorders. Understanding the neurobiological background of iPlasticity will be vital for iPlastic drug development and the numerous translational applications of iPlasticity clearly in sight.
Summary
Neuronal networks are tuned to optimally represent external and internal milieu through neuronal plasticity during critical periods of juvenile life. After the closure of the critical periods, plasticity is considered to be much more limited. In a series of landmark studies, we have shown that critical period-like plasticity can be reactivated in the adult mammalian brain by pharmacological treatment with the antidepressant fluoxetine. These ground-breaking studies establish a new principle, induced juvenile-like plasticity (iPlasticity) and define a new class of drugs, iPlastic drugs. For optimal results, iPlastic drug must be combined with physical or psychological rehabilitation, which guide the plastic networks and together allow better adaptation towards changing environment. iPlasticity may facilitate functional recovery after brain injury and underlie the enhanced efficacy of combined antidepressant treatment and psychotherapy.
We have uncovered iPlasticity as an exciting new concept and established experimental models to study the molecular, cellular and network level mechanisms underlying it. We will here focus on the role of neurotrophin BDNF, because our previous and unpublished work clearly shows that BDNF and its receptors TrkB and p75 are essential and sufficient for iPlasticity. We have found that a major developmental reorganization in TrkB signalling takes place coinciding with the end of critical periods, and its reversal may underlie iPlasticity. We will utilize our resources as a leading lab in BDNF effects in adult brain and through novel controlled transgenic models, genomics and proteomics, we will reveal the role of BDNF signalling through TrkB and p75 in brain maturation, iPlasticity and brain disorders. Understanding the neurobiological background of iPlasticity will be vital for iPlastic drug development and the numerous translational applications of iPlasticity clearly in sight.
Max ERC Funding
2 500 000 €
Duration
Start date: 2013-04-01, End date: 2018-03-31
Project acronym LIPSYD
Project Lipid Signaling at the Glutamatergic Synapse: Involvement in Brain Network Function and Psychiatric Disorders
Researcher (PI) Robert Nitsch
Host Institution (HI) UNIVERSITAETSMEDIZIN DER JOHANNES GUTENBERG-UNIVERSITAET MAINZ
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary We have recently reported on a novel mode of modulation of neuronal transmission at the glutamatergic junction. This signaling pathway involves lysophosphatidic acid (LPA) acting via presynaptic LPA2 receptors. This is in turn controlled by a molecule which we named plasticity related gene-1 (PRG-1, Bräuer et al., Nat Neurosci 2003) from the postsynaptic side (Trimbuch et al., Cell 2009). PRG-1 is a brain-specific membrane protein related to lipid phosphate phosphatases (LPPs) with a selective expression in neurons (Geist et al., CMLS 2011). We detected an important role of LPA-synthesizing pathways in bioactive signaling at the synapse acting via ATX and etablished nano-particles as LPA-biosensor using the characteristic spectral shift allowing detection in 2-photon imaging. We provide insights into the oligomeric assembly of PRG-1 in the membrane and assessed LPA-binding, uptake and intracellular interaction partners of the molecule. Animals lacking one PRG-1 allele exhibit a broad spectrum of behavioral pathology indicative of altered brain network function and psychiatric disorders. These changes are already present in animals lacking only 50% of PRG-1. A point mutation at R345T which appears to result in loss-of-function when re-expressed in the mouse was found in 5925 healthy individuals with a heterozygous frequency of approximately 0.86% (about 4.500.000 European citizens). Individuals carrying this loss-of-function mutation revealed functional alterations of sensory gating involved in psychiatric disorders. We plan to continue our studies on (1) synthesis and action of LPA, (2) molecular function of PRG-1 in bioactive lipid signaling, and (3) the role of PRG-1 signaling in brain network function and psychiatric disorders. Characterization of the molecular basis of this novel modulatory signaling pathway and its role in brain network function will be important for our understanding of its role in health and disease.
Summary
We have recently reported on a novel mode of modulation of neuronal transmission at the glutamatergic junction. This signaling pathway involves lysophosphatidic acid (LPA) acting via presynaptic LPA2 receptors. This is in turn controlled by a molecule which we named plasticity related gene-1 (PRG-1, Bräuer et al., Nat Neurosci 2003) from the postsynaptic side (Trimbuch et al., Cell 2009). PRG-1 is a brain-specific membrane protein related to lipid phosphate phosphatases (LPPs) with a selective expression in neurons (Geist et al., CMLS 2011). We detected an important role of LPA-synthesizing pathways in bioactive signaling at the synapse acting via ATX and etablished nano-particles as LPA-biosensor using the characteristic spectral shift allowing detection in 2-photon imaging. We provide insights into the oligomeric assembly of PRG-1 in the membrane and assessed LPA-binding, uptake and intracellular interaction partners of the molecule. Animals lacking one PRG-1 allele exhibit a broad spectrum of behavioral pathology indicative of altered brain network function and psychiatric disorders. These changes are already present in animals lacking only 50% of PRG-1. A point mutation at R345T which appears to result in loss-of-function when re-expressed in the mouse was found in 5925 healthy individuals with a heterozygous frequency of approximately 0.86% (about 4.500.000 European citizens). Individuals carrying this loss-of-function mutation revealed functional alterations of sensory gating involved in psychiatric disorders. We plan to continue our studies on (1) synthesis and action of LPA, (2) molecular function of PRG-1 in bioactive lipid signaling, and (3) the role of PRG-1 signaling in brain network function and psychiatric disorders. Characterization of the molecular basis of this novel modulatory signaling pathway and its role in brain network function will be important for our understanding of its role in health and disease.
Max ERC Funding
2 499 390 €
Duration
Start date: 2013-04-01, End date: 2018-03-31
Project acronym MU TUNING
Project Fine Tuning the Final Common Pathway: Molecular Determinants of Motor Unit Development and Plasticity
Researcher (PI) Till Marquardt
Host Institution (HI) UNIVERSITAETSKLINIKUM AACHEN
Call Details Starting Grant (StG), LS5, ERC-2012-StG_20111109
Summary Motor neurons (MNs) constitute the final common pathway in the generation of behaviors by linking the CNS with the movement apparatus. Herein, MNs diversify into fast, intermediate and slow types whose properties are tuned to the speed, force and endurance of the muscle fiber contractions they elicit. The MN-muscle fiber units display marked plasticity towards chronically altered physical activity, and show strong differences in their vulnerability towards degenerative conditions affecting the neuromuscular system, including amyotrophic lateral sclerosis and aging. Despite their central importance for determining neuromuscular output, plasticity and vulnerability the molecular mechanisms determining the functional MN types remain unknown. My group will use a cross-disciplinary approach by employing molecular genetic, cell biological, electrophysiological and motor behavior assays in mouse and chick to dissect molecular pathways determining MN type status and their contribution to neuromuscular system function and plasticity. Based on our preliminary data, this will focus on the contribution of non-canonical Notch signaling to MN type-specification and neuromuscular function, in addition to four newly identified neural activity modulators as candidate effectors of motor unit output and plasticity. This will be complemented by screening additional pathway components for roles in determining MN type properties through newly developed rapid gene tagging and electrophysiological interrogation in chick, followed by addressing their requirement for motor unit specification and function in mouse. Through an iterative cycle of (i) investigating candidate determinants of motor unit type, (ii) defining their role and mode of action in motor unit specification and function in the context of the neuromuscular system, and (iii) identifying essential downstream components, the proposal will explore molecular pathways operating in motor unit specification, function and plasticity.
Summary
Motor neurons (MNs) constitute the final common pathway in the generation of behaviors by linking the CNS with the movement apparatus. Herein, MNs diversify into fast, intermediate and slow types whose properties are tuned to the speed, force and endurance of the muscle fiber contractions they elicit. The MN-muscle fiber units display marked plasticity towards chronically altered physical activity, and show strong differences in their vulnerability towards degenerative conditions affecting the neuromuscular system, including amyotrophic lateral sclerosis and aging. Despite their central importance for determining neuromuscular output, plasticity and vulnerability the molecular mechanisms determining the functional MN types remain unknown. My group will use a cross-disciplinary approach by employing molecular genetic, cell biological, electrophysiological and motor behavior assays in mouse and chick to dissect molecular pathways determining MN type status and their contribution to neuromuscular system function and plasticity. Based on our preliminary data, this will focus on the contribution of non-canonical Notch signaling to MN type-specification and neuromuscular function, in addition to four newly identified neural activity modulators as candidate effectors of motor unit output and plasticity. This will be complemented by screening additional pathway components for roles in determining MN type properties through newly developed rapid gene tagging and electrophysiological interrogation in chick, followed by addressing their requirement for motor unit specification and function in mouse. Through an iterative cycle of (i) investigating candidate determinants of motor unit type, (ii) defining their role and mode of action in motor unit specification and function in the context of the neuromuscular system, and (iii) identifying essential downstream components, the proposal will explore molecular pathways operating in motor unit specification, function and plasticity.
Max ERC Funding
1 456 807 €
Duration
Start date: 2012-11-01, End date: 2017-10-31
