Project acronym CIRCUITASSEMBLY
Project Development of functional organization of the visual circuits in mice
Researcher (PI) Keisuke Yonehara
Host Institution (HI) AARHUS UNIVERSITET
Call Details Starting Grant (StG), LS5, ERC-2014-STG
Summary The key organizing principles that characterize neuronal systems include asymmetric, parallel, and topographic connectivity of the neural circuits. The main aim of my research is to elucidate the key principles underlying functional development of neural circuits by focusing on those organizing principles. I choose mouse visual system as my model since it contains all of these principles and provides sophisticated genetic tools to label and manipulate individual circuit components. My research is based on the central hypothesis that the mechanisms of brain development cannot be fully understood without first identifying individual functional cell types in adults, and then understanding how the functions of these cell types become established, using cell-type-specific molecular and synaptic mechanisms in developing animals. Recently, I have identified several transgenic mouse lines in which specific cell types in a visual center, the superior colliculus, are labeled with Cre recombinase in both developing and adult animals. Here I will take advantage of these mouse lines to ask fundamental questions about the functional development of neural circuits. First, how are distinct sensory features processed by the parallel topographic neuronal pathways, and how do they contribute to behavior? Second, what are the molecular and synaptic mechanisms that underlie developmental circuit plasticity for forming parallel topographic neuronal maps in the brain? Third, what are the molecular mechanisms that set up spatially asymmetric circuit connectivity without the need for sensory experience? I predict that my insights into the developmental mechanism of asymmetric, parallel, and topographic connectivity and circuit plasticity will be instructive when studying other brain circuits which contain similar organizing principles.
Summary
The key organizing principles that characterize neuronal systems include asymmetric, parallel, and topographic connectivity of the neural circuits. The main aim of my research is to elucidate the key principles underlying functional development of neural circuits by focusing on those organizing principles. I choose mouse visual system as my model since it contains all of these principles and provides sophisticated genetic tools to label and manipulate individual circuit components. My research is based on the central hypothesis that the mechanisms of brain development cannot be fully understood without first identifying individual functional cell types in adults, and then understanding how the functions of these cell types become established, using cell-type-specific molecular and synaptic mechanisms in developing animals. Recently, I have identified several transgenic mouse lines in which specific cell types in a visual center, the superior colliculus, are labeled with Cre recombinase in both developing and adult animals. Here I will take advantage of these mouse lines to ask fundamental questions about the functional development of neural circuits. First, how are distinct sensory features processed by the parallel topographic neuronal pathways, and how do they contribute to behavior? Second, what are the molecular and synaptic mechanisms that underlie developmental circuit plasticity for forming parallel topographic neuronal maps in the brain? Third, what are the molecular mechanisms that set up spatially asymmetric circuit connectivity without the need for sensory experience? I predict that my insights into the developmental mechanism of asymmetric, parallel, and topographic connectivity and circuit plasticity will be instructive when studying other brain circuits which contain similar organizing principles.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym EIMS
Project "Early infectious, inflammatory and immune mechanisms in schizophrenia"
Researcher (PI) Preben Bo Mortensen
Host Institution (HI) AARHUS UNIVERSITET
Call Details Advanced Grant (AdG), LS5, ERC-2011-ADG_20110310
Summary "The ambitious goal of this proposal is to identify causal mechanisms in schizophrenia, a devastating disease affecting about 1 percent of the population worldwide, and for which there is no current prevention or cure.
If my team and I are successful, we will discover etiological factors that can be targets for preventive interventions on the general population level and in high-risk groups, as well as inform the development of novel treatments.
I will use a truly unique population-based set of registers and biobanks, based upon a total national Danish birth cohort of more that 1.6 million individuals, and apply a novel combination of epidemiological design and methods and molecular biological techniques to the study of early risk factors for schizophrenia: I propose to combine cohort, nested case-control and case-sibling designs in studies of this total national birth cohort with detailed biological assessment of genetic and environmental risk factors operating during fetal life and around birth, in combination with detailed longitudinal information about the life course of cases, controls and their relatives.
Together with my team, I will for the first time in a human population empirically test a range of novel and specific hypotheses, tied together by a common theoretical framework of inflammatory and immune mechanisms interacting with individual genetic vulnerability during fetal life. Specifically the focus will be on infectious agents, markers of inflammation, effects of maternal auto-antibodies, and interactions with maternal vitamin D as well as genes involved in apoptosis and other relevant pathways. All findings will be tested in independent replication samples from the same population and further validated by comparison to healthy sibling controls. Because my studies are performed in a total population birth cohort, we will be able to make risk prediction suitable for the identification of targets for preventive strategies."
Summary
"The ambitious goal of this proposal is to identify causal mechanisms in schizophrenia, a devastating disease affecting about 1 percent of the population worldwide, and for which there is no current prevention or cure.
If my team and I are successful, we will discover etiological factors that can be targets for preventive interventions on the general population level and in high-risk groups, as well as inform the development of novel treatments.
I will use a truly unique population-based set of registers and biobanks, based upon a total national Danish birth cohort of more that 1.6 million individuals, and apply a novel combination of epidemiological design and methods and molecular biological techniques to the study of early risk factors for schizophrenia: I propose to combine cohort, nested case-control and case-sibling designs in studies of this total national birth cohort with detailed biological assessment of genetic and environmental risk factors operating during fetal life and around birth, in combination with detailed longitudinal information about the life course of cases, controls and their relatives.
Together with my team, I will for the first time in a human population empirically test a range of novel and specific hypotheses, tied together by a common theoretical framework of inflammatory and immune mechanisms interacting with individual genetic vulnerability during fetal life. Specifically the focus will be on infectious agents, markers of inflammation, effects of maternal auto-antibodies, and interactions with maternal vitamin D as well as genes involved in apoptosis and other relevant pathways. All findings will be tested in independent replication samples from the same population and further validated by comparison to healthy sibling controls. Because my studies are performed in a total population birth cohort, we will be able to make risk prediction suitable for the identification of targets for preventive strategies."
Max ERC Funding
2 471 736 €
Duration
Start date: 2012-05-01, End date: 2017-04-30
Project acronym GlymphEye
Project The Ocular Glymphatic System
Researcher (PI) Maiken Nedergaard
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Advanced Grant (AdG), LS5, ERC-2016-ADG
Summary The glymphatic system is a highly organized brain-wide mechanism by which fluid wastes are removed from the brain that was recently described by my team. The glymphatic system clears 65% of amyloid-beta from the normal adult brain. A rapidly evolving literature has shown that the major neurodegenerative diseases of the eye, macular degeneration and glaucoma, may also result from the toxicity of uncleared protein wastes, including amyloid-beta. Yet the eye, like the brain, has no traditional lymphatic vessels. In this application, I propose that two of the most significant causes of human visual loss, macular degeneration and glaucoma – previously thought of as both intractable and unrelated – are instead mechanistically allied disorders that not only share a common causal pathway, but may both be therapeutically modified by targeting dysregulation of the glymphatic pathway. As such, this proposal seeks to link the biology of a fundamentally new pathway for both metabolic substrate and waste transport in the adult brain, to diseases of the eye that have long been resistant to either understanding or treatment.
The objectives: WP1: Define the cellular mechanisms that drive ocular glymphatic transport of Amyloid-beta using an ex vivo preparation of the optic nerve. WP2: Use magnetic resonance imaging (MRI) to establish the existence of ocular glymphatic transport in live animals. WP3: Determine whether the ocular glymphatic system, like the brain lymphatic system, is critically regulated by the sleep-wake cycle. WP4: Test the hypothesis that age-dependent macular degeneration is caused by a suppression of ocular glymphatic transport, with secondary accumulation of toxic protein products in and subjacent to the retinal pigment epithelium? WP5: Define the impact of increased intraocular pressure on glymphatic export of amyloid-beta, and test the hypothesis that the decrease in ocular glymphatic transport contributes to degeneration of retinal ganglion cells in glaucoma.
Summary
The glymphatic system is a highly organized brain-wide mechanism by which fluid wastes are removed from the brain that was recently described by my team. The glymphatic system clears 65% of amyloid-beta from the normal adult brain. A rapidly evolving literature has shown that the major neurodegenerative diseases of the eye, macular degeneration and glaucoma, may also result from the toxicity of uncleared protein wastes, including amyloid-beta. Yet the eye, like the brain, has no traditional lymphatic vessels. In this application, I propose that two of the most significant causes of human visual loss, macular degeneration and glaucoma – previously thought of as both intractable and unrelated – are instead mechanistically allied disorders that not only share a common causal pathway, but may both be therapeutically modified by targeting dysregulation of the glymphatic pathway. As such, this proposal seeks to link the biology of a fundamentally new pathway for both metabolic substrate and waste transport in the adult brain, to diseases of the eye that have long been resistant to either understanding or treatment.
The objectives: WP1: Define the cellular mechanisms that drive ocular glymphatic transport of Amyloid-beta using an ex vivo preparation of the optic nerve. WP2: Use magnetic resonance imaging (MRI) to establish the existence of ocular glymphatic transport in live animals. WP3: Determine whether the ocular glymphatic system, like the brain lymphatic system, is critically regulated by the sleep-wake cycle. WP4: Test the hypothesis that age-dependent macular degeneration is caused by a suppression of ocular glymphatic transport, with secondary accumulation of toxic protein products in and subjacent to the retinal pigment epithelium? WP5: Define the impact of increased intraocular pressure on glymphatic export of amyloid-beta, and test the hypothesis that the decrease in ocular glymphatic transport contributes to degeneration of retinal ganglion cells in glaucoma.
Max ERC Funding
2 176 250 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym STC
Project Synaptic Tagging and Capture: From Synapses to Behavior
Researcher (PI) Sayyed Mohammad Sadegh Nabavi
Host Institution (HI) AARHUS UNIVERSITET
Call Details Starting Grant (StG), LS5, ERC-2015-STG
Summary It is shown that long-term potentiation (LTP) is the cellular basis of memory formation. However, since all but small fraction of memories are forgotten, LTP has been further divided into early LTP (e-LTP), the mechanism by which short-term memories are formed, and a more stable late LTP (L-LTP), by which long-term memories are formed. Remarkably, it has been shown that an e-LTP can be stabilized if it is preceded or followed by heterosynaptic L-LTP.
According to Synaptic Tagging and Capture (STC) hypothesis, e-LTP is stabilized by capturing proteins that are made by L-LTP induction. The model proposes that this mechanism underlies the formation of late associative memory, where the stability of a memory is not only defined by the stimuli that induce the change but also by events happening before and after these stimuli. As such, the model explicitly predicts that a short-term memory can be stabilized by inducing heterosynaptic L-LTP.
In this grant, I will put this hypothesis into test. Specifically, I will test two explicit predictions of STC model: 1) A naturally formed short-term memory can be stabilized by induction of heterosynaptic L-LTP. 2) This stabilization is caused by the protein synthesis feature of L-LTP. To do this, using optogenetics, I will engineer a short-term memory in auditory fear circuit, in which an animal transiently associates a foot shock to a tone. Subsequently, I will examine if optogenetic delivery of L-LTP to the visual inputs converging on the same population of neurons in the amygdala will stabilize the short-term tone fear memory.
To be able to engineer natural memory by manipulating synaptic plasticity I will develop two systems: 1) A two-color optical activation system which permits selective manipulation of distinct neuronal populations with precise temporal and spatial resolution; 2) An inducible and activity-dependent expression system by which those neurons that are activated by a natural stimulus will be optically tagged.
Summary
It is shown that long-term potentiation (LTP) is the cellular basis of memory formation. However, since all but small fraction of memories are forgotten, LTP has been further divided into early LTP (e-LTP), the mechanism by which short-term memories are formed, and a more stable late LTP (L-LTP), by which long-term memories are formed. Remarkably, it has been shown that an e-LTP can be stabilized if it is preceded or followed by heterosynaptic L-LTP.
According to Synaptic Tagging and Capture (STC) hypothesis, e-LTP is stabilized by capturing proteins that are made by L-LTP induction. The model proposes that this mechanism underlies the formation of late associative memory, where the stability of a memory is not only defined by the stimuli that induce the change but also by events happening before and after these stimuli. As such, the model explicitly predicts that a short-term memory can be stabilized by inducing heterosynaptic L-LTP.
In this grant, I will put this hypothesis into test. Specifically, I will test two explicit predictions of STC model: 1) A naturally formed short-term memory can be stabilized by induction of heterosynaptic L-LTP. 2) This stabilization is caused by the protein synthesis feature of L-LTP. To do this, using optogenetics, I will engineer a short-term memory in auditory fear circuit, in which an animal transiently associates a foot shock to a tone. Subsequently, I will examine if optogenetic delivery of L-LTP to the visual inputs converging on the same population of neurons in the amygdala will stabilize the short-term tone fear memory.
To be able to engineer natural memory by manipulating synaptic plasticity I will develop two systems: 1) A two-color optical activation system which permits selective manipulation of distinct neuronal populations with precise temporal and spatial resolution; 2) An inducible and activity-dependent expression system by which those neurons that are activated by a natural stimulus will be optically tagged.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
