Project acronym ADDICTIONCIRCUITS
Project Drug addiction: molecular changes in reward and aversion circuits
Researcher (PI) Nils David Engblom
Host Institution (HI) LINKOPINGS UNIVERSITET
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary Our affective and motivational state is important for our decisions, actions and quality of life. Many pathological conditions affect this state. For example, addictive drugs are hyperactivating the reward system and trigger a strong motivation for continued drug intake, whereas many somatic and psychiatric diseases lead to an aversive state, characterized by loss of motivation. I will study specific neural circuits and mechanisms underlying reward and aversion, and how pathological signaling in these systems can trigger relapse in drug addiction.
Given the important role of the dopaminergic neurons in the midbrain for many aspects of reward signaling, I will study how synaptic plasticity in these cells, and in their target neurons in the striatum, contribute to relapse in drug seeking. I will also study the circuits underlying aversion. Little is known about these circuits, but my hypothesis is that an important component of aversion is signaled by a specific neuronal population in the brainstem parabrachial nucleus, projecting to the central amygdala. We will test this hypothesis and also determine how this aversion circuit contributes to the persistence of addiction and to relapse.
To dissect this complicated system, I am developing new genetic methods for manipulating and visualizing specific functional circuits in the mouse brain. My unique combination of state-of-the-art competence in transgenics and cutting edge knowledge in the anatomy and functional organization of the circuits behind reward and aversion should allow me to decode these systems, linking discrete circuits to behavior.
Collectively, the results will indicate how signals encoding aversion and reward are integrated to control addictive behavior and they may identify novel avenues for treatment of drug addiction as well as aversion-related symptoms affecting patients with chronic inflammatory conditions and cancer.
Summary
Our affective and motivational state is important for our decisions, actions and quality of life. Many pathological conditions affect this state. For example, addictive drugs are hyperactivating the reward system and trigger a strong motivation for continued drug intake, whereas many somatic and psychiatric diseases lead to an aversive state, characterized by loss of motivation. I will study specific neural circuits and mechanisms underlying reward and aversion, and how pathological signaling in these systems can trigger relapse in drug addiction.
Given the important role of the dopaminergic neurons in the midbrain for many aspects of reward signaling, I will study how synaptic plasticity in these cells, and in their target neurons in the striatum, contribute to relapse in drug seeking. I will also study the circuits underlying aversion. Little is known about these circuits, but my hypothesis is that an important component of aversion is signaled by a specific neuronal population in the brainstem parabrachial nucleus, projecting to the central amygdala. We will test this hypothesis and also determine how this aversion circuit contributes to the persistence of addiction and to relapse.
To dissect this complicated system, I am developing new genetic methods for manipulating and visualizing specific functional circuits in the mouse brain. My unique combination of state-of-the-art competence in transgenics and cutting edge knowledge in the anatomy and functional organization of the circuits behind reward and aversion should allow me to decode these systems, linking discrete circuits to behavior.
Collectively, the results will indicate how signals encoding aversion and reward are integrated to control addictive behavior and they may identify novel avenues for treatment of drug addiction as well as aversion-related symptoms affecting patients with chronic inflammatory conditions and cancer.
Max ERC Funding
1 500 000 €
Duration
Start date: 2010-10-01, End date: 2015-09-30
Project acronym BrainInBrain
Project Neural circuits underlying complex brain function across animals - from conserved core concepts to specializations defining a species’ identity
Researcher (PI) Stanley HEINZE
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary The core function of all brains is to compute the current state of the world, compare it to the desired state of the world and select motor programs that drive behavior minimizing any mismatch. The circuits underlying these functions are the key to understand brains in general, but so far they are completely unknown. Three problems have hindered progress: 1) The animal’s desired state of the world is rarely known. 2) Most studies in simple models have focused on sensory driven, reflex-like processes, and not considered self-initiated behavior. 3) The circuits underlying complex behaviors in vertebrates are widely distributed, containing millions of neurons. With this proposal I aim at overcoming these problems using insects, whose tiny brains solve the same basic problems as our brains but with 100,000 times fewer cells. Moreover, the central complex, a single conserved brain region consisting of only a few thousand neurons, is crucial for sensory integration, motor control and state-dependent modulation, essentially being a ‘brain in the brain’. To simplify the problem further I will focus on navigation behavior. Here, the desired and actual states of the world are equal to the desired and current headings of the animal, with mismatches resulting in compensatory steering. I have previously shown how the central complex encodes the animal’s current heading. Now I will use behavioral training to generate animals with highly defined desired headings, and correlate neural activity with the animal’s ‘intentions’ and actions - at the level of identified neurons. To establish the involved conserved core circuitry valid across insects I will compare species with distinct lifestyles. Secondly, I will reveal how these circuits have evolved to account for each species’ unique ecology. The proposed work will provide a coherent framework to study key concepts of fundamental brain functions in unprecedented detail - using a single, conserved, but flexible neural circuit.
Summary
The core function of all brains is to compute the current state of the world, compare it to the desired state of the world and select motor programs that drive behavior minimizing any mismatch. The circuits underlying these functions are the key to understand brains in general, but so far they are completely unknown. Three problems have hindered progress: 1) The animal’s desired state of the world is rarely known. 2) Most studies in simple models have focused on sensory driven, reflex-like processes, and not considered self-initiated behavior. 3) The circuits underlying complex behaviors in vertebrates are widely distributed, containing millions of neurons. With this proposal I aim at overcoming these problems using insects, whose tiny brains solve the same basic problems as our brains but with 100,000 times fewer cells. Moreover, the central complex, a single conserved brain region consisting of only a few thousand neurons, is crucial for sensory integration, motor control and state-dependent modulation, essentially being a ‘brain in the brain’. To simplify the problem further I will focus on navigation behavior. Here, the desired and actual states of the world are equal to the desired and current headings of the animal, with mismatches resulting in compensatory steering. I have previously shown how the central complex encodes the animal’s current heading. Now I will use behavioral training to generate animals with highly defined desired headings, and correlate neural activity with the animal’s ‘intentions’ and actions - at the level of identified neurons. To establish the involved conserved core circuitry valid across insects I will compare species with distinct lifestyles. Secondly, I will reveal how these circuits have evolved to account for each species’ unique ecology. The proposed work will provide a coherent framework to study key concepts of fundamental brain functions in unprecedented detail - using a single, conserved, but flexible neural circuit.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym COGOPTO
Project The role of parvalbumin interneurons in cognition and behavior
Researcher (PI) Eva Marie Carlen
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary Cognition is a collective term for complex but sophisticated mental processes such as attention, learning, social interaction, language production, decision making and other executive functions. For normal brain function, these higher-order functions need to be aptly regulated and controlled, and the physiology and cellular substrates for cognitive functions are under intense investigation. The loss of cognitive control is intricately related to pathological states such as schizophrenia, depression, attention deficit hyperactive disorder and addiction.
Synchronized neural activity can be observed when the brain performs several important functions, including cognitive processes. As an example, gamma activity (30-80 Hz) predicts the allocation of attention and theta activity (4-12 Hz) is tightly linked to memory processes. A large body of work indicates that the integrity of local and global neural synchrony is mediated by interneuron networks and actuated by the balance of different neuromodulators.
However, much knowledge is still needed on the functional role interneurons play in cognitive processes, i.e. how the interneurons contribute to local and global network processes subserving cognition, and ultimately play a role in behavior. In addition, we need to understand how neuro-modulators, such as dopamine, regulate interneuron function.
The proposed project aims to functionally determine the specific role the parvalbumin interneurons and the neuromodulator dopamine in aspects of cognition, and in behavior. In addition, we ask the question if cognition can be enhanced.
We are employing a true multidisciplinary approach where brain activity is recorded in conjunctions with optogenetic manipulations of parvalbumin interneurons in animals performing cognitive tasks. In one set of experiments knock-down of dopamine receptors specifically in parvalbumin interneurons is employed to probe how this neuromodulator regulate network functions.
Summary
Cognition is a collective term for complex but sophisticated mental processes such as attention, learning, social interaction, language production, decision making and other executive functions. For normal brain function, these higher-order functions need to be aptly regulated and controlled, and the physiology and cellular substrates for cognitive functions are under intense investigation. The loss of cognitive control is intricately related to pathological states such as schizophrenia, depression, attention deficit hyperactive disorder and addiction.
Synchronized neural activity can be observed when the brain performs several important functions, including cognitive processes. As an example, gamma activity (30-80 Hz) predicts the allocation of attention and theta activity (4-12 Hz) is tightly linked to memory processes. A large body of work indicates that the integrity of local and global neural synchrony is mediated by interneuron networks and actuated by the balance of different neuromodulators.
However, much knowledge is still needed on the functional role interneurons play in cognitive processes, i.e. how the interneurons contribute to local and global network processes subserving cognition, and ultimately play a role in behavior. In addition, we need to understand how neuro-modulators, such as dopamine, regulate interneuron function.
The proposed project aims to functionally determine the specific role the parvalbumin interneurons and the neuromodulator dopamine in aspects of cognition, and in behavior. In addition, we ask the question if cognition can be enhanced.
We are employing a true multidisciplinary approach where brain activity is recorded in conjunctions with optogenetic manipulations of parvalbumin interneurons in animals performing cognitive tasks. In one set of experiments knock-down of dopamine receptors specifically in parvalbumin interneurons is employed to probe how this neuromodulator regulate network functions.
Max ERC Funding
1 400 000 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym ENDOSWITCH
Project Network Principles of Neuroendocrine Control:
Tuberoinfundibular Dopamine (TIDA) Oscillations and the Regulation of Lactation
Researcher (PI) Carl Christian Broberger
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary The hypothalamus is essential for our survival and orchestrates every vital function of the body, from defence against predators and energy metabolism to reproduction. Yet, the network mechanisms underlying these actions remain largely hidden in a black box . Here, we will focus on the hypothalamic neuroendocrine system, where we have identified a novel robust network oscillation in the tuberoinfundibular dopamine (TIDA) neurons that control prolactin release. This oscillation is synchronized between neurons via gap junctions, and phasic firing is transformed into tonic discharge by compounds that functionally oppose neuroendocrine dopamine actions. Using this novel preparation, we will investigate the 1) the cellular (conductance) and network (connectivity) mechanisms underlying TIDA rhythmicity; 2) how TIDA activity is affected by hormones and transmitters that affect lactation; 3) the functional significance of phasic vs. tonic discharge in the regulation of dopamine release and lactation; and 4) the generality of TIDA cellular and network properties to other parvocellular neuron populations. These questions will be addressed through several in vitro and in vivo electrophysiological techniques, including slice whole-cell recording, extracellular in vivo recording, voltammetry and optical recording. These experiments will provide novel insight into the link between network interactions and behaviour, and have important clinical implications for e.g. endocrine and reproductive disorders.
Summary
The hypothalamus is essential for our survival and orchestrates every vital function of the body, from defence against predators and energy metabolism to reproduction. Yet, the network mechanisms underlying these actions remain largely hidden in a black box . Here, we will focus on the hypothalamic neuroendocrine system, where we have identified a novel robust network oscillation in the tuberoinfundibular dopamine (TIDA) neurons that control prolactin release. This oscillation is synchronized between neurons via gap junctions, and phasic firing is transformed into tonic discharge by compounds that functionally oppose neuroendocrine dopamine actions. Using this novel preparation, we will investigate the 1) the cellular (conductance) and network (connectivity) mechanisms underlying TIDA rhythmicity; 2) how TIDA activity is affected by hormones and transmitters that affect lactation; 3) the functional significance of phasic vs. tonic discharge in the regulation of dopamine release and lactation; and 4) the generality of TIDA cellular and network properties to other parvocellular neuron populations. These questions will be addressed through several in vitro and in vivo electrophysiological techniques, including slice whole-cell recording, extracellular in vivo recording, voltammetry and optical recording. These experiments will provide novel insight into the link between network interactions and behaviour, and have important clinical implications for e.g. endocrine and reproductive disorders.
Max ERC Funding
1 493 958 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
Project acronym IN-BRAIN
Project IN VIVO REPROGRAMMING: A NOVEL ROUTE TO BRAIN REPAIR
Researcher (PI) Malin Parmar
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), LS5, ERC-2012-StG_20111109
Summary Recent progress on direct re-programming into functional neurons provides a new approach towards cell-based therapy for neurodegenerative disorders. The induced neurons (iNs) are a novel type of cell resulting from rapid and remarkable conversion of somatic cells into subtype-specific functional neurons. Importantly they are non-proliferating which make them interesting alternatives to induced pluripotent (iPS) cells as sources of patient specific neurons for exogenous cell replacement therapy and disease modeling.
Another major advantage with direct conversion over iPS cells is that the reprogramming could be performed in vivo. While direct conversion has been successful in organs such as the pancreas, where exocrine cells can be directly converted into insulin producing cells by viral injections in vivo (Zhou et al., Nature, 2008), the method is yet to be explored in the brain. Once direct conversion of non-neuronal cells into subtype specific neurons directly in the brain is established, it provides a new strategy for cell based brain repair that do not depend on exogenous cells.
The overall goal of this project is to provide proof-of-principle that induced neurogenesis is achievable in the adult brain through guided transcription factor reprogramming of non-neuronal cells, to determine which cells are best suited as cellular substrate for in vivo neural conversion, and to compare this approach with transplantation of converted fibroblasts.
The ability to directly reprogram cell fate using defined combinations of transcription factors have already turned basic studies of stem cell differentiation and cell therapy into a new direction. Establishing this technique in vivo would be another paradigm-shifting finding that opens up for novel strategies for brain repair
Summary
Recent progress on direct re-programming into functional neurons provides a new approach towards cell-based therapy for neurodegenerative disorders. The induced neurons (iNs) are a novel type of cell resulting from rapid and remarkable conversion of somatic cells into subtype-specific functional neurons. Importantly they are non-proliferating which make them interesting alternatives to induced pluripotent (iPS) cells as sources of patient specific neurons for exogenous cell replacement therapy and disease modeling.
Another major advantage with direct conversion over iPS cells is that the reprogramming could be performed in vivo. While direct conversion has been successful in organs such as the pancreas, where exocrine cells can be directly converted into insulin producing cells by viral injections in vivo (Zhou et al., Nature, 2008), the method is yet to be explored in the brain. Once direct conversion of non-neuronal cells into subtype specific neurons directly in the brain is established, it provides a new strategy for cell based brain repair that do not depend on exogenous cells.
The overall goal of this project is to provide proof-of-principle that induced neurogenesis is achievable in the adult brain through guided transcription factor reprogramming of non-neuronal cells, to determine which cells are best suited as cellular substrate for in vivo neural conversion, and to compare this approach with transplantation of converted fibroblasts.
The ability to directly reprogram cell fate using defined combinations of transcription factors have already turned basic studies of stem cell differentiation and cell therapy into a new direction. Establishing this technique in vivo would be another paradigm-shifting finding that opens up for novel strategies for brain repair
Max ERC Funding
1 500 000 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym LocomotorIntegration
Project Functional connectome of brainstem circuits that control locomotion
Researcher (PI) Ole Kiehn
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS5, ERC-2015-AdG
Summary Locomotion is a complex motor act that is used in many daily life activities and is the output measures of a plethora of brain behaviors. The planning and initiation of locomotion take place in the brain and brainstem, while the execution is accomplished by activity in neuronal networks in the spinal cord itself. Recent experiments have provided significant insight to the organization of the executive spinal locomotor networks. However, little is known about the brainstem control of these networks. Here, I propose to provide a unified understanding of the functional connectome of the key brainstem networks that control locomotion in mammals needed to select appropriate locomotor outputs. To obtain these goals we will develop a suite of transgenic mouse models with optogenetic or chemogenetic switches in defined populations of brainstem neurons combined with the possibility to use state-of-the-art cell-specific electrophysiological and anatomical connectivity studies. We will reveal the functional organization of ‘go’ and ‘stop’ command systems in the brainstem that are directly upstream from the spinal locomotor networks and the mechanisms for how spinal networks are selected. We will further functionally deconstruct the next network layer in midbrain structures that control the ‘go’ and ‘stop’ command systems. Our research takes a specific approach to provide mechanistic insight to the integrated movement function by building the motor matrix in a functional chain from the locomotor–related spinal cord neurons that have been identified to midbrain neurons. A segment of our research will link these networks to locomotor impairments after basal ganglia dysfunction. The work has the potential to make a breakthrough in our understanding of how complex movements are generated by the brain and has translational implications for patients with movement disorders. It will push boundaries in the universal effort that aims to comprehend how brain networks create behaviors.
Summary
Locomotion is a complex motor act that is used in many daily life activities and is the output measures of a plethora of brain behaviors. The planning and initiation of locomotion take place in the brain and brainstem, while the execution is accomplished by activity in neuronal networks in the spinal cord itself. Recent experiments have provided significant insight to the organization of the executive spinal locomotor networks. However, little is known about the brainstem control of these networks. Here, I propose to provide a unified understanding of the functional connectome of the key brainstem networks that control locomotion in mammals needed to select appropriate locomotor outputs. To obtain these goals we will develop a suite of transgenic mouse models with optogenetic or chemogenetic switches in defined populations of brainstem neurons combined with the possibility to use state-of-the-art cell-specific electrophysiological and anatomical connectivity studies. We will reveal the functional organization of ‘go’ and ‘stop’ command systems in the brainstem that are directly upstream from the spinal locomotor networks and the mechanisms for how spinal networks are selected. We will further functionally deconstruct the next network layer in midbrain structures that control the ‘go’ and ‘stop’ command systems. Our research takes a specific approach to provide mechanistic insight to the integrated movement function by building the motor matrix in a functional chain from the locomotor–related spinal cord neurons that have been identified to midbrain neurons. A segment of our research will link these networks to locomotor impairments after basal ganglia dysfunction. The work has the potential to make a breakthrough in our understanding of how complex movements are generated by the brain and has translational implications for patients with movement disorders. It will push boundaries in the universal effort that aims to comprehend how brain networks create behaviors.
Max ERC Funding
2 500 000 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym MEMORYSTICK
Project Plasticity and formation of lasting memories in health and disease. Genetic modeling of key regulators in adult and aging mammals and in neurodegenerative disease
Researcher (PI) Lars Olson
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary When an adult mammal acquires new skills and new knowledge, the degree to which transition will occur from temporary to permanent memories of such events is governed by factors such as emotional weight and importance of the experiences for survival. To execute the necessary structural synaptic reorganisations needed to permanently embed novel memories in the brain, a complex and precisely orchestrated molecular machinery is activated. We have found that rapid down-regulation of Nogo receptor 1 (NgR1) is one key element needed to allow permanent memories to form. Thus, our MemoFlex mice, with inducible overexpression of NgR1 in forebrain neurons, are severely impaired with respect to the ability to form lasting memories. When transgenic NgR1 is turned off in these mice, the ability to form lasting memories is restored. Several other genes are also involved in the process of consolidation of memories, including prompt activity-driven upregulation of BDNF. Very recently, we have discovered that Lotus, a newly identified negative regulator of NgR1, is also upregulated by activity, thus providing additional efficacy to the process of causing nerve endings to become temporarily insensitive to Nogo when plasticity is needed. Based on our experience with neurotrophic factors and the Nogo signaling system, and using additional transgenic mouse models, including the mtDNA Mutator mouse with premature, yet typical aging, NgR1 KO mice and mice modeling neurodegenerative diseases (such as APPSwePSEN mice and our MitoPark mice to model aspects of Alzheimer’s and Parkinson’s disease, respectively) we will examine the formation of lasting normal and pathological (addiction, posttraumatic stress disorder) memories in adult and aging individuals with and without additional neurodegenerative genotypes known to include cognitive impariment. This research will further the understanding of mechanisms behind memory dysfunction and help the design of memory-improving stratetegies.
Summary
When an adult mammal acquires new skills and new knowledge, the degree to which transition will occur from temporary to permanent memories of such events is governed by factors such as emotional weight and importance of the experiences for survival. To execute the necessary structural synaptic reorganisations needed to permanently embed novel memories in the brain, a complex and precisely orchestrated molecular machinery is activated. We have found that rapid down-regulation of Nogo receptor 1 (NgR1) is one key element needed to allow permanent memories to form. Thus, our MemoFlex mice, with inducible overexpression of NgR1 in forebrain neurons, are severely impaired with respect to the ability to form lasting memories. When transgenic NgR1 is turned off in these mice, the ability to form lasting memories is restored. Several other genes are also involved in the process of consolidation of memories, including prompt activity-driven upregulation of BDNF. Very recently, we have discovered that Lotus, a newly identified negative regulator of NgR1, is also upregulated by activity, thus providing additional efficacy to the process of causing nerve endings to become temporarily insensitive to Nogo when plasticity is needed. Based on our experience with neurotrophic factors and the Nogo signaling system, and using additional transgenic mouse models, including the mtDNA Mutator mouse with premature, yet typical aging, NgR1 KO mice and mice modeling neurodegenerative diseases (such as APPSwePSEN mice and our MitoPark mice to model aspects of Alzheimer’s and Parkinson’s disease, respectively) we will examine the formation of lasting normal and pathological (addiction, posttraumatic stress disorder) memories in adult and aging individuals with and without additional neurodegenerative genotypes known to include cognitive impariment. This research will further the understanding of mechanisms behind memory dysfunction and help the design of memory-improving stratetegies.
Max ERC Funding
2 330 974 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym MoNaLISA
Project Long-term molecular nanoscale imaging of neuronal function
Researcher (PI) Ilaria Testa
Host Institution (HI) KUNGLIGA TEKNISKA HOEGSKOLAN
Call Details Starting Grant (StG), LS5, ERC-2014-STG
Summary Synaptic function is difficult to analyze in living neurons using conventional optics, since the synaptic organelles and protein clusters are small and tightly spaced. The solution to this problem can come from the field of super-resolution fluorescence microscopy, or nanoscopy. However, the current approaches to nanoscopy are still far from reaching this goal. Single molecule-based approaches (including STORM and PALM) provide high spatial resolution, but slow recording, insufficient for live imaging. Ensemble approaches (including SSIM and STED) are able to record faster, but with poorer resolution or with high, potentially toxic, laser powers. It is currently impossible to image the same neuron for hours and days, with both high spatial (~30 nm) and temporal (10-1000 Hz) resolution, and with minimal photodamage. My aim is to fill this gap, by developing, for the first time, a microscope that combines the advantages of both single molecule-based and ensemble approaches. I will base the microscope on RESOLFT, a low-photodamage ensemble approach that I have pioneered recently. I will use line patterns to speed up the recording and 2photon-switching for 3D ability. I will combine this with sensitive detection schemes that allow single-molecule detection and counting, relying on my previous expertise with PALM and GSDIM. The new set-up, termed molecular nanoscale long-term imaging with sequential acquisition (MoNaLISA), will track neuronal organelles and proteins on different time scales, spanning from milliseconds to days, with a resolution close to the molecular scale. To obtain the first proof-of-principle results, I will address several issues still open in the synaptic transmission field, relating to synaptic vesicle recycling, biogenesis and degradation. Overall, my project will introduce a novel paradigm to imaging in the life sciences, which will enable fast and quantitative nano-imaging of cells and tissues.
Summary
Synaptic function is difficult to analyze in living neurons using conventional optics, since the synaptic organelles and protein clusters are small and tightly spaced. The solution to this problem can come from the field of super-resolution fluorescence microscopy, or nanoscopy. However, the current approaches to nanoscopy are still far from reaching this goal. Single molecule-based approaches (including STORM and PALM) provide high spatial resolution, but slow recording, insufficient for live imaging. Ensemble approaches (including SSIM and STED) are able to record faster, but with poorer resolution or with high, potentially toxic, laser powers. It is currently impossible to image the same neuron for hours and days, with both high spatial (~30 nm) and temporal (10-1000 Hz) resolution, and with minimal photodamage. My aim is to fill this gap, by developing, for the first time, a microscope that combines the advantages of both single molecule-based and ensemble approaches. I will base the microscope on RESOLFT, a low-photodamage ensemble approach that I have pioneered recently. I will use line patterns to speed up the recording and 2photon-switching for 3D ability. I will combine this with sensitive detection schemes that allow single-molecule detection and counting, relying on my previous expertise with PALM and GSDIM. The new set-up, termed molecular nanoscale long-term imaging with sequential acquisition (MoNaLISA), will track neuronal organelles and proteins on different time scales, spanning from milliseconds to days, with a resolution close to the molecular scale. To obtain the first proof-of-principle results, I will address several issues still open in the synaptic transmission field, relating to synaptic vesicle recycling, biogenesis and degradation. Overall, my project will introduce a novel paradigm to imaging in the life sciences, which will enable fast and quantitative nano-imaging of cells and tissues.
Max ERC Funding
1 725 000 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym NEURAL RENEWAL
Project Neurogenesis in the adult human brain
Researcher (PI) Jonas Kristoffer Frisén
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary One of the characteristics of the central nervous system is its plasticity, with for example a remarkable capacity to store new information. It was for long time thought that there was very little plasticity in terms of exchanging cells and that we essentially were limited to the neurons we were born with. It is now well established that new neurons are added to certain regions of the adult brain in most mammals, although it has been very difficult to study in humans.
The proposed project aims to unveil the cell lineage producing new neurons in the adult human brain and to assess the extent of neurogenesis and how it may change in for example aging and neurological and psychiatric diseases. We propose to take advantage of the rapid development of sequencing technology to assess the origin and lineage of new cells in the human brain by phylogenetic fate mapping. This will be combined with the analysis of the turnover of neurons in the adult human brain by a retrospective birth dating methodology which we recently have developed based on the integration of nuclear bomb test derived 14C. This is a cross-disciplinary project that bridges from basic cell and molecular biology, latest generation DNA sequencing technology via clinical medicine and mathematical modeling to nuclear physics.
A possible role for alterations in adult neurogenesis in the etiology of both depression and schizophrenia has recently received much interest. However, the link between neurogenesis and psychiatric diseases is based on a series of indirect indications, mainly in experimental animals. It is pivotal to gain direct information on the relationship between neurogenesis and psychiatric and neurological diseases in humans.
Summary
One of the characteristics of the central nervous system is its plasticity, with for example a remarkable capacity to store new information. It was for long time thought that there was very little plasticity in terms of exchanging cells and that we essentially were limited to the neurons we were born with. It is now well established that new neurons are added to certain regions of the adult brain in most mammals, although it has been very difficult to study in humans.
The proposed project aims to unveil the cell lineage producing new neurons in the adult human brain and to assess the extent of neurogenesis and how it may change in for example aging and neurological and psychiatric diseases. We propose to take advantage of the rapid development of sequencing technology to assess the origin and lineage of new cells in the human brain by phylogenetic fate mapping. This will be combined with the analysis of the turnover of neurons in the adult human brain by a retrospective birth dating methodology which we recently have developed based on the integration of nuclear bomb test derived 14C. This is a cross-disciplinary project that bridges from basic cell and molecular biology, latest generation DNA sequencing technology via clinical medicine and mathematical modeling to nuclear physics.
A possible role for alterations in adult neurogenesis in the etiology of both depression and schizophrenia has recently received much interest. However, the link between neurogenesis and psychiatric diseases is based on a series of indirect indications, mainly in experimental animals. It is pivotal to gain direct information on the relationship between neurogenesis and psychiatric and neurological diseases in humans.
Max ERC Funding
2 491 235 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
Project acronym NEURONSINMOTION
Project Linking glutamatergic spinal cord and brainstem neuronal circuits to the control of locomotor behavior
Researcher (PI) Ole Kiehn
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary Locomotion is an essential motor act that for the most part is controlled by neuronal circuits in the spinal cord itself, called central pattern generators (CPGs), although their activity is turned on from centers in the brainstem. Understanding the operation of CPG circuits in mammals has been a significant challenge to neuroscientists over the last 50 years. The CPG for walking generates rhythm, as well as the precise patterns of muscular activity. The neural assembly that is directly involved in generating the locomotor rhythm is completely unknown. There is strong evidence from pharmacological and lesion studies showing that glutamatergic neurons are responsible for this function. Here, I propose to identify these key glutamatergic neuronal CPG circuits. As a first step we will use state-of-the-art RNA-sequencing to obtain the complete transcriptome of glutamatergic subpopulations in the ventral spinal cord of the mouse to define new postnatally expressed molecular markers. To link glutamatergic neuronal subpopulations to the locomotor behavior we will use transgenic mouse systems to incorporate light-activated switches in a cell specific way. These tools will provide a new basis for functional and network studies needed to understand the CPG operation. We also propose to use mouse models with optogenetic switches to provide a molecular identification of the glutamatergic locomotor command systems and their integration in the CPG. Our analysis will provide a unified characterization of the neuronal organization of the mammalian CPG and its immediate control from the brain. Understanding the locomotor CPG and its control in mammals is of outmost importance for improving rehabilitation of spinal cord injured patients and designing new repair strategies.
Summary
Locomotion is an essential motor act that for the most part is controlled by neuronal circuits in the spinal cord itself, called central pattern generators (CPGs), although their activity is turned on from centers in the brainstem. Understanding the operation of CPG circuits in mammals has been a significant challenge to neuroscientists over the last 50 years. The CPG for walking generates rhythm, as well as the precise patterns of muscular activity. The neural assembly that is directly involved in generating the locomotor rhythm is completely unknown. There is strong evidence from pharmacological and lesion studies showing that glutamatergic neurons are responsible for this function. Here, I propose to identify these key glutamatergic neuronal CPG circuits. As a first step we will use state-of-the-art RNA-sequencing to obtain the complete transcriptome of glutamatergic subpopulations in the ventral spinal cord of the mouse to define new postnatally expressed molecular markers. To link glutamatergic neuronal subpopulations to the locomotor behavior we will use transgenic mouse systems to incorporate light-activated switches in a cell specific way. These tools will provide a new basis for functional and network studies needed to understand the CPG operation. We also propose to use mouse models with optogenetic switches to provide a molecular identification of the glutamatergic locomotor command systems and their integration in the CPG. Our analysis will provide a unified characterization of the neuronal organization of the mammalian CPG and its immediate control from the brain. Understanding the locomotor CPG and its control in mammals is of outmost importance for improving rehabilitation of spinal cord injured patients and designing new repair strategies.
Max ERC Funding
2 500 000 €
Duration
Start date: 2011-08-01, End date: 2016-07-31
