Project acronym CentSatRegFunc
Project Dissecting the function and regulation of centriolar satellites: key regulators of the centrosome/cilium complex
Researcher (PI) Elif Nur Firat Karalar
Host Institution (HI) KOC UNIVERSITY
Call Details Starting Grant (StG), LS3, ERC-2015-STG
Summary Centrosomes are the main microtubule-organizing centers of animal cells. They influence the morphology of the microtubule cytoskeleton and function as the base of primary cilium, a nexus for important signaling pathways. Structural and functional defects in centrosome/cilium complex cause a variety of human diseases including cancer, ciliopathies and microcephaly. To understand the relationship between human diseases and centrosome/cilium abnormalities, it is essential to elucidate the biogenesis of centrosome/cilium complex and the control mechanisms that regulate their structure and function. To tackle these fundamental problems, we will dissect the function and regulation of centriolar satellites, the array of granules that localize around the centrosome/cilium complex in mammalian cells. Only recently interest in the satellites has grown because mutations affecting satellite components were shown to cause ciliopathies, microcephaly and schizophrenia.
Remarkably, many centrosome/cilium proteins localize to these structures and we lack understanding of when, why and how these proteins localize to satellites. The central hypothesis of this grant is that satellites ensure proper centrosome/cilium complex structure and function by acting as transit paths for modification, assembly, storage, stability and trafficking of centrosome/cilium proteins. In Aim 1, we will identify the nature of regulatory and molecular relationship between satellites and the centrosome/cilium complex. In Aim 2, we will elucidate the role of satellites in proteostasis of centrosome/cilium proteins. In Aim 3, we will investigate the functional significance of satellite-localization of centrosome/cilium proteins during processes that go awry in human disease. Using a multidisciplinary approach, the proposed research will expand our knowledge of the spatiotemporal regulation of the centrosome/cilium complex and provide new insights into pathogenesis of ciliopathies and primary microcephaly.
Summary
Centrosomes are the main microtubule-organizing centers of animal cells. They influence the morphology of the microtubule cytoskeleton and function as the base of primary cilium, a nexus for important signaling pathways. Structural and functional defects in centrosome/cilium complex cause a variety of human diseases including cancer, ciliopathies and microcephaly. To understand the relationship between human diseases and centrosome/cilium abnormalities, it is essential to elucidate the biogenesis of centrosome/cilium complex and the control mechanisms that regulate their structure and function. To tackle these fundamental problems, we will dissect the function and regulation of centriolar satellites, the array of granules that localize around the centrosome/cilium complex in mammalian cells. Only recently interest in the satellites has grown because mutations affecting satellite components were shown to cause ciliopathies, microcephaly and schizophrenia.
Remarkably, many centrosome/cilium proteins localize to these structures and we lack understanding of when, why and how these proteins localize to satellites. The central hypothesis of this grant is that satellites ensure proper centrosome/cilium complex structure and function by acting as transit paths for modification, assembly, storage, stability and trafficking of centrosome/cilium proteins. In Aim 1, we will identify the nature of regulatory and molecular relationship between satellites and the centrosome/cilium complex. In Aim 2, we will elucidate the role of satellites in proteostasis of centrosome/cilium proteins. In Aim 3, we will investigate the functional significance of satellite-localization of centrosome/cilium proteins during processes that go awry in human disease. Using a multidisciplinary approach, the proposed research will expand our knowledge of the spatiotemporal regulation of the centrosome/cilium complex and provide new insights into pathogenesis of ciliopathies and primary microcephaly.
Max ERC Funding
1 499 819 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym Human Decisions
Project The Neural Determinants of Perceptual Decision Making in the Human Brain
Researcher (PI) Redmond O'connell
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Call Details Starting Grant (StG), LS5, ERC-2014-STG
Summary How do we make reliable decisions given sensory information that is often weak or ambiguous? Current theories center on a brain mechanism whereby sensory evidence is integrated over time into a “decision variable” which triggers the appropriate action upon reaching a criterion. Neural signals fitting this role have been identified in monkey electrophysiology but efforts to study the neural dynamics underpinning human decision making have been hampered by technical challenges associated with non-invasive recording. This proposal builds on a recent paradigm breakthrough made by the applicant that enables parallel tracking of discrete neural signals that can be unambiguously linked to the three key information processing stages necessary for simple perceptual decisions: sensory encoding, decision formation and motor preparation. Chief among these is a freely-evolving decision variable signal which builds at an evidence-dependent rate up to an action-triggering threshold and precisely determines the timing and accuracy of perceptual reports at the single-trial level. This provides an unprecedented neurophysiological window onto the distinct parameters of the human decision process such that the underlying mechanisms of several major behavioral phenomena can finally be investigated. This proposal seeks to develop a systems-level understanding of perceptual decision making in the human brain by tackling three core questions: 1) what are the neural adaptations that allow us to deal with speed pressure and variations in the reliability of the physically presented evidence? 2) What neural mechanism determines our subjective confidence in a decision? and 3) How does aging impact on the distinct neural components underpinning perceptual decision making? Each of the experiments described in this proposal will definitively test key predictions from prominent theoretical models using a combination of temporally precise neurophysiological measurement and psychophysical modelling.
Summary
How do we make reliable decisions given sensory information that is often weak or ambiguous? Current theories center on a brain mechanism whereby sensory evidence is integrated over time into a “decision variable” which triggers the appropriate action upon reaching a criterion. Neural signals fitting this role have been identified in monkey electrophysiology but efforts to study the neural dynamics underpinning human decision making have been hampered by technical challenges associated with non-invasive recording. This proposal builds on a recent paradigm breakthrough made by the applicant that enables parallel tracking of discrete neural signals that can be unambiguously linked to the three key information processing stages necessary for simple perceptual decisions: sensory encoding, decision formation and motor preparation. Chief among these is a freely-evolving decision variable signal which builds at an evidence-dependent rate up to an action-triggering threshold and precisely determines the timing and accuracy of perceptual reports at the single-trial level. This provides an unprecedented neurophysiological window onto the distinct parameters of the human decision process such that the underlying mechanisms of several major behavioral phenomena can finally be investigated. This proposal seeks to develop a systems-level understanding of perceptual decision making in the human brain by tackling three core questions: 1) what are the neural adaptations that allow us to deal with speed pressure and variations in the reliability of the physically presented evidence? 2) What neural mechanism determines our subjective confidence in a decision? and 3) How does aging impact on the distinct neural components underpinning perceptual decision making? Each of the experiments described in this proposal will definitively test key predictions from prominent theoretical models using a combination of temporally precise neurophysiological measurement and psychophysical modelling.
Max ERC Funding
1 382 643 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym MEME
Project Memory Engram Maintenance and Expression
Researcher (PI) Tomas RYAN
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary The goal of this project is to understand how specific memory engrams are physically stored in the brain. Connectionist theories of memory storage have guided research into the neuroscience of memory for over a half century, but have received little direct proof due to experimental limitations. The major confound that has limited direct testing of such theories has been an inability to identify the cells and circuits that store specific memories. Memory engram technology, which allows the tagging and in vivo manipulation of specific engram cells, has recently allowed us to overcome this empirical limitation and has revolutionised the way memory can be studied in rodent models. Based on our research it is now known that sparse populations of hippocampal neurons that were active during a defined learning experience are both sufficient and necessary for retrieval of specific contextual memories. More recently we have established that hippocampal engram cells preferentially synapse directly onto postsynaptic engram cells. This “engram cell connectivity” could provide the neurobiological substrate for the storage of multimodal memories through a distributed engram circuit. However it is currently unknown whether engram cell connectivity itself is important for memory function. The proposed integrative neuroscience project will employ inter-disciplinary methods to directly probe the importance of engram cell connectivity for memory retrieval, storage, and encoding. The outcomes will directly inform a novel and comprehensive neurobiological model of memory engram storage.
Summary
The goal of this project is to understand how specific memory engrams are physically stored in the brain. Connectionist theories of memory storage have guided research into the neuroscience of memory for over a half century, but have received little direct proof due to experimental limitations. The major confound that has limited direct testing of such theories has been an inability to identify the cells and circuits that store specific memories. Memory engram technology, which allows the tagging and in vivo manipulation of specific engram cells, has recently allowed us to overcome this empirical limitation and has revolutionised the way memory can be studied in rodent models. Based on our research it is now known that sparse populations of hippocampal neurons that were active during a defined learning experience are both sufficient and necessary for retrieval of specific contextual memories. More recently we have established that hippocampal engram cells preferentially synapse directly onto postsynaptic engram cells. This “engram cell connectivity” could provide the neurobiological substrate for the storage of multimodal memories through a distributed engram circuit. However it is currently unknown whether engram cell connectivity itself is important for memory function. The proposed integrative neuroscience project will employ inter-disciplinary methods to directly probe the importance of engram cell connectivity for memory retrieval, storage, and encoding. The outcomes will directly inform a novel and comprehensive neurobiological model of memory engram storage.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-02-01, End date: 2022-01-31
Project acronym RLPHARMFMRI
Project Beyond dopamine: Characterizing the computational functions of midbrain modulatory neurotransmitter systems in human reinforcement learning using model-based pharmacological fMRI
Researcher (PI) John O'doherty
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary Understanding how humans and other animals are able to learn from experience and use this information to select future behavioural strategies to obtain the reinforcers necessary for survival, is a fundamental research question in biology. Considerable progress has been made in recent years on the neural computational underpinnings of this process following the observation that the phasic activity of dopamine neurons in the midbrain resembles a prediction error from a formal computational theory known as reinforcement learning (RL). While much is known about the functions of dopamine in RL, much less is known about the computational functions of other modulatory neurotransmitter systems in the midbrain such as the cholinergic, norcpinephrine, and serotonergic systems. The goal of this research proposal to the ERC, is to begin a systematic study of the computational functions of these other neurotransmitter systems (beyond dopamine) in RL. To do this we will combine functional magnetic resonance imaging in human subjects while they perform simple decision making tasks and undergo pharmacological manipulations to modulate systemic levels of these different neurotransmitter systems. We will combine computational model-based analyses with fMRI and behavioural data in order to explore the effects that these pharmacological modulations exert on different parameters and modules within RL. Specifically, we will test the contributions that the cholinergic system makes in setting the learning rate during RL and in mediating computations of expected uncertainty in the distribution of rewards available, we will test for the role of norepinephrine in balancing the rate of exploration and exploitation during decision making, as well as in encoding the level of unexpected uncertainty, and we will explore the possible role of serotonin in setting the rate of temporal discounting for reward, or in encoding prediction errors during aversive as opposed to reward-learning.
Summary
Understanding how humans and other animals are able to learn from experience and use this information to select future behavioural strategies to obtain the reinforcers necessary for survival, is a fundamental research question in biology. Considerable progress has been made in recent years on the neural computational underpinnings of this process following the observation that the phasic activity of dopamine neurons in the midbrain resembles a prediction error from a formal computational theory known as reinforcement learning (RL). While much is known about the functions of dopamine in RL, much less is known about the computational functions of other modulatory neurotransmitter systems in the midbrain such as the cholinergic, norcpinephrine, and serotonergic systems. The goal of this research proposal to the ERC, is to begin a systematic study of the computational functions of these other neurotransmitter systems (beyond dopamine) in RL. To do this we will combine functional magnetic resonance imaging in human subjects while they perform simple decision making tasks and undergo pharmacological manipulations to modulate systemic levels of these different neurotransmitter systems. We will combine computational model-based analyses with fMRI and behavioural data in order to explore the effects that these pharmacological modulations exert on different parameters and modules within RL. Specifically, we will test the contributions that the cholinergic system makes in setting the learning rate during RL and in mediating computations of expected uncertainty in the distribution of rewards available, we will test for the role of norepinephrine in balancing the rate of exploration and exploitation during decision making, as well as in encoding the level of unexpected uncertainty, and we will explore the possible role of serotonin in setting the rate of temporal discounting for reward, or in encoding prediction errors during aversive as opposed to reward-learning.
Max ERC Funding
1 841 404 €
Duration
Start date: 2010-01-01, End date: 2010-09-30
