Project acronym BrainNanoFlow
Project Nanoscale dynamics in the extracellular space of the brain in vivo
Researcher (PI) Juan Alberto VARELA
Host Institution (HI) THE UNIVERSITY COURT OF THE UNIVERSITY OF ST ANDREWS
Summary Aggregates of proteins such as amyloid-beta and alpha-synuclein circulate the extracellular space of the brain (ECS) and are thought to be key players in the development of neurodegenerative diseases. The clearance of these aggregates (among other toxic metabolites) is a fundamental physiological feature of the brain which is poorly understood due to the lack of techniques to study the nanoscale organisation of the ECS. Exciting advances in this field have recently shown that clearance is enhanced during sleep due to a major volume change in the ECS, facilitating the flow of the interstitial fluid. However, this process has only been characterised at a low spatial resolution while the physiological changes occur at the nanoscale. The recently proposed "glymphatic" pathway still remains controversial, as there are no techniques capable of distinguishing between diffusion and bulk flow in the ECS of living animals. Understanding these processes at a higher spatial resolution requires the development of single-molecule imaging techniques that can study the brain in living animals. Taking advantage of the strategies I have recently developed to target single-molecules in the brain in vivo with nanoparticles, we will do "nanoscopy" in living animals. Our proposal will test the glymphatic pathway at the spatial scale in which events happen, and explore how sleep and wake cycles alter the ECS and the diffusion of receptors in neuronal plasma membrane. Overall, BrainNanoFlow aims to understand how nanoscale changes in the ECS facilitate clearance of protein aggregates. We will also provide new insights to the pathological consequences of impaired clearance, focusing on the interactions between these aggregates and their putative receptors. Being able to perform single-molecule studies in vivo in the brain will be a major breakthrough in neurobiology, making possible the study of physiological and pathological processes that cannot be studied in simpler brain preparations.
Aggregates of proteins such as amyloid-beta and alpha-synuclein circulate the extracellular space of the brain (ECS) and are thought to be key players in the development of neurodegenerative diseases. The clearance of these aggregates (among other toxic metabolites) is a fundamental physiological feature of the brain which is poorly understood due to the lack of techniques to study the nanoscale organisation of the ECS. Exciting advances in this field have recently shown that clearance is enhanced during sleep due to a major volume change in the ECS, facilitating the flow of the interstitial fluid. However, this process has only been characterised at a low spatial resolution while the physiological changes occur at the nanoscale. The recently proposed "glymphatic" pathway still remains controversial, as there are no techniques capable of distinguishing between diffusion and bulk flow in the ECS of living animals. Understanding these processes at a higher spatial resolution requires the development of single-molecule imaging techniques that can study the brain in living animals. Taking advantage of the strategies I have recently developed to target single-molecules in the brain in vivo with nanoparticles, we will do "nanoscopy" in living animals. Our proposal will test the glymphatic pathway at the spatial scale in which events happen, and explore how sleep and wake cycles alter the ECS and the diffusion of receptors in neuronal plasma membrane. Overall, BrainNanoFlow aims to understand how nanoscale changes in the ECS facilitate clearance of protein aggregates. We will also provide new insights to the pathological consequences of impaired clearance, focusing on the interactions between these aggregates and their putative receptors. Being able to perform single-molecule studies in vivo in the brain will be a major breakthrough in neurobiology, making possible the study of physiological and pathological processes that cannot be studied in simpler brain preparations.
Project acronym DISKtoHALO
Project From the accretion disk to the cluster halo: the multi-scale physics of black hole feedback
Researcher (PI) Christopher REYNOLDS
Summary It is firmly established that supermassive black holes (SMBHs) have a profound influence on the evolution of galaxies and galaxy groups/clusters. Yet, almost 20 years after this realization, fundamental questions remain. What determines the efficiency with which an active galactic nucleus (AGN) couples to its surroundings? Why does AGN feedback appear to be ineffective in low-mass galaxies? In maintenance-mode feedback, how does the AGN regulate to closely balance cooling? How does the nature of AGN feedback change as we consider higher redshifts and push back to the epoch of the first galaxies? AGN feedback is a truly multi-scale phenomenon. Observations show that AGN have an energetic impact on galactic-, group-, and cluster-halo scales. Yet the efficiency with which an accreting SMBH releases energy, and the partitioning of that energy into radiation, winds, and relativistic jets, is dictated by complex processes in the accretion disk on AU scales, 10^10 times smaller than the halo. Furthermore, especially in massive systems where feedback proceeds via the heating of a hot circumgalactic or intracluster medium (CGM/ICM), the relevant microphysics of the hot baryons is unclear, requiring an understanding of plasma instabilities on 10^-9pc scales. We propose a set of projects that explore the multiscale physics of AGN feedback. Magnetohydrodynamic models of accretion disks will be constructed to study the AGN radiation/winds/jets and calibrate observable proxies of SMBH mass and accretion rate. We will use the machinery of plasma physics to characterize the CGM/ICM microphysics relevant to the thermalization of AGN-injected energy. Finally, we will produce new galaxy-, group- and cluster-scale models incorporating the new microphysical prescriptions and AGN models. Our new theoretical understanding of AGN feedback as a function of halo mass, environment, and cosmic time is essential for interpreting the torrent of data from current and future observatories
It is firmly established that supermassive black holes (SMBHs) have a profound influence on the evolution of galaxies and galaxy groups/clusters. Yet, almost 20 years after this realization, fundamental questions remain. What determines the efficiency with which an active galactic nucleus (AGN) couples to its surroundings? Why does AGN feedback appear to be ineffective in low-mass galaxies? In maintenance-mode feedback, how does the AGN regulate to closely balance cooling? How does the nature of AGN feedback change as we consider higher redshifts and push back to the epoch of the first galaxies? AGN feedback is a truly multi-scale phenomenon. Observations show that AGN have an energetic impact on galactic-, group-, and cluster-halo scales. Yet the efficiency with which an accreting SMBH releases energy, and the partitioning of that energy into radiation, winds, and relativistic jets, is dictated by complex processes in the accretion disk on AU scales, 10^10 times smaller than the halo. Furthermore, especially in massive systems where feedback proceeds via the heating of a hot circumgalactic or intracluster medium (CGM/ICM), the relevant microphysics of the hot baryons is unclear, requiring an understanding of plasma instabilities on 10^-9pc scales. We propose a set of projects that explore the multiscale physics of AGN feedback. Magnetohydrodynamic models of accretion disks will be constructed to study the AGN radiation/winds/jets and calibrate observable proxies of SMBH mass and accretion rate. We will use the machinery of plasma physics to characterize the CGM/ICM microphysics relevant to the thermalization of AGN-injected energy. Finally, we will produce new galaxy-, group- and cluster-scale models incorporating the new microphysical prescriptions and AGN models. Our new theoretical understanding of AGN feedback as a function of halo mass, environment, and cosmic time is essential for interpreting the torrent of data from current and future observatories
Project acronym FORMSofLABOUR
Project Forms of Labour: Gender, Freedom and Experience of Work in the Preindustrial Economy
Researcher (PI) Jane WHITTLE
Host Institution (HI) THE UNIVERSITY OF EXETER
Summary The history of labour and its role in Europe's preindustrial development has very largely been the history of adult men. FORMSofLABOUR seeks to put other workers in the picture, particularly women and servants, not simply by 'adding them on' but by showing how a full understanding of women's work and of service offers a radical critique of existing approaches to work and to the idea of free labour. It focuses on England in the period 1300-1700 viewed in a comparative Western European perspective, and addressed these issues through three themes. (1) A revolutionary research technique which collects evidence of work tasks from court records to simulate a time-use study is used to explore the experience of work. This technique allows the work activities of women and men, young and old, employees and family members to be illuminated, with evidence of tasks, location and timing of work, creating an entirely new perspective on England's early modern economy. (2) The theoretical underpinnings of the history of women's work in the preindustrial economy are explored, reassessing key debates using interdisciplinary perspectives from economics and political science, as well as new archival evidence from themes 1 and 3. Gendered work patterns are viewed through the lens of freedom, rather than patriarchy, to create a step-change in our understanding of gender and work. (3) The issue of the extent to which labour was 'free' after the end of serfdom is interrogated through a careful examination of the range of forms of labour and the nature of labour laws, using a variety of archival evidence combined with a comparisons with serfdom and slavery, and the adoption of insights from development economics and anthropology. Together these interlocking themes create a new history of work in the economy which formed the background to grand narratives of Smith and Marx, arguing that with women and servants had been in picture, the story of economic development is transformed.
The history of labour and its role in Europe's preindustrial development has very largely been the history of adult men. FORMSofLABOUR seeks to put other workers in the picture, particularly women and servants, not simply by 'adding them on' but by showing how a full understanding of women's work and of service offers a radical critique of existing approaches to work and to the idea of free labour. It focuses on England in the period 1300-1700 viewed in a comparative Western European perspective, and addressed these issues through three themes. (1) A revolutionary research technique which collects evidence of work tasks from court records to simulate a time-use study is used to explore the experience of work. This technique allows the work activities of women and men, young and old, employees and family members to be illuminated, with evidence of tasks, location and timing of work, creating an entirely new perspective on England's early modern economy. (2) The theoretical underpinnings of the history of women's work in the preindustrial economy are explored, reassessing key debates using interdisciplinary perspectives from economics and political science, as well as new archival evidence from themes 1 and 3. Gendered work patterns are viewed through the lens of freedom, rather than patriarchy, to create a step-change in our understanding of gender and work. (3) The issue of the extent to which labour was 'free' after the end of serfdom is interrogated through a careful examination of the range of forms of labour and the nature of labour laws, using a variety of archival evidence combined with a comparisons with serfdom and slavery, and the adoption of insights from development economics and anthropology. Together these interlocking themes create a new history of work in the economy which formed the background to grand narratives of Smith and Marx, arguing that with women and servants had been in picture, the story of economic development is transformed.
Project acronym GMGalaxies
Project Understanding the diversity of galaxy morphology in the era of large spectroscopic surveys
Researcher (PI) Andrew PONTZEN
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Summary Galaxies are the building blocks of structure in the Universe; this proposal seeks to understand how their shapes, colours and dynamics are determined. For example, what happened in the history of some galaxies to transform them into passive ellipticals while others, seemingly of the same mass and in the same environment, are star-forming spirals? Even such a basic question about the link between morphology and star formation has not yet been answered, revealing our theories of galaxy formation are inadequate. This is a major concern in an era where understanding the shapes of galaxies and how they relate to the underlying dark matter is essential for progress in precision cosmology. This project will build the missing link between the history of a galaxy and its observational properties (i.e. between cause and effect) by using numerical simulations. Current research in this area rightly gives significant attention to the crucial problem of how feedback – energy input from supernovae, active galactic nuclei, and more – affect observable properties. But as well as investigating this avenue, GM Galaxies will uniquely make use of my new technique ("genetic modification") to systematically investigate the role of the galaxy's merging and accretion history at high resolution. To distinguish the fingerprints of history from the effects of feedback, we will compare to rich new data from integral field unit surveys; these reveal, for example, galactic metallicity and velocity maps. My pilot study for this project shows that such measures of a galaxy disambiguate between alternative formation routes to galaxies which would appear similar by photometric measures alone. Similarly, we will make predictions for the observable properties of the gas reservoir surrounding galaxies and for integral field observations at high redshift. In this way we will make a predictive account of how galactic structure is determined by the interaction of the accretion history with feedback.
Galaxies are the building blocks of structure in the Universe; this proposal seeks to understand how their shapes, colours and dynamics are determined. For example, what happened in the history of some galaxies to transform them into passive ellipticals while others, seemingly of the same mass and in the same environment, are star-forming spirals? Even such a basic question about the link between morphology and star formation has not yet been answered, revealing our theories of galaxy formation are inadequate. This is a major concern in an era where understanding the shapes of galaxies and how they relate to the underlying dark matter is essential for progress in precision cosmology. This project will build the missing link between the history of a galaxy and its observational properties (i.e. between cause and effect) by using numerical simulations. Current research in this area rightly gives significant attention to the crucial problem of how feedback – energy input from supernovae, active galactic nuclei, and more – affect observable properties. But as well as investigating this avenue, GM Galaxies will uniquely make use of my new technique ("genetic modification") to systematically investigate the role of the galaxy's merging and accretion history at high resolution. To distinguish the fingerprints of history from the effects of feedback, we will compare to rich new data from integral field unit surveys; these reveal, for example, galactic metallicity and velocity maps. My pilot study for this project shows that such measures of a galaxy disambiguate between alternative formation routes to galaxies which would appear similar by photometric measures alone. Similarly, we will make predictions for the observable properties of the gas reservoir surrounding galaxies and for integral field observations at high redshift. In this way we will make a predictive account of how galactic structure is determined by the interaction of the accretion history with feedback.
Project acronym ICYBOB
Project Initial Conditions of YMCs, Birth of OB associations and long term evolution of stellar clusters
Researcher (PI) Clare Louise DOBBS
Summary The goal of this proposal is to establish a new era of stellar cluster evolution research by performing numerical simulations on different scales, and of different stages of a cluster's life, from the formation of YMCs, the formation and evolution of OB associations, to the evolution of clusters and associations in galaxies. The PI is one of the pioneers of galactic simulations of GMC and star formation was one of the first numericists to perform galactic scale simulations of molecular cloud formation and evolution, and has produced some of the most realistic and sophisticated isolated simulations of galaxies in this field to date. The next challenge is to follow cluster evolution, something which has not yet been attempted numerically. And, with the GaiaAIA instrument set to transform stellar astronomy in our Galaxy, our work will provide a fundamental theoretical counterpart. Key questions we will address include i) how does gas disperse from new clusters and what happens to that gas, ii) how do YMCs form, iii) how do new clustersGiant Molecular Clouds (GMCs) evolve into OB associations, and ivii) how long can clusters survive for as they orbit a galaxy and what causes their destruction.
The goal of this proposal is to establish a new era of stellar cluster evolution research by performing numerical simulations on different scales, and of different stages of a cluster's life, from the formation of YMCs, the formation and evolution of OB associations, to the evolution of clusters and associations in galaxies. The PI is one of the pioneers of galactic simulations of GMC and star formation was one of the first numericists to perform galactic scale simulations of molecular cloud formation and evolution, and has produced some of the most realistic and sophisticated isolated simulations of galaxies in this field to date. The next challenge is to follow cluster evolution, something which has not yet been attempted numerically. And, with the GaiaAIA instrument set to transform stellar astronomy in our Galaxy, our work will provide a fundamental theoretical counterpart. Key questions we will address include i) how does gas disperse from new clusters and what happens to that gas, ii) how do YMCs form, iii) how do new clustersGiant Molecular Clouds (GMCs) evolve into OB associations, and ivii) how long can clusters survive for as they orbit a galaxy and what causes their destruction.
Project acronym LeaRNN
Project Principles of Learning in a Recurrent Neural Network
Researcher (PI) Marta Zlatic
Summary Forming memories, generating predictions based on memories, and updating memories when predictions no longer match actual experience are fundamental brain functions. Dopaminergic neurons provide a so-called "teaching signal" that drives the formation and updates of associative memories across the animal kingdom. Many theoretical models propose how neural circuits could compute the teaching signals, but the actual implementation of this computation in real nervous systems is unknown. This project will discover the basic principles by which neural circuits compute the teaching signals that drive memory formation and updates using a tractable insect model system, the Drosophila larva. We will generate, for the first time in any animal, the following essential datasets for a distributed, multilayered, recurrent learning circuit, the mushroom body-related circuitry in the larval brain. First, building on our preliminary work that provides the synaptic-resolution connectome of the circuit, including all feedforward and feedback pathways upstream of all dopaminergic neurons, we will generate a map of functional monosynaptic connections. Second, we will obtain cellular-resolution whole-nervous system activity maps in intact living animals, as they form, extinguish, or consolidate memories to discover the features represented in each layer of the circuit (e.g. predictions, actual reinforcement, and prediction errors), the learning algorithms, and the candidate circuit motifs that implement them. Finally, we will develop a model of the circuit constrained by these datasets and test the predictions about the necessity and sufficiency of uniquely identified circuit elements for implementing learning algorithms by selectively manipulating their activity. Understanding the basic functional principles of an entire multilayered recurrent learning circuit in an animal has the potential to revolutionize, not only neuroscience and medicine, but also machine-learning and robotics.
Forming memories, generating predictions based on memories, and updating memories when predictions no longer match actual experience are fundamental brain functions. Dopaminergic neurons provide a so-called "teaching signal" that drives the formation and updates of associative memories across the animal kingdom. Many theoretical models propose how neural circuits could compute the teaching signals, but the actual implementation of this computation in real nervous systems is unknown. This project will discover the basic principles by which neural circuits compute the teaching signals that drive memory formation and updates using a tractable insect model system, the Drosophila larva. We will generate, for the first time in any animal, the following essential datasets for a distributed, multilayered, recurrent learning circuit, the mushroom body-related circuitry in the larval brain. First, building on our preliminary work that provides the synaptic-resolution connectome of the circuit, including all feedforward and feedback pathways upstream of all dopaminergic neurons, we will generate a map of functional monosynaptic connections. Second, we will obtain cellular-resolution whole-nervous system activity maps in intact living animals, as they form, extinguish, or consolidate memories to discover the features represented in each layer of the circuit (e.g. predictions, actual reinforcement, and prediction errors), the learning algorithms, and the candidate circuit motifs that implement them. Finally, we will develop a model of the circuit constrained by these datasets and test the predictions about the necessity and sufficiency of uniquely identified circuit elements for implementing learning algorithms by selectively manipulating their activity. Understanding the basic functional principles of an entire multilayered recurrent learning circuit in an animal has the potential to revolutionize, not only neuroscience and medicine, but also machine-learning and robotics.
Project acronym MOPPEX
Project MOlecules as Probes of the Physics of EXternal galaxies
Researcher (PI) Serena Viti
Host Institution (HI) UNIVERSITEIT LEIDEN
Summary Molecules pervade the cooler, denser parts of our Universe, in particular the reservoirs of the matter that forms stars and planets, and the gas in the centres of galaxies. In the Milky Way we routinely use molecules to discover and explore these regions and the more complex the chemistry, the more details of the gas the molecules reveal. There are one hundred billion galaxies in the observable Universe. About 200 or so are our neighbours. However, due to their distance, we are still not able to zoom in and observe individual clouds of dense gas. Nevertheless with the advent of ever more sensitive telescopes such as ALMA, we are discovering that chemistry in external galaxies is as complex as in our own Milky Way. Molecules, it seems, are universal and widespread. In MOPPEX I use molecules to shed light on the physical and chemical structure of our local galaxies, namely (i) what the energetic processes that determine their appearance are and (ii) where the matter that will form stars or fuels black holes is, with the ultimate goal to understand how galaxies form, evolve and interact with each other. To achieve this objective I propose a multi-faceted program that combines state of the art chemical and statistical models in conjunction with interferometric observations. More specifically, the success of MOPPEX relies on (i) in-house and open source suites of chemical models and an in-house line radiative transfer model, (ii) a new suite of tools comprising of modular statistical and machine learning algorithms, and (iii) large datasets of observational data on two nearby galaxies differing in types. My ultimate objective is to fundamentally change the way molecular observations are interpreted for external galaxies and thus to cause a paradigm shift in the use of molecules as tools to determine the chemistry and physics of galaxies.
Molecules pervade the cooler, denser parts of our Universe, in particular the reservoirs of the matter that forms stars and planets, and the gas in the centres of galaxies. In the Milky Way we routinely use molecules to discover and explore these regions and the more complex the chemistry, the more details of the gas the molecules reveal. There are one hundred billion galaxies in the observable Universe. About 200 or so are our neighbours. However, due to their distance, we are still not able to zoom in and observe individual clouds of dense gas. Nevertheless with the advent of ever more sensitive telescopes such as ALMA, we are discovering that chemistry in external galaxies is as complex as in our own Milky Way. Molecules, it seems, are universal and widespread. In MOPPEX I use molecules to shed light on the physical and chemical structure of our local galaxies, namely (i) what the energetic processes that determine their appearance are and (ii) where the matter that will form stars or fuels black holes is, with the ultimate goal to understand how galaxies form, evolve and interact with each other. To achieve this objective I propose a multi-faceted program that combines state of the art chemical and statistical models in conjunction with interferometric observations. More specifically, the success of MOPPEX relies on (i) in-house and open source suites of chemical models and an in-house line radiative transfer model, (ii) a new suite of tools comprising of modular statistical and machine learning algorithms, and (iii) large datasets of observational data on two nearby galaxies differing in types. My ultimate objective is to fundamentally change the way molecular observations are interpreted for external galaxies and thus to cause a paradigm shift in the use of molecules as tools to determine the chemistry and physics of galaxies.
Project acronym RACOM
Project Rome and the Coinages of the Mediterranean: 200 BCE to 64 CE
Researcher (PI) Kevin Edward Templar BUTCHER
Host Institution (HI) THE UNIVERSITY OF WARWICK
Summary Silver coinage formed the backbone of state finance in Classical antiquity. The fineness and quality of a coinage is often taken by historians to be a comment on the fiscal health of the issuing state, yet very little is really known about its fineness and chemical composition, and many of the existing analyses are inadequate to answer key questions. Samples for analysis are commonly taken from the surfaces, or from just beneath the surfaces, of silver coins, and these are not representative of the original alloys used, leading to erroneous estimates of overall composition. The aim of the project is to examine financial and monetary strategies from c. 150 BCE to a major coin reform in c. 64 CE – a period that witnessed the creation of an overarching currency for the Mediterranean world and increasing monetisation – by providing a detailed and reliable set of analyses of the chemical composition of all major silver coinages of the period, obtained by taking samples from deep within the coins. It will also evaluate two new, non-destructive techniques to see how they compare with established protocols. The period witnessed a major increase in long distance trade and probably also economic growth and a rise in per capita income. Roman conquest led to greater economic and monetary integration of the Mediterranean area, and Rome's apparent currency monopoly may have had its own consequences for the development of coinage and management of finances. Flows of precious metals to Rome and other important centres of power helped to finance Roman expansion, and understanding the chemical composition of silver coinage will transform our understanding of Roman monetary strategy as an instrument of imperialism.
Silver coinage formed the backbone of state finance in Classical antiquity. The fineness and quality of a coinage is often taken by historians to be a comment on the fiscal health of the issuing state, yet very little is really known about its fineness and chemical composition, and many of the existing analyses are inadequate to answer key questions. Samples for analysis are commonly taken from the surfaces, or from just beneath the surfaces, of silver coins, and these are not representative of the original alloys used, leading to erroneous estimates of overall composition. The aim of the project is to examine financial and monetary strategies from c. 150 BCE to a major coin reform in c. 64 CE – a period that witnessed the creation of an overarching currency for the Mediterranean world and increasing monetisation – by providing a detailed and reliable set of analyses of the chemical composition of all major silver coinages of the period, obtained by taking samples from deep within the coins. It will also evaluate two new, non-destructive techniques to see how they compare with established protocols. The period witnessed a major increase in long distance trade and probably also economic growth and a rise in per capita income. Roman conquest led to greater economic and monetary integration of the Mediterranean area, and Rome's apparent currency monopoly may have had its own consequences for the development of coinage and management of finances. Flows of precious metals to Rome and other important centres of power helped to finance Roman expansion, and understanding the chemical composition of silver coinage will transform our understanding of Roman monetary strategy as an instrument of imperialism.
Project acronym Somnostat
Project The Homeostatic Regulation and Biological Function of Sleep
Researcher (PI) Gero Andreas MIESENBÖCK
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Summary Sleep is vital and universal, but its biological function remains unknown. This project will seek to understand why we need to sleep by studying how the brain responds to sleep loss. My previous work in Drosophila showed that rising sleep pressure activates two dozen sleep-inducing neurons in the dorsal fan-shaped body (dFB) of the central complex. Sleep need is encoded in the electrical excitability of these neurons, which fluctuates because two potassium conductances, voltage-gated Shaker and the leak channel Sandman, are modulated antagonistically. As a consequence, dFB neurons are electrically silent during waking and persistently active during sleep. The key open question addressed in this project is the nature of the molecular changes that drive dFB neurons into the electrically active state. My preliminary data point to two dFB-intrinsic transducers of sleep pressure. First, the Shaker β subunit Hyperkinetic responds via a bound nicotinamide cofactor to oxidative by-products of mitochondrial electron transport, revealing a potential connection between energy metabolism, oxidative stress, and sleep, three processes implicated independently in lifespan, aging, and disease. To strengthen this connection, we will monitor sleep and the biophysics of dFB neurons after perturbing mitochondrial respiration or cellular redox chemistry and vice versa. Second, Rho GTPases relay currently unknown signals to the machinery responsible for the regulated endocytosis of Sandman, whose extraction from the plasma membrane is a prerequisite for switching the sleep-promoting activity of dFB neurons on. To identify these signals, we will investigate cell-autonomous, synaptic, and non-synaptic mechanisms of GTPase control. Because clear parallels exist between dFB neurons and sleep-active neurons in the mammalian hypothalamus, mechanistic insights that can currently be gained only in Drosophila are expected to have broad validity for understanding sleep and its disruptions.
Sleep is vital and universal, but its biological function remains unknown. This project will seek to understand why we need to sleep by studying how the brain responds to sleep loss. My previous work in Drosophila showed that rising sleep pressure activates two dozen sleep-inducing neurons in the dorsal fan-shaped body (dFB) of the central complex. Sleep need is encoded in the electrical excitability of these neurons, which fluctuates because two potassium conductances, voltage-gated Shaker and the leak channel Sandman, are modulated antagonistically. As a consequence, dFB neurons are electrically silent during waking and persistently active during sleep. The key open question addressed in this project is the nature of the molecular changes that drive dFB neurons into the electrically active state. My preliminary data point to two dFB-intrinsic transducers of sleep pressure. First, the Shaker β subunit Hyperkinetic responds via a bound nicotinamide cofactor to oxidative by-products of mitochondrial electron transport, revealing a potential connection between energy metabolism, oxidative stress, and sleep, three processes implicated independently in lifespan, aging, and disease. To strengthen this connection, we will monitor sleep and the biophysics of dFB neurons after perturbing mitochondrial respiration or cellular redox chemistry and vice versa. Second, Rho GTPases relay currently unknown signals to the machinery responsible for the regulated endocytosis of Sandman, whose extraction from the plasma membrane is a prerequisite for switching the sleep-promoting activity of dFB neurons on. To identify these signals, we will investigate cell-autonomous, synaptic, and non-synaptic mechanisms of GTPase control. Because clear parallels exist between dFB neurons and sleep-active neurons in the mammalian hypothalamus, mechanistic insights that can currently be gained only in Drosophila are expected to have broad validity for understanding sleep and its disruptions.