Lin Tian, Ph.D. - US grants

Quantum physics has been applied to study problems in computing complexity in recent years, which has become a new frontier in computer science. Computer hardware that is operated according to the laws of quantum mechanics can realize novel quantum protocols and bring enormous speed-up for certain computationally hard problems. The key issue in implementing such hardware is in achieving highly accurate and fast control on the quantum logic elements so that they can beat the hazardous effects from the environmental noise. For solid-state quantum processors, including superconducting systems and semiconductor systems, such control is usually achieved via adjustable local parameters, where careful designing of the circuit and the connections to external sources are required. In this project, a quantum global mode will be exploited to achieve efficient implementation of the quantum protocols. Here, the quantum global mode is the microwave photon mode in a nanoscale quantum resonator that has millimeter wavelength, can couple with multiple quantum logic elements simultaneously, and has demonstrated microsecond quantum coherence times. Meanwhile, the global mode will also be considered as a probe to measure quantum entanglement and quantum coherence effects in the solid-state quantum processors. Two questions will be studied in this project. First, solid-state quantum simulators that can emulate quantum many-body systems involving arrays of solid-state elements will be studied, where the global quantum mode will act as a control as well as a detector of the quantum phase transitions in the simulators. Second, a universal quantum computer of spurious two-level fluctuators in the superconducting system will be studied where the global mode can provide individual control, effective coupling, and readout of the fluctuator states. Both the hardware aspect and the software aspect will be investigated.

TECHNICAL SUMMARY

This CAREER award supports theoretical research and education on novel quantum phenomena in nanoscale condensed matter devices and their applications in quantum information. As their dimensions approach the atomic limit, nanoscale devices can sometimes be treated as simple macroscopic quantum objects, such as spins and harmonic oscillators. Such quantum objects can be studied by quantum optics, which is a well-developed tool that has achieved success in studying atomic systems. A theoretical framework to study coherent, dissipative, and collective behavior of nanoscale devices will be developed in two main topics by combining techniques of quantum optics with microscopic concepts of condensed matter physics. First, continuous variable quantum information processing will be studied in nanomechanical resonators which feature tiny mechanical vibrations that can carry quantum information. The coupling between nanomechanical resonators and solid-state electronic circuits will be explored to study ground state cooling, entanglement and Bell-inequality tests, and continuous variable quantum protocols, where the mechanical mode serves as an excellent quantum storage element. Second, nonlinear effects of superconducting quantum emulators coupling to a superconducting resonator will be studied, where the emulators are made of superconducting qubits to simulate quantum many-body Hamiltonians. The nature of the quantum phase transition will be studied in this nonlinear system, and a numerical package will be developed. In both topics, questions that are of particular importance for nanoscale devices will be studied, including the proper design of circuits and the effects of low-frequency fluctuations.

The research in this project connects the fields of quantum optics, condensed matter physics, and quantum information. The quantum effects in nanoscale devices can be explored to study fundamental issues in quantum mechanics, novel problems in condensed matter physics, and the development of a new generation of solid-state quantum devices. In particular, this project seeks realistic quantum computing architectures using the nanoscale devices as information carriers.

This CAREER award is made to the University of California (UC), Merced, which is a newly started research university established to serve the educational needs in the San Joaquin Valley. It is the only UC campus that is designated as a Hispanic serving institution. The educational activities in this project will provide training for students from underrepresented groups, including minority and women students, to encourage and help them to pursue careers in physics. A pipeline of activities will be organized, including women physicist networking group, Saturday lecture series for high school students at a local museum in Merced County, and development of undergraduate research projects and courses using the Peer Instruction Technique.

NONTECHNICAL SUMMARY

This CAREER award supports theoretical research and education on novel quantum mechanical effects in small solid-state devices on the nanometer (one billionth of a meter) size regime. On this scale the distinction between materials, atoms, and devices becomes blurred. Many such devices can be the building blocks of a quantum computer, which is a device for computation that makes use of quantum mechanical phenomena, and if successfully built on a large scale, will be much faster than any currently available classical computer for some algorithms. As the potential elements for storing information quantum mechanically, these devices can profoundly influence the information technology and national security.

The research bridges the disciplines of condensed matter physics, quantum optics, and quantum information science. It focuses on two main topics. One is to explore tiny nanometer-sized mechanical resonators as carriers of quantum information. The mechanical vibrations in such resonators can be connected with solid-state electronic circuits to store and manipulate information. One focus area along this line is to study the approaches that can bring the tiny mechanical vibrations into the quantum regime by extracting the thermal noise in the system to generate ?cooling? of the resonators. The other topic is to study phenomena in superconducting quantum circuits, which carry electrical current without dissipation. These effects can introduce phenomena that are new to condensed matter physics.

The quantum effects in nanoscale devices can be explored not only to study fundamental physics issues, such as the detection of gravitational waves and the boundary between the quantum and the classical worlds, but it can also help in developing a new generation of solid-state devices that are based on quantum mechanical effects for metrology and information applications.

This CAREER award is made to the University of California (UC), Merced, which is a newly started research university established to serve the educational needs in the San Joaquin Valley. It is the only UC campus that is designated as a Hispanic serving institution. The educational activities in this project will provide training and learning opportunities for students from groups typically underrepresented in science and engineering disciplines, including minority and women students, to encourage and help them to pursue careers in physics. A pipeline of activities will be organized, including women physicist networking group, Saturday lecture series for high school students at a local museum in Merced County, and development of undergraduate research projects and courses using the Peer Instruction Technique.

One of the primary challenges in neuroscience is to understand how sensory experiences drive the changes in brain circuits that underlie learning. Notably, the current lack of adequate tools to monitor the functional properties of individual synaptic connections has been holding back efforts to define how complex neuronal firing patterns drive changes in neuronal connectivity in the brain. This EAGER proposal is focused on the development and application of radically novel fluorescent probes to visualize integrated neural activity at individual synapses. If successful, these innovative probes will be transformative for the field; broad application of these probes by the neuroscience community will enable discovery of the rules that link sensory-driven neural activity to the structural changes in synaptic connectivity underlying learning. This knowledge would revolutionize current understanding of the dynamic changes in brain structure and function during learning. Furthermore, this project will foster close collaboration between groups of investigators with complementary expertise, and thus will create a vibrant environment for interdisciplinary training of the next generation of scientists.

This EAGER proposal addresses one of the major unsolved problems in neuroscience: how complex patterns of neural activity at multiple synapses interact to drive experience-dependent changes in circuit connectivity. The specific goal is to develop and apply novel fluorescent probes for visualizing the history of neural activity at individual synapses. These innovative probes will facilitate mapping the function and structure of the neural circuitry underlying a specific physiological process or behavioral task. To accomplish this goal, a multidisciplinary approach will be used that incorporates genetic strategies, computation-guided protein design, two-photon imaging, and electrophysiology. First, candidate sensors will be generated through a high-throughput, multi-step sensor screening process. Next, the sensitivity and kinetics of the sensors will be characterized in neurons in vitro, ex vivo, and in vivo. Finally, the sensors will be implemented in brain slices to probe the activity-dependent mechanisms that drive the formation and stabilization of synaptic connections. Ultimately, these sensors will be used to define the activity-dependent mechanisms that drive circuit changes in vivo during complex behavioral tasks. The proposed research would provide much needed imaging tools of synaptic activity that are compatible with a variety of advanced imaging techniques, such as wide-field, confocal and two-photon microscopy, and would dramatically enhance understanding of how the history of neural activity at individual synapses and their neighbors can influence long-term stability of neural circuit connections.

? DESCRIPTION (provided by applicant): The goal of this proposal is to develop a toolbox of genetically encoded indicators for biogenic amines, the most important family of neuromodulators. All nervous systems are subject to neuromodulation, which reconfigure the dynamics of neural circuitry by transforming the intrinsic firing properties of targeted neurons and regulating their synaptic plasticity. The altered dynamics of the neuromodulators have been implicated in a number of human neurological and psychiatric diseases, including Parkinson's, schizophrenia and addiction. Biogenic amines are a group of neuromodulators used by all animal brains to regulate the development, structure and function of neural circuits. Although the anatomical characterization and functional significance of biogenic amine projections are understood to a moderate degree, the precise mechanisms by which these molecules exert control over behavior are not fully understood. To decipher the mechanisms by which these molecules exert their influence on the brain and behavior, we must perform sensitive and specific measurements of neuromodulator transients, both broadly (volume modulation) and locally (targeted modulation), with the requisite spatial and temporal resolution, ideally in intac circuits. Existing methods, encompassing microdialysis and cyclic voltammetry, are useful, but not adequate for this task at hand. One potential solution would be to develop genetically encoded indicators based on fluorescent proteins combined with modern microscopy allowing direct and specific measurement of diverse types of neuromodulators with enhanced spatial and temporal resolutions. Recently we have successfully established technology platform for the development of genetically encoded indicators of neural activity, which have led to several high-quality optical probes for simultaneous imaging of large-scale neuronal populations in living animals. Building upon highly optimized platform for sensor sensors and extensive experience in sensor characterization and application in neuroscience, we propose to develop a high-quality toolkit of optical sensors for the biogenic amine neuromodulators, especially for dopamine, the most behavioral pervasive neuromodulator. Our specific aims will start by designing and screening sensors for each of the biogenic amines using combined computational redesign and direct revolution. We will then develop synaptic targeting strategies to display the sensors in dendrites and axons to improve their utility for synaptic imaging. We will finally characterize the performance of these sensors in living neurons and in rat brain slices and demonstrate their capabilities of probing dynamics of dopamine transients in living animals. State-of-the-art sensors for these molecules will facilitate the non-invasive, precise, direct and continual measurement of released neuromodulators at both the synaptic and circuit levels in live model organisms. Such technology advance in optical recordings will facilitate neural circuitry mapping and paint a dynamic picture of neuromodulation systems in regulating neural circuitry and behavior. Given the clear relevance of the biogenic amines to the neurological diseases, these sensors are especially beneficial for long-term studies of human stem cell and animal disease models (specially the Parkinson's disease) and evaluating the effects of candidate therapeutics.

DESCRIPTION (provided by applicant): One of the greatest challenges in neuroscience is to decipher the logic of the neural circuitry and link it to learning, memory, and behavior. Neural circuitry is a dynamic network that incorporates neuronal activity at a variety of spatial and temporal scales. Therefore, analysis of neural circuitry demands broad and dense sampling of neuronal activity across time and brain structures. Recent breakthroughs in modern microscope and protein based fluorescence sensors have brought this goal within reach. For example, application of genetically encoded calcium indicators, such as GCaMP3, combined with two-photon microscopy, has facilitated the large- scale recording of neural activity in a genetically-identified population at multiple time scales in awake, behaving animals. These applications have greatly advanced our understanding of the dynamics of neural circuitry and its control of behavior-a critical first step toward understanding complex brain function. Building upon the momentum of calcium imaging, the immediate need to accelerate future analyses of the dynamics of neural circuitry is to develop a broader suite of optical sensors to expand the kinds of neuronal activity that can be measured. One particular area of interest is synaptic transmission, a critical event of information processing in the brain that is difficult to access wth the optical tools currently available. There are two key questions that need to be addressed before we can develop a dynamic picture of synaptic transmission. First, we must understand how synaptic connectivity is linked to its activity; second, we must determine how different types of neurotransmitters balance with each other in a defined circuitry. Therefore, I plan to develop two classes of novel protein-based fluorescent sensors, using methods that have emerged only recently, to enable monitoring of synaptic transmission from these two different angles. For the first project outlined in this proposal, I will develop sensors specially designed for simultaneous recording of both synaptic activity and connectivity. Recently, I have been involved in developing a genetically-encoded neurotransmitter sensor (iGluSnfr) to directly measure released glutamate. This sensor, for the first time, offers the potential for monitoring excitatory synaptic activity in time and space. However, its ability to report synaptic connectivity, a piece f important information stored in the neural circuitry, is currently lacking. Therefore, I will develp strategies to split iGluSnfr into pre- and post-synaptic components. This designer sensor will permit simultaneous recording of both synaptic activity and connectivity, thus providing a way to find the synapses that are activity-dependent in a defined circuitry. For the second project outlined in this proposal, I will develop a new sensor to direct monitor inhibitory communication between neurons at synapses. It is known that based on the kind of neurotransmitters released, the communication between neurons can be either excitatory or inhibitory. Imbalanced excitatory and inhibitory synapses in specific neural circuitry have been implicated in an array of neurological disorders, including depression, addiction, autism, schizophrenia and epilepsy. Yet, optical sensors for directly monitoring inhibitory signals with needed spatiotemporal resolution are still missing. I will leverage computational modeling to redesign iGluSnFr to sense inhibitory neurotransmitters, such as ?-aminobutyric acid (GABA). Similarly, the splitting strategy to be developed in project one will be further utilized to split the GABA sensor into pre- and post-synaptic components. Taken together, a successful outcome of the proposed research would provide much needed imaging tools to enable neuroscientists to obtain a comprehensive view of both excitatory and inhibitory synapses in action at the cellular, tissue, and whole-animal level.

? DESCRIPTION (provided by applicant): The goal of this proposal is to develop a toolbox of genetically encoded indicators for biogenic amines, the most important family of neuromodulators. All nervous systems are subject to neuromodulation, which reconfigure the dynamics of neural circuitry by transforming the intrinsic firing properties of targeted neurons and regulating their synaptic plasticity. The altered dynamics of the neuromodulators have been implicated in a number of human neurological and psychiatric diseases, including Parkinson's, schizophrenia and addiction. Biogenic amines are a group of neuromodulators used by all animal brains to regulate the development, structure and function of neural circuits. Although the anatomical characterization and functional significance of biogenic amine projections are understood to a moderate degree, the precise mechanisms by which these molecules exert control over behavior are not fully understood. To decipher the mechanisms by which these molecules exert their influence on the brain and behavior, we must perform sensitive and specific measurements of neuromodulator transients, both broadly (volume modulation) and locally (targeted modulation), with the requisite spatial and temporal resolution, ideally in intac circuits. Existing methods, encompassing microdialysis and cyclic voltammetry, are useful, but not adequate for this task at hand. One potential solution would be to develop genetically encoded indicators based on fluorescent proteins combined with modern microscopy allowing direct and specific measurement of diverse types of neuromodulators with enhanced spatial and temporal resolutions. Recently we have successfully established technology platform for the development of genetically encoded indicators of neural activity, which have led to several high-quality optical probes for simultaneous imaging of large-scale neuronal populations in living animals. Building upon highly optimized platform for sensor sensors and extensive experience in sensor characterization and application in neuroscience, we propose to develop a high-quality toolkit of optical sensors for the biogenic amine neuromodulators, especially for dopamine, the most behavioral pervasive neuromodulator. Our specific aims will start by designing and screening sensors for each of the biogenic amines using combined computational redesign and direct revolution. We will then develop synaptic targeting strategies to display the sensors in dendrites and axons to improve their utility for synaptic imaging. We will finally characterize the performance of these sensors in living neurons and in rat brain slices and demonstrate their capabilities of probing dynamics of dopamine transients in living animals. State-of-the-art sensors for these molecules will facilitate the non-invasive, precise, direct and continual measurement of released neuromodulators at both the synaptic and circuit levels in live model organisms. Such technology advance in optical recordings will facilitate neural circuitry mapping and paint a dynamic picture of neuromodulation systems in regulating neural circuitry and behavior. Given the clear relevance of the biogenic amines to the neurological diseases, these sensors are especially beneficial for long-term studies of human stem cell and animal disease models (specially the Parkinson's disease) and evaluating the effects of candidate therapeutics.

? DESCRIPTION (provided by applicant): Down Syndrome (DS) is a neurodevelopmental disorder, affecting 1 in every 700 newborns in the US. DS patients exhibit impaired language ability and developmental delays in cognitive functions, including learning and memory. Though DS is caused by the presence of an extra copy of chromosome 21, how such genetic change leads to altered physical and neurocognitive growth remains largely unknown. Consequently, no therapies or drugs are currently available for impaired cognition associated with DS. A major obstacle to understanding DS has been the lack of model systems representing the development of human neural circuitry. Recent advances in induced pluripotent stem cells (iPSCs) technology have made it possible to investigate pathogenesis of DS in human cellular models. These elegant recent studies revealed altered neuronal morphology associated with DS, however, no significant physiological alterations in neuronal and synaptic activity were observed in neurons derived from iPSCs of DS patients. Astrocytes are an important and somewhat underappreciated neural cell. At synapses, astrocytes make contacts with pre- and post- synaptic neurons, acting as integrators and modulators of neural circuitry throughout the brain. Our preliminary results, as well as work of others indicate that astrocytes differentiated from DS patient-specific iPSCs adversely affect neurons. We therefore hypothesize that astrocytes play an important role in modulating neuronal activity in DS brains and that reconstruction of synapses formed between hiPSC-derived neurons and astrocytes may provide a window for the observation of neuronal phenotypes reflective of DS pathophysiology. We believe that a new culture system enabling analysis of neuron-astrocyte crosstalk with cell-type specificity and at the level of synapses will be better suited to study human neural circuitry than currently available culture and animal models. We propose to develop microfluidics-based cell culture system for modeling and analyzing the diseased neuron-astrocyte network of DS. The neural cells will be derived from patient-specific iPSCs and then organized into functional units of neural circuitry - tirpartite synapses - using microfluidics and surface micropatterning approaches. For sensing synaptic activity, we will implement genetically encoded intracellular biosensors to monitor the communication at synapses. This project will be an important step towards our understanding of DS pathophysiology by connecting genetic mutations associated with DS to the structure and function of the human neural circuitry.

Brain functions are executed by intricately coordinated networks of neurons, whose modes of operation are highly sensitive to a constellation of neuromodulators. More specifically, neuromodulators such as dopamine, norepinephrine, serotonin, and acetylcholine exert dramatic control over global brain processes such as arousal, attention, emotion, or cognitive perception. Altered neuromodulator signaling has been linked to neurological and psychiatric disorders such as Parkinson's disease, schizophrenia, depression and addiction. Similarly, opioid neuropeptides play important roles in the modulation of cognition and behavior. While the anatomical structures that produce neuromodulatory signals are well known, little is known about the spatial and temporal evolution of these signals in the innervated brain regions. This is because current measurement techniques, such as microdialysis or cyclic voltammetry, lack the spatial or temporal resolution (and often the molecular specificity) to resolve respective signals. This technical challenge has been a long-standing barrier to our understanding of how neuromodulation alters neural circuit function in order to influence behavior. To address this challenge, this project will develop, validate, and disseminate novel genetically encoded fluorescent proteins for large-scale optical measurement of monoamine neuromodulator and opioid neuropeptide signaling in behaving animals, by bringing together a multi-disciplinary team of investigators with unique and complementary expertise. These sensor proteins have the potential to revolutionize neuroscience in a way similar to genetically encoded indicators for calcium, glutamate, and voltage, which are now in widespread use. Combined with calcium and voltage imaging, neuromodulator sensors will reveal how these systems impinge on cellular and circuit function. In particular, proposed sensors will enable minimally invasive, high-resolution, long-term, and direct measurement of neuromodulator and neuropeptide signaling at synaptic, cellular, and system levels. Sensors for neuromodulatory signaling have remained elusive for a long time. Our team recently developed a first generation of genetically encoded indicators for serotonin (5-HT), norepinephrine (NE), and dopamine (DA) that can report nano- to micromolar concentration changes with high spatial and temporal resolution. Building on this work, the following specific aims are proposed: 1) Optimize and diversify genetically encoded sensors for the monoamines using computational modeling, directed evolution and high-throughput screening; 2) Develop and optimize genetically encoded sensors for opiate neuropeptides using novel protein scaffolds; and 3) Systematically validate the novel neuromodulator and neuropeptide sensors in acute brain slices and behaving animals. Together, this work will provide the neuroscience community with a wide range of well-characterized multi-color indicators for probing the functional role of neuromodulators and neuropeptides in regulating neural circuit function and behavior in both health and disease.

This project will study the transformation of quantum information from microwave electronic devices to optical elements via opto-electromechanical interfaces. Passing information with high fidelity (sometimes called state-conversion) between these devices would facilitate the construction of a hybrid quantum network, a form of quantum computer. Such hybrid networks could be scaled up in size more easily than some other proposed quantum computer architectures, and they are designed to exploit the various strengths of their component subsystems. Because mechanical motion can be coupled to electromagnetic fields at frequencies ranging from acoustic to optical wavelengths, opto-electromechanical interfaces made of mechanical resonators and cavity photons provide a promising candidate to advance this goal. This project will design interfaces with which quantum information can be transmitted uni-directionally while simultaneously preventing noise transmission. The time-dependence of the couplings will also be studied to better engineer the shape of photon pulses. Ideal pulse shape ensures high-fidelity photon absorption or information retrieval from a quantum bit. This project also includes educational and STEM activities that can broaden the participation of women and minority students. These activities include course development, women-STEM lectures, Student Physics Society activities, and Bobcat day events.

Technical description. This project supports the study of quantum state conversion between microwave and optical photons via hybrid optoelectromechanical interface. Hybrid quantum devices are composed of distinctively different subsystems. By exploiting the strength of each subsystem, hybrid devices can facilitate the construction of scalable quantum computers. An essential question in hybrid quantum networks bridging microwave and optical frequencies is how to achieve noiseless and lossless transmission of quantum information between the subsystems. The objectives of this project include (1) designing optoelectromechanical interfaces for nonreciprocal state conversion and routing between microwave and optical photons and (2) developing numerical methods to control the pulse shape of photons transmitted through optoelectromechanical interfaces. Nonreciprocal state conversion controls the direction of state flow and prevents noise from being spread to other parts of the quantum network. The group will design nonreciprocal interfaces operated under optimal conditions with significantly reduced mechanical noise. The effective gauge phase between the linearized light-matter couplings will be studied to achieve this goal. Meanwhile, the pulse shape of incoming photons is crucial for achieving high-fidelity storage or retrieval of photon state from a quantum bit. The team will use an optimal control technique to design time-dependent electro- and opto-mechanical couplings to achieve desirable pulse shape. This project can provide insights on the potential and limitation of hybrid quantum networks and deepen our understanding of the role of quantum interfaces in hybrid systems.

One of the major challenges in neuroscience is to understand the experience-dependent mechanisms that drive the changes in neural circuits that underlie complex behaviors, and how these mechanisms are altered in disease. Altered synaptic transmission has been implicated in a number of human neurological and psychiatric disorders, including epilepsy, schizophrenia, autism and addiction. Considerable recent evidence from our labs and others has demonstrated that specific patterns of neural activity at individual synapses can drive the growth, stabilization and elimination of synaptic connections. However, how complex patterns of neural activity at multiple synapses in vivo interact to drive changes in circuit connectivity remains poorly defined. Specifically, the relative role of neural activity at clustered versus distributed synaptic inputs, and that of integrated versus patterned neural activity, in driving synaptic and circuit plasticity has been difficult to determine, primarily due to the lack of adequate imaging probes to monitor the history of activity at individual synapses. New tools are needed. The overall objective of this research proposal is to develop novel glutamate sensors for large-scale monitoring of the activity of individual synapses in the living behaving animal. We will focus on two specific objectives: (1) developing glutamate integrators for visualizing the history of neural activity at individual synapses in large fields of view during short behavioral epochs and (2) developing glutamate highlighters with slower kinetics that will enable large-scale monitoring of transient responses at individual synapses in the living animal. Existing tools for monitoring glutamatergic signaling at individual synapses, such as the genetically- encoded glutamate sensor, iGluSnFR, are excellent for characterizing the activity of individual synapses in small fields of view with high temporal precision; however, due to the fast kinetics and transient nature of the glutamatergic responses at individual synapses, these sensors are not suitable for real-time monitoring of synapses in large fields of view. Here, we propose to develop glutamate sensors that permit monitoring activity at individual synapses over larger fields of view and also with the spatial and temporal resolution to mark activated synapses amongst the distributed circuitry. Indeed, our proposed glutamate integrators will transform the activity of transient synaptic inputs into permanent labels of active synapses, enabling access to information mapping neural activity to the structure of the neural circuitry underlying a specific physiological process or behavioral task. To accomplish these goals, we will use a multidisciplinary approach incorporating genetic strategies, computation-guided protein design, two-photon imaging, glutamate uncaging and electrophysiology. First, we will use high-throughput, multi- step sensor screening, photophysical characterization, and ligand-binding specificity measurements to generate candidate sensors. Next, we will generate synaptically targeted sensors, and characterize the sensitivity and kinetics of lead sensors in dissociated neuronal culture and in brain slices. Finally, we will characterize the expression, sensitivity and kinetics of lead sensors in vivo in zebrafish and in mice. If successful, the proposed research will provide much needed imaging tools of synaptic activity that are compatible with a variety of advanced imaging techniques, such as wide-field, confocal and two-photon microscopy, and would dramatically enhance our understanding of how the history of neural activity at individual synapses and their neighbors can influence long-term stability of neural circuit connections.

Project summary The mammalian brain is remarkably dynamic and can quickly adjust its functional state in response to changes in the environment. For example, when a salient event occurs, the brain enters a mode that enhances memory formation. Such brain state changes occur too rapidly to be due to anatomical rewiring. Instead, they are thought to arise from the action of neuromodulators (NMs) and neuropeptides (NPs). Unlike small-molecule NMs, such as acetylcholine and monoamines, NPs are not generally released as the major neurotransmitter from specialized neurons and they are not recycled after release. Instead most neurons synthesize and release NPs in addition to fast transmitters such as glutamate and GABA, and peptide clearance is governed by diffusion and proteolysis. Although long utilized as anatomical markers, our understanding of NP signaling is only cursory. Insights into the cellular code of peptidergic communication are only now emerging from large- scale transcriptional profiling studies that reveal the distribution of peptides and their receptors across cell types. These have revealed a differentiated anatomic distribution of NP-receptor pairs across cell types that poise NPs as important mediators of trans-cellular communication in neural circuits. However, the functional significance of NP signaling is extremely difficult, if not impossible, to study using current tools, which do not reveal the timing and location of NP signaling in vivo, or the consequences of NP signaling on neural circuit activity. Thus, new technologies are needed to enable gain- and loss-of-function studies that precisely target the normal location and timing of NP activity in behaving animals. To overcome these technical barriers, we assembled a multi-disciplinary team to develop, validate, apply, and disseminate next-generation optical toolkits for functional analysis of the spatiotemporal dynamics of NP signaling during behavior. Our toolkits include: 1) photoactivatable agents to rapidly deliver NPs (or drugs that target NP receptors) to their sites of action with high spatiotemporal precision; 2) genetically-encoded NP sensors to report when NPs are released and over what temporal and spatial scales they act: 3) new optical and genetic approaches for cell- and region-specific recording and manipulation of NP action using these probes at multiple sites in the mammalian brain simultaneously. Combining these methods with functional studies in behaving animals, we aim to establish paradigms for determining the necessity and sufficiency of NP signaling for the modulation of circuits in vivo. We will determine the context and location of NP release, the ensuing spatiotemporal pattern of NP receptor activation, and the effects this has on neuronal physiology and behavior. We will actively disseminate these toolkits to the neuroscience community. Broad applications in various brain regions and species will reveal the dynamic contribution of NPs to the control of brain circuits and plasticity. This knowledge will provide building blocks and pave the ways to refine theory and develop novel therapeutics for neurological and neuropsychiatric disorders.

Nontechnical Summary

This project supports theoretical research and education on the implementation of a special purpose quantum computer with practical devices.

Quantum computers with 50-100 qubits and decoherence times not long enough for general-purpose quantum computing can now be built in laboratories. With such devices, a quantum simulator, a special-purpose quantum computer, may be able to solve problems that cannot be solved with classical computers. A prerequisite to implementing quantum simulation is to prepare the simulator in an appropriate many-body ground state, something that could also benefit the solution of combinatorial optimization problems. These many-body states are often unknown, highly entangled, and hard to prepare with quantum logic gates. Despite previous efforts, it remains a challenging question to prepare such many-body states with high fidelity. The PI aims to develop a universal and implementable algorithm to efficiently and accurately generate such many-body ground states by coupling the quantum simulator to an auxiliary system that induces nonlinearity. This novel approach exploits a generic but unique property of nonlinear systems to suppress unwanted transitions between the ground state and the excited states. The objectives of this project include the development of the general framework for the algorithm, benchmarking the algorithm, and studying the effect of circuit noise. The algorithm will be tested on four models that represent problems of different interests in quantum simulation. Both numerical simulation using classical computers and hardware emulation using a superconducting cloud platform will be employed to test the algorithm. Because it exploits generic nonlinear dynamics, this algorithm can be applied to a broad range of problems.

The project not only has potential scientific impact on quantum computing and quantum simulation, but it can also open the door to a new direction that uses nonlinear physics for efficient quantum computing. The educational component of this project will broaden the participation of women and minority students and improve the diversity of the workforce in quantum technology. The PI will develop a course on advanced quantum computing, actively recruit students and postdocs from underrepresented groups, and organize activities with the women-in-STEM group and the Society of Physics Students at UC Merced. These activities will engage students at UC Merced, a Hispanic serving institute, in quantum research.


Technical Summary

This project supports theoretical research and education on the implementation of quantum simulation with noisy intermediate-scale quantum devices.

A quantum simulator is a special-purpose quantum computer that can solve classically-hard problems. Efficient preparation of a many-body system in its ground state is a prerequisite for exploring quantum dynamics and many-body correlations in quantum simulators. Understanding the feasibility and limits on state preparation also benefits the study of combinatorial optimization problems in adiabatic quantum computing. Despite previous efforts, it remains a challenging question to prepare many-body states with high fidelity due to the lack of knowledge of the energy spectrum, the rapid decrease of energy gaps with the size of the quantum simulator, and the limited decoherence times in practical devices. The PI aims to develop a universal and implementable algorithm to efficiently and accurately generate many-body ground states by coupling a quantum simulator to an auxiliary system that induces nonlinearity. This novel approach exploits the unique dynamics in the vicinity of bifurcation points, which is a generic property in nonlinear systems, to enable self-governed adiabatic evolution with significantly suppressed diabatic transitions. The project includes three objectives: 1. developing the generic framework, operational protocol, and requirements on the quantum circuits for the algorithm, 2. benchmarking the algorithm and comparing its performance with other methods, and 3. qualitatively studying the effect of circuit noise. The algorithm will be tested on four models representing different interests in quantum simulation: the transverse-field Ising model, an exact-cover problem, a finite-sized Jaynes-Cummings lattice, and toy models with multiple energy gaps. Both numerical simulation and hardware emulation using the IBM Q cloud platform will be employed to test the algorithm. Because it exploits generic nonlinear dynamics, this algorithm can be applied to a broad range of problems without knowledge of the energy spectrum or the construction of unphysical multipartite interactions.

The project not only has potential scientific impact on quantum computing and quantum simulation, but it can also open the door to a new direction that uses nonlinear physics for efficient quantum computing. The educational component of this project will broaden the participation of women and minority students and improve the diversity of the workforce in quantum technology. The PI will develop a course on advanced quantum computing, actively recruit students and postdocs from underrepresented groups, and organize activities with the women-STEM group and the Society of Physics Students at UC Merced. These activities will engage students at UC Merced, a Hispanic serving institute, in quantum research.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Abstract Activity of the brain across structures is an orchestrated process that spans a broad range of time and space scales. Highly coordinated communication is what activate responses to stimuli, makes behavior possible, and generates memories. To observe exchanges of information at the cellular and synaptic level, neuroscientists have been increasingly using non-invasive imaging techniques that rely on genetically encoded indicators based on fluorescent proteins (FPs). Calcium sensors, such as GCaMPs, are routinely used to probe neuronal firing, and, more recently, indicators targeting small molecule neurotransmitters/modulators (e.g.: glutamate, GABA, dopamine) were developed and quickly gained popularity in the field. Small-molecules indicators allow direct visualization of chemical communication, providing a large amount of information on the type of inputs used in neuronal networks in association with stimuli. Sensors based on fluorescent proteins are suitable for imaging fast, transient synaptic responses, however they are not able to provide information on integrated signals from large scale areas in the brain. Here, we propose a new sensor design for probing small molecules in the brain. We take advantage of chemical fluorophore, which are brighter, more photostable and have broader color-spectrum compared to FPs. The development of various in-cell labeling strategies have put the chemical fluorophore under genetic control. We thus propose to develop chemigenetic sensors based on self-labeling proteins (SNAP-tag, Halo-tag), which is engineered to become dependent on the presence of a neurotransmitter/modulator. In a preliminary study, we coupled a split version of SNAP-tag to a glutamate-binding protein (GltI, from E. coli) and showed that labeling of the construct with a fluorescent dye occurs proportionally to the amount of glutamate in solution. Aim 1 will build upon our preliminary results to improve the design of the construct and optimize the dynamic range of the sensor. We will use rational engineering, as well as random mutagenesis combined with high- throughput screening to improve the current design. We will then proceed with characterization of the sensor in vitro, as well as ex vivo in HEK cells and dissociated neurons. Ultimately, we will perform testing in cultured and acute hippocampal slices with 2-photon microscopy. Aim 2 will expand the scope of the sensor by exploring a broader range of fluorescent dyes and color variants to probe into the multiplexing capabilities of the sensor. Furthermore, we will incorporate the modular design into binding proteins derived from sensors for other neurotransmitters/modulators, with particular attention to GABA, acetylcholine and serotonin. We will also explore the use of Halo-tag as a self-labeling protein, to increase the multiplexing ability of our approach to more than one type of input signal.

Future quantum computers will need to utilize different physical types of qubits that need to communicate and convert between each other with high fidelity and high efficiency. While photons are ideal for quantum communication, different qubit systems couple to photons of vastly different frequency ranges. The strain field generated by the mechanical wave in a solid-state material is a promising approach to enable coupling with a broad range of qubits with theoretically high efficiency. With a traveling velocity of five orders of magnitude lower than photons, acoustic waves are ideal for quantum interconnect between multiple qubits. The quantum acoustic technology developed in this project and the integration with NV-defect center qubits is an essential first step toward a chip-scale hybrid, multiple qubit systems. The proposed research both addresses the imminent issue of frequency inhomogeneity that has been plaguing solid-state optical qubits and explores the frontier of strong coupling of mechanical modes with spin qubits. The project will make significant advances from previous studies of discrete systems to realizing a monolithic quantum system that includes waveguides, optical and acoustic cavities, and acoustic transducers to directly interface with qubits, all integrated on a novel material platform. The approach offers a path to the realization of the integrated quantum computing system based on hybrid solid-state qubits interconnected with photons and phonons. The research leverages the tremendous technological development in the acoustic MEMS technology and advances it to the quantum regime, with the potential outcome that can impact both quantum information science and microwave photonics for classical communication. Education and outreach activities aim to increase the participation of students from underrepresented groups and improve the diversity of the STEM workforce and include course development in advanced quantum computing and K-12 science outreach programs with publicly accessible online courses.

Technical Abstract:
The project aims to develop a novel integrated quantum acoustic device platform for optomechanical transduction and quantum state manipulation of solid-state spin qubits based on defect centers in diamond. The integrated devices will be built on the high-performance heterogeneous material platform of gallium phosphide (GaP) on the crystalline diamond. The platform uniquely utilizes the layer of piezoelectric GaP for the dual functions of optical waveguiding and acoustic wave generation and guiding, thereby to achieve tremendously enhanced acousto-optic interaction. The effort will include three main thrusts. The first thrust will realize integrated acousto-optic frequency shifter (AOFS) to address the optical frequency inhomogeneity problem of qubits based on defect centers. AOFS can achieve single-sideband, carrier-suppressed frequency shift of photons from qubits freely over a range of ±3GHz and with an efficiency better than 80%. The second thrust will investigate the coupling of itinerant acoustic waves to ensembles and single defect centers. The acoustic coupling strength will be enhanced to reach the strong coupling regime and realize time-dependent control over the states of the qubits. The final thrust will realize the strong coupling of acoustic modes confined in a high-Q cavity with single defect centers embedded therein. Quantum state manipulation and quantum entanglement of the qubits by utilizing the acoustic mode will be achieved. Ensembles of NV-centers coupled to the cavity acoustic mode in the strong-coupling regime and novel physics effects in this regime will be explored.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Project summary The mammalian brain is remarkably dynamic and can quickly adjust its functional state in response to changes in the environment. For example, when a salient event occurs, the brain enters a mode that enhances memory formation. Such brain state changes occur too rapidly to be due to anatomical rewiring. Instead, they are thought to arise from the action of neuromodulators (NMs) and neuropeptides (NPs). Unlike small-molecule NMs, such as acetylcholine and monoamines, NPs are not generally released as the major neurotransmitter from specialized neurons and they are not recycled after release. Instead most neurons synthesize and release NPs in addition to fast transmitters such as glutamate and GABA, and peptide clearance is governed by diffusion and proteolysis. Although long utilized as anatomical markers, our understanding of NP signaling is only cursory. Insights into the cellular code of peptidergic communication are only now emerging from large- scale transcriptional profiling studies that reveal the distribution of peptides and their receptors across cell types. These have revealed a differentiated anatomic distribution of NP-receptor pairs across cell types that poise NPs as important mediators of trans-cellular communication in neural circuits. However, the functional significance of NP signaling is extremely difficult, if not impossible, to study using current tools, which do not reveal the timing and location of NP signaling in vivo, or the consequences of NP signaling on neural circuit activity. Thus, new technologies are needed to enable gain- and loss-of-function studies that precisely target the normal location and timing of NP activity in behaving animals. To overcome these technical barriers, we assembled a multi-disciplinary team to develop, validate, apply, and disseminate next-generation optical toolkits for functional analysis of the spatiotemporal dynamics of NP signaling during behavior. Our toolkits include: 1) photoactivatable agents to rapidly deliver NPs (or drugs that target NP receptors) to their sites of action with high spatiotemporal precision; 2) genetically-encoded NP sensors to report when NPs are released and over what temporal and spatial scales they act: 3) new optical and genetic approaches for cell- and region-specific recording and manipulation of NP action using these probes at multiple sites in the mammalian brain simultaneously. Combining these methods with functional studies in behaving animals, we aim to establish paradigms for determining the necessity and sufficiency of NP signaling for the modulation of circuits in vivo. We aim to determine the context and location of NP release, the ensuing spatiotemporal pattern of NP receptor activation, and the effects this has on neuronal physiology and behavior. We will actively disseminate these toolkits to the neuroscience community. Broad applications in various brain regions and species will reveal the dynamic contribution of NPs to the control of brain circuits and plasticity. This knowledge will provide building blocks and pave the ways to refine theory and develop novel therapeutics for neurological and neuropsychiatric disorders.

PROJECT SUMMARY / ABSTRACT: Differentiation and Integration of Trisomy 21 iPSCs into Cerebral Tissues: Modeling Down Syndrome using Patient-specific iPSC-derived CNS Organoids and Humanized Chimeric Mice. Down syndrome (DS) is caused by trisomy 21, the triplication of human chromosome 21 (HSA21), and is the most common genetic cause of intellectual disability. We have successfully established and characterized multiple lines of iPSCs derived from DS patients. Particularly, we have established more than 50 DS Trisomy 21 iPSC lines, and obtained multiple pairs of corresponding isogenic disomy 21 control lines from these DS iPSCs. In addition, we have implemented CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated) technology in making genetic corrections in iPSCs. Modeling of human genetic diseases has previously been largely dependent upon availability of either pathological analysis of postmortem human tissue samples or recapitulation of human disease in transgenic animal models; better research tools for disease modeling are needed. Patient-specific iPSCs are excellent tools and versatile resources for this kind of translational research. As iPSCs are generated on an individual basis, iPSCs may be the optimal cellular material to use for disease modeling, drug discovery, and development of patient-specific therapies. We have already generated a significant amount of preliminary data. We have used a highly efficient CRSPR system to precisely control and normalize genes of interest on HSA21. We have also developed a system of 3- dimentional (3D) CNS organoid (CO) culture from DS iPSCs, which better recapitulates brain development and disease pathogenesis than the conventional 2-dimentional (2D) flat culture, and allows for in-depth characterization by electrophysiological assays. The CNS organoid technology represents an excellent approach for disease modeling; the cerebral organoids generated from patient iPSCs can be used as a model to recapitulate complex neural developmental diseases such as DS. In addition, we have generated a humanized chimeric mouse model, in which DS iPSC derived astrocytes are grafted to the neonatal mouse brains. The detailed genetic etiology for the various symptoms in DS remains elusive. Taking the advantage of these unique tools and resources, we will create novel in vitro and in vivo models of DS with human iPSCs derived from patients to recapitulate the defects in neural differentiation in DS. In support of the feasibility of this proposal, we have obtained the necessary materials and expertise to be used in this study, and have published a rather massive paper on DS iPSCs [Chen C, Jiang P, Xue H, Peterson SE, Tran HT, McCann AE, Parast MM, Li S, Pleasure DE, Laurent LC, Loring JF, Liu Y, Deng W. (2014) Role of astroglia in Down?s syndrome revealed by patient-derived human-induced pluripotent stem cells. Nature Communications. 5:4430 doi: 10.1038/ncomms5430 (2014)]. Our preliminary data show that both trisomy and the isogenic disomy DS astrocytes are able to repopulate the mouse brain, allowing for further interrogation of in vivo behavior of these cells and examination of their effects on neuroinflammation and cognition of the animals. Building upon prior work on multiple genes in pathways of astrocyte-mediated inflammation, we propose to produce both in vitro CNS organoids and in vivo chimeric mouse models to investigate the critical role of these astrocytic inflammatory genes (S100B, IFNAR1, IFNAR2) in development and function of DS patient-derived iPSCs. Taken together, we will use a novel platform of both an in vitro 3D organoid culture system and an in vivo humanized chimeric mouse model using DS patient-derived iPSCs. These models will provide fundamental insights into neural function in the physiological environment of 3D organoids and in early development of human cells in a living animal. The completion of the project will immensely bolster DS pathogenesis studies using patient iPSCs, as well as biochemical and molecular approaches complemented with investigation into neural network functionality. These insights will undoubtedly impact on the treatment of patients with DS.

Project Summary The dynamic adaptability of the mammalian brain to environmental changes is remarkable, as it is the complexity of the networks of neurons underlying the operations that allow for such adaptations. Although we have some understanding of the anatomical and functional basis of this, we are still lacking a detailed picture of how the modulation of neuronal activity works. What is the timing and locations of these neuromodulator release and relationship with excitatory/inhibitory circuits? How does the neuromodulators circuitry accomplish the regulation of firing and synaptic properties of targeted neurons? Filling these gaps in knowledge would advance our understanding of all aspects of neuromodulator biology and allow discovery of new therapeutic strategies. To help close this gap, we have used creative approaches to the development of genetically encoded to directly report behaviorally triggered and modulated neuromodulator release including serotonin (5-HT), dopamine (DA) and norepinephrine (NE). We have disseminated these indicators to the neuroscience community and spurred major discoveries of novel mechanisms regulating neuromodulator release underlying motivation and addiction. Build on this initial success, we propose to further expand the effectiveness of this toolbox of NM sensors to enable imaging sparse release at depth and subcellular resolution. Our specific goals are to (1) improve the sensitivity of our current sensors to enable robust imaging of sparse neuromodulator release, push their spatial resolution to the subcellular level and increase linearity of response at lower concentrations; (2) expand their spectral range to red/far-red to enhance imaging depth, SNR and in vivo multiplex measurement and manipulation of multiple circuit components using two or three distinct colors, and (3) characterize the possible interference of current sensors with endogenous signaling and systematically validate emerging sensors with a wide-ranging microscopy approaches in vivo. Our strategy relies on a dynamic collaboration between the sensor design team and end users to obtain continuous feedback to implement efficient improvements to the sensors. It is our goal to rapidly disseminate a wide range of well-characterized, highly sensitive indicators for the neuroscience community to be employed to study behaving mice, fish, flies and worms, to enrich our knowledge on the functional roles of neuromodulators in the brain circuitry.

Project Summary: Project 4 - Novel Genetically Encoded Indicators for Interrogating Neuron-Astrocyte Communication Across Timescales Astrocytes, the most abundant cell type in the brain, have long thought to be primarily passive support cells. Considerable evidence from the labs has shown that astrocyte-synapse displays a dynamic and bi-directional relationship, with local synaptic transmission and neuromodulation being capable of shaping astrocytic activity and PAP structural plasticity, and astrocyte shaping synapse formation and modulating plasticity and signaling via secreted factors and adhesion molecules. These critical advances in understanding astrocyte biology in vivo are primarily due to recent applications of modern techniques initially designed for studying neurons to direct manipulation and interrogation of astrocytes. Though the concept of astrocytes as integral and modulatory components of neural circuit is emerging, a mechanistic understanding of causative and correlative roles of astrocytes in operating neural circuit and contribution to the complex behaviors is still lacking, which necessities and drives the development of improved tools. Thus, a large-scale protein engineering effort to develop an improved tool to address unsolved questions to achieve a mechanistic understanding of causal and correlative roles of astrocyte in neuronal circuit function and contributions to behavior is being proposed. Provided items include: 1. a set of optimized red-shifted glutamate, GABA, DA, and NE sensors, 2. a set of green and red-shifted synaptic glutamate/GABA sensors to probe neuron-astrocyte connectivity and extracellular NT transients at tripartite synapses, and 3. interrogate cross-talk between PKA and calcium in astrocytes and optimized green and red-shifted kinases sensors for in vivo applications. These new sensors will be applied to study 1) how experience-dependent changes that drive complex patterns of neurotransmitter or neuromodulatory signaling lead to the changes in astrocytic activity and 2) how astrocytes modulate synaptic activity via structural plasticity across various temporal scales. The contribution is significant because these improved tools will permit new hypotheses being tested in astrocyte biology. This toolset will provide needed tools to facilitate experiments proposed here and provide a rich resource to the field to bring full swing the investigation of astrocyte-neuron interaction underlying complex behavioral and cognitive processes that are inaccessible via currently existing approaches.

Project Summary: Overall ?What is the function of glial cells in neural centers? The answer is still not known, and it may remain unsolved for many years to come until scientists find direct methods to attack it.? (Ramon y Cajal, 1901). This prophecy turned out to be accurate. Astrocytes, one of the most abundant cell types in the brain, have long been thought of as primarily passive support cells. Over the past two decades, studies indicate that astrocytes play pivotal roles in nervous system development, function, and diseases. However, a major unresolved issue in neuroscience is how astrocytes integrate diverse neuronal signals under healthy conditions, modulate neural circuit structure and function at multiple temporal and spatial scales, and how aberrant excitation and molecular output influences sensorimotor behavior and contributes to disease. The overall goal of this U19 Team-Research BRAIN Circuit Program proposal is to address this fundamental issue by developing a deeper mechanistic understanding of astrocytes? roles in neural circuit operation, complex behaviors, and brain computation theories. Two overarching questions will be addressed: 1) How do astrocytes temporally and spatially integrate molecular signals from the diverse types of local and projection neurons activated during sensorimotor behaviors. 2) How do astrocytes convert this information into functional outputs that modulate neural circuit structure and function at different spatial and temporal scales. A multidisciplinary, comprehensive effort is proposed to address these questions that can only be completed through close collaboration between researchers with unique and complementary expertise. An innovative multi-scale approach integrating functional, anatomical, and genetic analyses with theoretical modeling will be leveraged. This approach involves quantitative behavioral assays, large-scale imaging of cellular and molecular dynamics, targeted cell-type-specific manipulations, high- throughput omic techniques, genetic profiling, protein engineering, machine learning, and computational modeling. By integrating experimental and theoretical approaches, molecular, cellular, and circuit mechanisms will be determined through which astrocytes influence neural circuits and contribute to complex behaviors and brain computation theories. The experimental and data analysis tools developed as part of this project will be invaluable for the broader neuroscience community.