2017 — 2019 |
Tegmark, Max (co-PI) [⬀] Flavell, Steven Boyden, Edward [⬀] Boyden, Edward [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Ncs-Fo: Collaborative Research: Ground-Truth Analysis and Modeling of Entire Individual C. Elegans Nervous Systems @ Massachusetts Institute of Technology
How does the brain compute? Understanding this process could lead to many advances in science and technology. The Boyden, Flavell, Barabasi, and Tegmark groups propose to examine how the cells within the brain of a simple animal work together to generate the computations that underlie behavior. The teams will study C. elegans, a small worm with just a few hundred neurons, yet capable of learning and adaptive behavior in complex real-world environments. The teams will apply new technologies to measure and control the neural circuits of C. elegans, in order to investigate how they works. The project will also generate new mathematical tools to analyze the data that is collected - tools that could help analyze how the brain goes wrong in disorders such as Parkinson's or Alzheimer's. Using the data acquired, the project will reveal how brain circuits compute, which could inspire new algorithms for machine learning and computer information processing. These in turn could have broad impact on economic prosperity as well as in advancing human quality of life.
The Boyden, Flavell, Barabasi, and Tegmark groups will launch a novel integrative endeavor to reveal how entire nervous systems - from sensory input neurons, to motor output neurons, and including the networks that underlie learning, decision making, and other processes - work together as emergent wholes to generate the computations that underlie behavior. They will utilize C. elegans, with just 302 neurons, yet capable of learning and adaptive behavior in complex real-world environments. They will optimize and deploy novel technologies, including a new fluorescent voltage indicator for C. elegans, and a method for 3-D visualization of entire nervous systems with molecular information via physical expansion by up to 10,000 fold in volume. They will record neural and behavioral dynamics, imaging the activity of neurons throughout entire brains and even entire nervous systems of freely moving as well as fictively behaving C. elegans engaged in complex decision-making tasks, or forming new memories. They will then use expansion microscopy to map the structure and molecular profiles of entire individual nervous systems. They will analyze the resultant network structures to determine how individual variation in these features connect to details of an individual's behavior, and make mathematical models of the relevant neural circuits capable of predicting how the nervous system would respond in complex contexts. The outcome of their work will yield radical new theories of how nervous systems operate, as well as a diversity of tools for the neuroscience and computational communities.
This project is funded by Integrative Strategies for Understanding Neural and Cognitive Systems (NSF-NCS), a multidisciplinary program jointly supported by the Directorates for Computer and Information Science and Engineering (CISE), Education and Human Resources (EHR), Engineering (ENG), and Social, Behavioral, and Economic Sciences (SBE).
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0.915 |
2017 — 2021 |
Flavell, Steven Willem |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuromodulatory Control of Collective Circuit Dynamics in C. Elegans @ Massachusetts Institute of Technology
Many animal behaviors are organized into long-lasting states, perhaps most strikingly in the sleep/wake and emotional states that mammals display. However, the fundamental mechanisms that allow animals to initiate, maintain and terminate these states are unknown. Biogenic amine and neuropeptide neuromodulators are critical for the generation of behavioral states, but a mechanistic understanding of how neuromodulators act on circuits to generate stable circuit-wide patterns of neural activity has been lacking, largely due to the complexity of neuromodulation in mammalian circuits. We have chosen to tackle this problem using C. elegans, a nematode whose nervous system consists of 302 neurons with a fully defined wiring diagram. We previously characterized C. elegans movement patterns and showed that feeding animals transition between two stable arousal states, roaming and dwelling. We characterized the neural circuit that generates roaming and dwelling states, and found that two opposing neuromodulators, serotonin and the neuropeptide PDF, act on a defined neural circuit to generate this bi-stable behavior: serotonin action on the circuit stabilizes dwelling states, while PDF stabilizes roaming states. Now that we have defined a neuromodulatory circuit that generates persistent behavioral states, we are poised to resolve several fundamental questions about neural circuit function and organization. Here, we propose to dissect mechanisms of neural circuit persistence by examining how specific neuromodulators reconfigure neural circuits to stabilize circuit-wide activity patterns that give rise to long-lasting behavioral states. Resolving this question requires whole-circuit measurements of neural activity as animals freely transition between states. Thus, we have already developed a new imaging technology that allows us to simultaneously monitor the activity of every neuron in a circuit in freely-moving C. elegans animals. By combining this imaging technology with genetic/optogenetic manipulations and new analysis/modeling methods, we will illustrate a new multi-disciplinary approach that can be used to dissect the mechanisms by which collective neural dynamics arise in a circuit. First, we will first identify the circuit-wide patterns of activity that define different behavioral states (Aim 1). Second, we will perturb this system to examine how neuromodulators act on specific neurons in the circuit to generate these stable circuit-wide patterns of activity (Aim 2). Finally, we will determine how activity in this neuromodulatory circuit is altered by changes in the environment and, after simultaneously recording the sensory neurons that feed into this circuit, we will develop a network model that describes how noisy sensory inputs are transformed into a bi-stable behavioral state output (Aim 3). These studies will provide new mechanistic insights into how neuromodulators orchestrate whole-circuit changes in activity to influence behavior. By providing quantitative links between specific sites of neuromodulation, whole-circuit dynamics, and emergent behaviors, these studies will yield a generalizable model for circuit function that will bear on studies of sleep/wake states, emotional states, and cognitive states.
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1 |
2020 — 2021 |
Flavell, Steven Willem |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dissecting the Functional Organization of the Serotonergic System in C. Elegans @ Massachusetts Institute of Technology
The serotonergic system impacts a wide range of human behaviors and is a common target of psychiatric drugs. In mammals, neural circuits that receive serotonergic inputs are composed of diverse cell types, each of which expresses a subset of 14 distinct serotonin (5-HT) receptors. The impact of 5-HT release on circuit function involves the coordinated activation of many receptor types in distinct neurons. However, we do not yet understand the fundamental principles by which 5-HT acts at many sites within a circuit to coherently alter circuit function. Here, we propose to resolve this question in C. elegans. The C. elegans nervous system is particularly attractive for whole-circuit questions in neuroscience because it consists of exactly 302 neurons, every neuron can be identified in every animal, the synaptic connections between these neurons (the ?connectome?) have been fully defined, and excellent genetic tools can be used to manipulate single cells in this well-defined system. Moreover, this animal?s transparency allows us to use cutting-edge imaging approaches ? including whole-brain calcium imaging ? to monitor neural activity in freely-behaving animals. Importantly, 5-HT signaling is well- conserved from C. elegans to mammals: C. elegans orthologs of human genes encode for 5-HT synthesis enzymes (TPH), vesicular and membrane transporters (VMAT, SERT), 5-HT receptors (5-HT1, 5-HT2, etc) and more. Thus, studies of this animal should reveal general principles of 5-HT function that can be subsequently applied to more complex animals. The studies in this proposal build off recently published work from my lab and new preliminary data. In a recent study, we found that food ingestion by C. elegans activates a specific 5-HTergic neuron, called NSM, whose release of 5-HT drives slow locomotion while animals feed. We also showed that this neuron?s dynamical response to food ingestion controls locomotion dynamics: different patterns of 5-HT release drive different locomotion changes. In new preliminary data, we have systematically examined how patterned 5-HT release impacts locomotion, begun mapping out the 5-HT receptors that mediate these effects, and developed an approach to monitor 5-HT-induced changes in whole-brain activity. In the current proposal, we will use this well-constrained experimental paradigm and these cutting-edge imaging approaches to probe the functional architecture of the 5-HT system and examine how 5-HT receptors interact to control brain function. Specifically, we will first map out the 5-HT receptors and circuits that mediate behavioral responses to different patterns of 5-HT release (Aim 1). In a second aim, we will use new calcium imaging approaches to determine how different patterns of 5-HT release engage different 5-HT receptor types to alter whole-brain activity (Aim 2). Finally, we will also examine how aversive cues that antagonize 5-HT signaling modulate the function of serotonergic circuits, allowing animals to balance aversive and appetitive inputs (Aim 3). These studies will reveal how patterned 5-HT release engages specific 5-HT receptor types to impact brain function, yielding a new framework for 5-HT circuit organization and function.
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