Nilay Yapici - US grants

Nervous systems evolved to solve many of the same problems in species as diverse as worms, fishes, and humans. Using collections of neurons, from 100 or fewer in small invertebrates to hundreds of millions in humans, animals behave in ways that allow survival and reproduction in demanding and often hostile environments. A major hurdle to revealing the principles by which diverse species achieve these goals is being able to monitor the structure and function with high resolution throughout the brain - a necessity because behavior emerges from broad interactions of neurons across brains, even in the simplest organisms. A team of investigators will push optical imaging to this goal through the development of a NeuroNex Neurotechnology Hub at Cornell University. Experts from physics, engineering and biology will work together to develop, demonstrate the utility of, and disseminate to other neuroscientists a suite of imaging tools that will overcome current technology barriers in studying how brains work. Furthermore, the Hub will provide a unique opportunity to educate the next generation of neuroscience researchers to work in interdisciplinary teams that combine the neuroscience, technology development, and big data analysis expertise required to make progress in understanding the brain. Graduate student trainees will also receive instruction in science communication and mentoring in career planning. Opportunities for undergraduate researchers will be provided and the PIs and other project members will become actively engaged in outreach to local-area schools, the broad public, and policymakers.

Large scale, noninvasive recording of neural activity in awake and behaving animals is essential to understand the function of the nervous system. This NeuroNex Neurotechnology Hub will develop and disseminate innovative neurotechnologies for noninvasive recording of neural activity across a large depth and volume, at multiple places in the central and peripheral nervous system, and with high spatial and temporal resolution. The newly developed optical imaging technologies will be employed in behaving animal models across multiple species in different phyla, including mammals, teleost fish, flies, and birds, and will be demonstrated by attacking important neuroscience questions in fruit fly, zebrafish, and mice. We will create a new lab, the Laboratory for Innovative Neurotechnology at Cornell (LINC), which will be shared by the Hub PIs and serve as the physical embodiment of the hub, and close the loop between technology development and biological questions. LINC will serve as a hub for dissemination by hosting, connecting, and training researchers and developers across multiple disciplines from both academia and industry. The dissemination of these new technologies will catalyze studies of how brains produce behavior in species across a broad range of sizes throughout animal phylogeny. This NeuroNex Neurotechnology Hub award is co-funded by the Division of Emerging Frontiers within the Directorate for Biological Sciences and the Division of Chemical, Bioengineering, Environmental, and Transport Systems within the Directorate of Engineering as part of the BRAIN Initiative and NSF's Understanding the Brain activities.

ABSTRACT In normal individuals, food intake is strictly regulated by sensory, homeostatic and hedonic neural circuits, which balance energy intake with energy expenditure. Failure to regulate food perception and appetite result in maladaptive eating behaviors and an increase in the occurrence of metabolic syndromes and eating disorders. Neural circuits that regulate food intake have been extensively investigated in rodent models. However, the complexity of the mammalian brain makes it very challenging to explain the underlying molecular mechanisms and circuit dynamics controlling food intake. I propose to use a genetically tractable model organism, the fly (Drosophila melanogaster), to understand the fundamental principles of how the brain integrates the sensory percept of food with the sensation of hunger to regulate food intake on the level of molecules, cells and circuits. Flies are an excellent model to investigate these processes because they have 1000-fold fewer neurons in the brain than mice, and yet they still show hunger states and specific food intake control remarkably similar to those in vertebrates. Furthermore, the fly nervous system is more accessible for genetic modifications, anatomical studies and monitoring the activity of large populations of neurons in behaving animals. Previously, I have shown that flies, like humans, regulate their food intake by integrating the taste and nutrient value of food with hunger sensation in the nervous system. I identified a novel class of excitatory interneurons (IN1) in the fly brain that regulate food ingestion. In this project, we will first identify the IN1 food intake circuitry using optogenetics and anterograde transsynaptic circuit tracing. Next, we will reveal how IN1 neurons and downstream circuitry change activity during food search in a virtual reality foraging assay using two-photon microscopy. Finally, using cutting- edge three-photon technology, we will capture the activity of IN1 neurons chronically in an intact fly as flies are being food deprived. Functional dissection of IN1 circuitry will lead us to fundamental principles that the nervous system uses to regulate food intake. In parallel with our food intake circuit dissection efforts, we also identified 8 evolutionary conserved genes in a large genetic screen for flies that fail to show compensatory feeding after 24 hours of food deprivation. We will anatomically and functionally dissect the role of these genes and the neural circuits they control in regulating food intake. Finally, we will test the interaction of the candidate food intake genes and the IN1 circuitry in regulating food perception and appetite control. Modelling the food intake and appetite control systematically in a genetically tractable organism allows us to reveal new molecular and neural control mechanisms. Once, we discover key mechanisms underlying food intake and appetite, we can search for similar processes in more complex mammalian models and in patients suffering from obesity or eating disorders to develop treatment strategies that will intervene with the pathogenesis of these life threating diseases.

Animal nervous systems have evolved species specific adaptive behaviors which allows them to cope with adverse environmental conditions. For example, in temperate climates, the onset of winter marks a steep decline in environmental temperatures, leading to food scarcity and adverse thermal effects. Animals must respond to these thermal fluctuations in their environment in order to maintain body homeostasis which is critical for their survival. Many animal species have the ability to undergo some type of programmed dormancy to avoid such conditions. For example, most insects and some mammals respond to a sharp decrease in day length and/or temperature with an arrest in development and reproduction that protects them or their progeny from lethality. During this dormant state, often triggered by cold temperatures, metabolic rate is significantly decreased and developmental processes are slowed down. Despite decades of research on the biology of dormancy, our understanding of how the nervous system integrates changes in temperature and light conditions to decrease metabolic rate and reproductive potential is limited. Especially we still do not know the molecular and neural mechanisms that regulate the changes in excitatory and inhibitory transmission of temperature sensitive neurons during thermal fluctuations in the environment. Here, we propose to use a genetically tractable model organism, the fly (Drosophila melanogaster), to investigate temperature sensitive neural circuits that change activity in response to cold temperatures and trigger reproductive dormancy. Flies are an excellent model to investigate how nervous system responds to adverse environmental conditions, because flies have 1000-fold fewer neurons in the brain than vertebrates, and yet they still show temperature specific behaviors. Furthermore, the fly nervous system is more accessible for genetic modifications, anatomical studies and monitoring the activity of large populations of neurons in behaving animals. Our preliminary results suggest that a neuropeptide, Allatostatin C (AstC) and its receptor (AstC-R2) in the brain might be a key player in triggering reproductive dormancy during cold temperatures and short-day lengths. In this project, we will first identify the neural circuits that AstC and AstC-R2 act on to regulate reproductive dormancy in flies. Next, we will capture the activity of AstC and AstC-R2 neurons in vivo and observe how they change activity in response to changes in temperature and day light levels. Last, we will test whether the function of AstC-R2 is conserved in the yellow fever mosquito, Aedes aegypti. Our results will not only contribute to the basic understanding of neural mechanisms regulating reproductive dormancy in insects but also will identify novel targets for the development of drugs that can control insect populations especially disease carrying mosquitoes in the wild.