Collaborative Research: NCS-FR: Understanding the neuropeptide modulation of brain circuits by advanced nanomaterials and imaging

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Human brain activity is modified by a group of molecules called neuromodulators. However, little is known about how these molecules work and affect brain activity, due to inadequate tools. This project seeks to develop a state-of-the-art toolbox to study these important molecules. These new tools will enable scientists to track the movement of neuromodulators in the brain, determine their action on brain circuits, and reveal how they alter behavior. The interdisciplinary team takes a broad approach of combining bioengineering, cellular physiology, whole-brain imaging and behavior to develop and optimize these tools. Completion of this project will have several broad impacts. Scientifically, researchers will have access to a new set of tools for turning on or off the delivery of neuromodulators to specific regions of the brain in awake animals using light. The results will advance our understanding of how neuromodulators impact brain activity in localized brain regions and across the brain. The collaborative team will provide interdisciplinary training for graduate students and postdoctoral researchers with cutting-edge technologies in the fields of nanotechnology, engineering, chemistry, and neuroscience. This project will provide STEM education to K-12 students both in the lab and through community outreach programs. Finally, this project will also offer mentoring and research opportunities for women and underrepresented minorities.Neuropeptides are important neuromodulators in the brain and yet remarkably little is known about their spatiotemporal spread, action on neural circuits, and effect on behavior. This proposal focuses on developing new neurotechnologies to study neuropeptide diffusion upon spatiotemporally controlled release (thread 1), their actions on brain circuits and behavior (thread 2), and brain-wide and circuit-specific activation patterns (thread 3). Specifically, this work will develop and understand a new class of photoswitchable nanovesicles that can be activated with widely available diode lasers and light emitting diodes. We will integrate this with a neuropeptide sensor, namely the cell-based neurotransmitter fluorescent-engineered receptor (CNiFER), to study neuropeptide (somatostatin, oxytocin) diffusion in the cortex and striatum upon photorelease. We will then investigate the impact of photoreleased oxytocin on brain circuits and social behavior in freely-moving animals. These efforts are closely integrated with the development of a new fluorescence resonance energy transfer (FRET)-based miniscope to detect behaviorally released neurotransmitters. Through a multi-modal functional magnetic resonance imaging platform, this research will determine the brain-wide and circuit- specific activation patterns of photoreleased oxytocin, thus enabling for the first time the integration of determining local neuropeptide signaling with brain-wide effects. These newly developed techniques will advance our understanding of the role of neuromodulators in the brain and more broadly, promote new neuropharmacology research where targeted delivery and localized release of a compound are currently unavailable.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.