Project Summary: Technologies for monitoring chemical signaling in neuronal activities have long been desired to understand the mysterious function of the brain, and the unravel underlying mechanisms of neurological disorders such as epilepsy and Alzheimer’s disease. This project creates novel bio- orthogonal nanosensors for in-vitro and in-vivo imaging of physiological ions and small molecule neurotransmitters such as acetylcholine. Physiological ions such as K+, Na+, Cl-, and Ca2+ are key to membrane potential of the neuron, and propagation of action potentials. In-vitro and in- vivo recording of levels of these ions during neuronal communication has been focus of research for decades. The neurotransmitter acetylcholine (ACh) is involved in memory and learning with implications in Alzheimer’s disease and psychiatric disorders. Studying ACh is important for unravelling the pathophysiology of neurodegenerative and understudying the connection between the gut microbiome and brain health. The scope of work proposed in this application has potential to contribute major advances in public health through better understanding of disease pathophysiology. The immediate goal of this proposal to create bio-orthogonal fluorous nanosensors with dual functionalities. To sense ionic neurotransmitters and to release these compounds upon light stimulation. The nanoparticles will be developed using fluorous materials. Fluorous compounds (molecules with high content of fluorine atoms) are extremely non-polar and non-polarizable to the extent that they are not miscible with water and fatty substances. That is, fluorinated compounds are both hydrophobic and lipophobic. As a matter of fact, living systems are made of water and lipophilic compounds, making fluorocarbons bio-orthogonal, meaning that they do not interfere with biology. This feature allows development of stable and nontoxic nanosensors with widespread applications. The scientific questions that this proposal is answering are (i) Can we control the fluorous- aqueous interface and use partially fluorinated voltage sensitive dyes for contact-free readout of interfacial potential? (ii) Can we record chemical signaling in neuronal communication using a platform and modular fluorous nanosensor? (iii) Can we trap fluorinated metastable-photo-acids in superhydrophobic nanoparticles and use blue light for local release of ionic moieties? (iv) Can we use local release of ions to start a dialogue with nerve cells, and mimic the chemical signaling?